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Pfizer's BRAFTOVI® Combination Regimen Cuts the Risk of Death in Half for Patients with BRAF V600E-Mutant Metastatic Colorectal Cancer
Pivotal results from the Phase 3 BREAKWATER trial showed 51% risk reduction in death compared to standard-of-care treatment BRAFTOVI combination regimen also demonstrated 47% risk reduction in disease progression or death compared to standard-of-care treatment, meeting the trial's dual primary endpoint of progression-free survival First and only combination regimen with targeted therapy to improve survival outcomes for treatment-naïve patients with BRAF V600E-mutant metastatic colorectal cancer NEW YORK, May 30, 2025--(BUSINESS WIRE)--Pfizer Inc. (NYSE: PFE) today announced statistically significant and clinically meaningful survival results from the Phase 3 BREAKWATER trial evaluating BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as ERBITUX®) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) in patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. These data will be presented today in an oral presentation (Abstract LBA3500) at the 2025 American Society of Clinical Oncology (ASCO®) Annual Meeting and have been simultaneously published in the New England Journal of Medicine. In a second interim analysis of overall survival (OS), a key secondary endpoint, the BRAFTOVI combination regimen reduced the risk of death by 51% compared to standard-of-care chemotherapy with or without bevacizumab (Hazard Ratio [HR] 0.49; 95% Confidence Interval [CI], 0.38, 0.63, p<0.0001). Median OS was 30.3 months (95% CI, 21.7, Not Estimated) with BRAFTOVI in combination with cetuximab and mFOLFOX6 compared to 15.1 months with chemotherapy with or without bevacizumab (95% CI, 13.7, 17.7). In the primary analysis of progression-free survival (PFS), the BRAFTOVI combination regimen reduced the risk of disease progression or death by 47% compared to standard-of-care chemotherapy with or without bevacizumab (HR 0.53; 95% CI, 0.41, 0.68, p<0.0001) as assessed by blinded independent central review (BICR). Median PFS was 12.8 months (95% CI, 11.2, 15.9) with the BRAFTOVI combination regimen compared to 7.1 months (95% CI, 6.8, 8.5). "Patients with metastatic colorectal cancer whose tumors harbor a BRAF V600E mutation generally face a daunting prognosis, as this aggressive tumor often does not respond well to standard-of-care chemotherapy," said Elena Élez, M.D., Ph.D., senior investigator at Vall d'Hebron Institute of Oncology in Barcelona, Spain, and co-principal investigator of the BREAKWATER trial. "The BREAKWATER results are the first promising survival outcomes ever reported for BRAF-mutant metastatic colorectal cancer in the first-line setting, representing a practice-changing breakthrough for patients." CRC is the third most common type of cancer in the world1 BRAF mutations are estimated to occur in 8-12% of people with mCRC and represent a poor prognosis.2 The BRAF V600E mutation is the most common BRAF mutation and the risk of mortality in patients with CRC harboring this mutation is more than double that of patients with no known BRAF mutation present.2-4 "The BRAFTOVI combination helped significantly reduce the risk of disease progression or death, potentially altering the course of disease for people with metastatic colorectal cancer with a BRAF V600E mutation," said Johanna Bendell, M.D., Chief Oncology Development Officer, Pfizer. "These unprecedented results from the BREAKWATER trial further establish the benefit of the BRAFTOVI combination regimen and its potential to become a new standard-of-care, building on Pfizer's legacy in precision medicine and commitment to delivering breakthrough medicines that help people with cancer live better and longer lives." The updated objective response rate (ORR) by BICR confirmed the improvement previously observed with the BRAFTOVI combination regimen compared to patients receiving chemotherapy with or without bevacizumab (65.7%; 95% CI, 59.4, 71.4 and 37.4%; 95% CI, 31.6, 43.7, respectively). The estimated median duration of response and median time to response were also maintained from the prior primary analysis. Results from the primary analysis of ORR were presented at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and were simultaneously published in Nature Medicine in January 2025. Additional data from a separate arm of the BREAKWATER study evaluating BRAFTOVI in combination with cetuximab will also be presented at ASCO. "The risk of death for patients with BRAF V600E-mutant metastatic colorectal cancer is more than double compared to those with no known mutation," said Michael Sapienza, Chief Executive Officer, Colorectal Cancer Alliance. "These survival outcomes from the BREAKWATER study bring renewed hope to patients and their loved ones, providing the possibility of more time together. We are thrilled to see important cancer research propel us closer to our goal of ending this disease." At the time of this analysis, the safety profile of BRAFTOVI in combination with cetuximab and mFOLFOX6 continued to be consistent with the known safety profile of each respective agent. No new safety signals were identified. The most common side effects (≥30%) were nausea, anemia, diarrhea, decreased appetite, vomiting, neutrophil count decrease, arthralgia, and rash. Among patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6, 13.8% experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI. The BRAFTOVI combination regimen received accelerated approval by the U.S. Food and Drug Administration (FDA) in December 2024 for patients with BRAF V600E -mutant mCRC based on a clinically meaningful and statistically significant improvement in confirmed ORR in treatment-naïve patients, the study's other dual primary endpoint.5 Continued approval for this indication is contingent upon verification of clinical benefit. The approval was among the first in the industry to be conducted under the FDA's Project FrontRunner, which seeks to support the development and approval of new cancer drugs for advanced or metastatic disease. The BREAKWATER survival data are being discussed with the U.S. FDA to support potential conversion to full approval in 2025. Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented, which are written in non-technical language. Those interested in learning more can visit to access the summaries. About BREAKWATERBREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial of BRAFTOVI with cetuximab, alone or in combination with mFOLFOX6 in participants with previously untreated BRAF V600E-mutant metastatic CRC. Patients were randomized to receive BRAFTOVI 300 mg orally once daily in combination with cetuximab (discontinued after randomization of 158 patients), BRAFTOVI 300 mg orally once daily in combination with cetuximab and mFOLFOX6 (n=236) or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab (control-arm) (n=243). The dual primary endpoints are ORR and progression-free survival (PFS) as assessed by blinded independent central review (BICR). Overall survival is a key secondary endpoint. About Colorectal Cancer (CRC)CRC is the third most common type of cancer in the world, with approximately 1.8 million new diagnoses in 2022.1 It is the second leading cause of cancer-related deaths.6 Overall, the lifetime risk of developing CRC is about 1 in 24 for men and 1 in 26 for women.6 In the U.S. alone, an estimated 154,270 people will be diagnosed with cancer of the colon or rectum in 2025, and approximately 53,000 are estimated to die from the disease each year.7 For 20% of those diagnosed with CRC, the disease has metastasized, or spread, making it harder to treat, and up to 50% of patients with localized disease eventually develop metastases.8 BRAF mutations are estimated to occur in 8-12% of people with mCRC and represent a poor prognosis for these patients.2 The BRAF V600E mutation is the most common BRAF mutation and the risk of mortality in patients with CRC with the BRAF V600E mutation is more than double that of patients with no known BRAF mutation present.2-4 Despite the high unmet need in BRAF V600E-mutant mCRC, prior to December 20, 2024, there were no approved biomarker-driven therapies specifically indicated for people with previously untreated BRAF V600E-mutant mCRC.9,10 About BRAFTOVI® (encorafenib)BRAFTOVI is an oral small molecule kinase inhibitor that targets BRAF V600E. Inappropriate activation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK) has been shown to occur in certain cancers, including CRC. Pfizer has exclusive rights to BRAFTOVI in the U.S., Canada, Latin America, Middle East, and Africa. Ono Pharmaceutical Co., Ltd. has exclusive rights to commercialize the product in Japan and South Korea, Medison has exclusive rights to commercialize the product in Israel and Pierre Fabre Laboratories has exclusive rights to commercialize the product in all other countries, including Europe and Asia (excluding Japan and South Korea). INDICATION AND USAGEBRAFTOVI® (encorafenib) is indicated, in combination with cetuximab and mFOLFOX6, for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). BRAFTOVI is also indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy. Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF CRC. IMPORTANT SAFETY INFORMATION Refer to the prescribing information for cetuximab and individual product components of mFOLFOX6 for recommended dosing and additional safety information. WARNINGS AND PRECAUTIONS New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. In BEACON CRC (previously treated BRAF V600E mutation-positive mCRC), cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC) skin papilloma was reported in 2.6%, basal cell carcinoma in 1.3%, squamous cell carcinoma of skin in 0.9%, keratoacanthoma in 0.4% and malignant melanoma in situ in 0.4% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment. Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI. Cardiomyopathy: Cardiomyopathy manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. Safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Hepatotoxicity: Hepatotoxicity can occur. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.2% for alkaline phosphatase, 1.3% for ALT, and 0.9% for AST. Monitor liver laboratory tests before initiation of BRAFTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Hemorrhage: In BEACON CRC (previously treated BRAF V600E mutation-positive mCRC), hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%). In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), hemorrhage occurred in 30% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Uveitis: Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), an increase of QTcF >500 ms was measured in 3.6% (8/222) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms. Embryo-Fetal Toxicity: BRAFTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose. Risks Associated with Combination Treatment: BRAFTOVI is indicated for use as part of a regimen in combination with cetuximab, or in combination with cetuximab and mFOLFOX6. Refer to the prescribing information for cetuximab and individual product components of mFOLFOX6 for additional risk information. Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose. Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility. ADVERSE REACTIONS BREAKWATER Trial (previously untreated BRAF V600E mutation-positive mCRC) Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction (3.5%) and pyrexia (3.5%). Fatal gastrointestinal perforation occurred in 0.9% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Most common adverse reactions (≥25%, all grades) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were peripheral neuropathy (62% vs 53%), nausea (51% vs 48%), fatigue (49% vs 38%), rash (31% vs 4%), diarrhea (34% vs 47%), decreased appetite (33% vs 25%), vomiting (33% vs 21%), hemorrhage (30% vs 18%), abdominal pain (26% vs 27%), and pyrexia (26% vs 14%). Most common laboratory abnormalities (≥10%, grade 3 or 4) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were: increased lipase (51% vs 25%), decreased neutrophil count (36% vs 34%), decreased hemoglobin (13% vs 5%), decreased white blood cell count (12% vs 7%), and increased glucose (11% vs 2%). BEACON CRC Trial (previously treated BRAF V600E mutation-positive mCRC) Most common adverse reactions (≥25%, all grades) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: fatigue (51% vs 50%), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%). Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab was pancreatitis. Most common laboratory abnormalities (all grades) (≥20%) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: anemia (34% vs 48%) and lymphopenia (24% vs 35%). DRUG INTERACTIONS Strong or moderate CYP3A4 inhibitors: Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose. Strong CYP3A4 inducers: Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers. Sensitive CYP3A4 substrates: Avoid the coadministration of BRAFTOVI with CYP3A4 substrates (including hormonal contraceptives) for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations. Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI. Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval. View the full Prescribing Information. About Pfizer OncologyAt Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world's most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives. About Pfizer: Breakthroughs That Change Patients' LivesAt Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at In addition, to learn more, please visit us on and follow us on X at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us on Facebook at Disclosure NoticeThe information contained in this release is as of May 30, 2025. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about Pfizer Oncology and the BRAFTOVI® (encorafenib) plus cetuximab and mFOLFOX6 combination for the treatment of metastatic colorectal cancer (CRC) with a BRAF V600E mutation, including their potential benefits and discussions of the BREAKWATERsurvival data with regulatory authorities, including the FDA, to support potential conversion from accelerated approval to full approval for the combination regimen in this indication , that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of BRAFTOVI plus cetuximab and mFOLFOX6; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when the accelerated approval for BRAFTOVI plus cetuximab and mFOLFOX6 for the treatment of patients with metastatic CRC with a BRAF V600E mutation will be converted to full approval in the U.S.; whether and when any drug applications may be filed in any additional jurisdictions for BRAFTOVI plus cetuximab and mFOLFOX6 for the treatment of patients with metastatic CRC with a BRAF V600E mutation or in any jurisdictions for any other potential indications for BRAFTOVI; whether and when any such other applications may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy and, if approved, whether BRAFTOVI plus cetuximab and mFOLFOX6 will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of BRAFTOVI or BRAFTOVI plus cetuximab and mFOLFOX6; risks and uncertainties related to issued or future executive orders or other new, or changes in, laws or regulations; uncertainties regarding the impact of COVID-19 on Pfizer's business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2024, and in its subsequent reports on Form 10-Q, including in the sections thereof captioned "Risk Factors" and "Forward-Looking Information and Factors That May Affect Future Results", as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at and ERBITUX® is a registered trademark of Eli Lilly and Company its subsidiaries, or affiliates. References American Cancer Society. Global Cancer Facts & Figures 5th Edition. Available at: Last accessed: March 2025. Josep Tabernero et al., The Evolving Treatment Landscape in BRAF-V600E–Mutated Metastatic Colorectal Cancer. Am Soc Clin Oncol Educ Book 42, 254-263(2022). DOI:10.1200/EDBK_349561 Safaee Ardekani G, Jafarnejad SM, Tan L, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PloS ONE. 2012;7(10):e47054. Schirripa M, Biason P, Lonardi S, et al. Class 1, 2, and 3 BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization. Clin Cancer Res. 2019;25(13):3954-3961. doi:10.1158/ Kopetz S, Yoshino T, Van Cutsem E, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025;31(3):901-908. doi:10.1038/s41591-024-03443-3 American Cancer Society. Key Statistics for Colorectal Cancer. Available at: Last accessed: March 2025. American Cancer Society. Cancer Facts & Figures 2025. Available at: Last accessed: March 2025. Ciardiello F, Ciardiello D, Martini G, et al. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72:372–40. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer. V.1.2025 © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed March 2025. To view the most recent and complete version of the guideline, go online to Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10–32. View source version on Contacts Media Contact:+1 (212) 733-1226PfizerMediaRelations@ Investor Contact:+1 (212) 733-4848IR@
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3 days ago
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Merck Announces MK-1084, an Investigational KRAS G12C Inhibitor, Shows Antitumor Activity in Phase 1 Trial of Patients With Advanced Colorectal Cancer and Non-Small Cell Lung Cancer Whose Tumors Harbor KRAS G12C Mutations
Manageable safety profile and encouraging antitumor activity observed for MK-1084 in KANDLELIT-001, both as a monotherapy and in studied combinations RAHWAY, N.J., May 30, 2025--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced today safety and efficacy results from the open-label Phase 1 KANDLELIT-001 study, a clinical trial evaluating MK-1084, an investigational next-generation KRAS G12C inhibitor, alone and in combination with other therapies in certain patients with KRAS G12C-mutant solid tumors, including advanced colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). In patients with advanced KRAS G12C-mutated CRC and NSCLC, a manageable safety profile and antitumor activity were observed with MK-1084 either as a monotherapy or in the combinations. "We are encouraged by the promising early data from the KANDLELIT-001 study and look forward to further researching the potential for MK-1084, as monotherapy or in combinations, including with KEYTRUDA in certain settings in patients with KRAS mutations, which are among the most prevalent mutations in cancer," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. "We are committed to evaluating the potential for innovative approaches to help even more patients with cancer and these results further demonstrate the potential of our robust and differentiated pipeline." In CRC, the study assessed MK-1084 as monotherapy, as well as in combination with cetuximab with or without chemotherapy (oxaliplatin and leucovorin plus 5-fluorouracil [mFOLFOX6]). For efficacy, the study evaluated overall response rate (ORR), with the following results for efficacy evaluable patients: MK-1084 Monotherapy Previously treated CRC1 N=53 MK-1084 + Cetuximab Previously treated CRC2 N=39 MK-1084 + Cetuximab + mFOLFOX63 Metastatic CRC with 0-1 lines of prior therapy N=29 Confirmed response, % (95% CI) ORR 38% (25-52) 46% (30-63) 38% (21-58) Unconfirmed response, % (95% CI) ORR 43% (30-58) 56% (40-72) 66% (46-82) 1 Median follow-up for all advanced CRC patients in these arms = 23.2 months (range, 0.2-37.7) 2 Median follow-up for all patients in this treatment arm = 9.2 months (range, 0.5-15.6) 3 Median follow-up for all patients in this treatment arm = 4.6 months (range, 0.1 -9.5) In NSCLC, MK-1084 was evaluated as monotherapy, as well as in combination with KEYTRUDA with or without chemotherapy (carboplatin and pemetrexed), with the following ORR results for efficacy evaluable patients: MK-1084 Monotherapy Previously treated NSCLC4 N=21 MK-1084 + KEYTRUDA Untreated metastatic NSCLC whose tumors express PD-L1 tumor proportion score [TPS] ≥1%5 N=69 MK-1084 + KEYTRUDA+ Chemotherapy (carboplatin and pemetrexed) Untreated metastatic NSCLC6 N =40 ORR, % (95% CI) 38% (18-62) 77% (65-86) 53% (36-69) 4 Median follow-up for all NSCLC patients in these arms = 18.9 months (range, 0.0-36.4) 5 Median follow-up for all patients in this treatment arm = 12.1 months (range, 0.8-33.4) 6 Median follow-up for all patients in this treatment arm = 8.5 months (range, 0.5-16.5) Across all arms of the KANDLELIT-001 study, MK-1084 had a manageable safety profile. Treatment-related adverse events (TRAEs) occurred in 58% (n=71) of patients in the MK-1084 monotherapy arm, 94% (n=68) of patients in the MK-1084 and KEYTRUDA arm, 93% (n=39) of patients in the MK-1084 in combination with KEYTRUDA and chemotherapy arm, 95% (n=39) of patients in the MK-1084 and cetuximab arm and 97% (n=32) of patients in the MK-1084 with cetuximab and mFOLFOX6 arm. These KANDLELIT-001 CRC and NSCLC data are being presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #3508 and #8605, respectively). In addition to KANDLELIT-001, MK-1084 will be investigated in the Phase 3 KANDLELIT-012 study, which is investigating MK-1084 in combination with cetuximab and mFOLFOX6 for the first-line treatment of certain patients with locally advanced unresectable or metastatic CRC who have KRAS G12C-mutated tumors and the Phase 3 KANDLELIT-004 study, which is investigating MK-1084 in combination with KEYTRUDA for the first-line treatment of certain patients with metastatic NSCLC who have KRAS G12C-mutated tumors and express PD-L1 (TPS ≥50%). MK-1084 is being developed under a collaboration and license agreement with Taiho Pharmaceutical Co. Ltd and Astex Pharmaceuticals (UK), a wholly owned subsidiary of Otsuka Pharmaceutical Co., Ltd. About KANDLELIT-001 KANDLELIT-001 is a Phase 1, open-label multicenter clinical trial (Clinical NCT05067283) designed to assess safety, tolerability, pharmacokinetics and efficacy of MK-1084 as monotherapy and in combination with other therapies in patients with KRAS G12C mutated advanced solid tumors. The primary endpoints of the trial were safety and tolerability, as assessed by number of patients who experienced a dose-limiting toxicity, adverse events and treatment discontinuations. Secondary endpoints include objective response rate (ORR) and duration of response. Selected KEYTRUDA® (pembrolizumab) Indications in the U.S. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information. Selected Important Safety Information for KEYTRUDA Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA as a Single Agent KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients. KEYTRUDA With Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypophysitis KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Thyroid Disorders KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti– PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT. Increased Mortality in Patients With Multiple Myeloma In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials. Embryofetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%). In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054. In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%). In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%). In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism. In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%). Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%). In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%). In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism. In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each). In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%). In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%). In KEYNOTE-A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%). In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%). In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%). Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. In KEYNOTE-811, fatal adverse reactions occurred in 3 patients who received KEYTRUDA in combination with trastuzumab and CAPOX (capecitabine plus oxaliplatin) or FP (5-FU plus cisplatin) and included pneumonitis in 2 patients and hepatitis in 1 patient. KEYTRUDA was discontinued due to adverse reactions in 13% of 350 patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. Adverse reactions resulting in permanent discontinuation of KEYTRUDA in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%). In the KEYTRUDA arm vs placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 47%), rash (35% vs 28%), hypothyroidism (11% vs 5%), and pneumonia (11% vs 5%). In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%). In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%). Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 292 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients; those ≥1% included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary tract infection (32%), fatigue (26%), hypothyroidism (20%), constipation (18%), decreased appetite and weight loss (17% each), abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria, rash (11% each), and pelvic pain (10%). In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each). KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%). In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%). In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritus (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%). In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%). In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%). In KEYNOTE-868, when KEYTRUDA was administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with advanced or recurrent endometrial carcinoma (n=382), serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy (n=377). Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone, with the exception of rash (33% all Grades; 2.9% Grades 3-4). Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%). Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose. Pediatric Use In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (30%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Geriatric Use Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Additional Selected KEYTRUDA Indications in the U.S. Melanoma KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. Malignant Pleural Mesothelioma KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Cancer KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma: who are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. Biliary Tract Cancer KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. Triple-Negative Breast Cancer KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Merck's focus on cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the "company") includes "forward-looking statements" within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company's management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company's Annual Report on Form 10-K for the year ended December 31, 2024 and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site ( Please see Prescribing Information for KEYTRUDA (pembrolizumab) at and Medication Guide for KEYTRUDA at View source version on Contacts Media Contacts:Julie Cunningham(617) 519-6264Sienna Choi(908) 873-4311Investor Contacts:Peter Dannenbaum(732) 594-1579Steve Graziano(732) 594-1583
Business Wire
3 days ago
- Business
- Business Wire
Parabilis Medicines to Present Overview of Ongoing Phase 1/2 Study of FOG-001, a β-catenin
CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Parabilis Medicines, a clinical-stage biopharmaceutical company committed to creating extraordinary medicines for people living with cancer, today announced the presentations of trial-in-progress posters on the Company's first-in-human clinical trial evaluating FOG-001, the first and only direct inhibitor of β-catenin TCF4, at the ASCO Annual Meeting, which begins on May 30 in Chicago, Illinois, and the ESMO Gastrointestinal Cancers Congress 2025, which begins on July 2 in Barcelona, Spain. FOG-001 is being evaluated in a Phase 1/2 trial (NCT05919264). The multicenter, open-label, non-randomized trial aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of FOG-001 in patients with solid tumors with Wnt pathway activating mutations (WPAM+), including colorectal cancer (CRC) and desmoid tumors. More than 65 patients with locally advanced or metastatic tumors have been dosed with FOG-001 to date, and early clinical data demonstrate monotherapy antitumor activity and in-tumor target engagement. Phase 1/2 data are expected to be shared publicly in 2025. The trial is currently enrolling patients with desmoid tumors in its monotherapy arm. It is also enrolling multiple cohorts of microsatellite-stable CRC (MSS-CRC) patients to evaluate combination regimens of FOG-001, supported by strong scientific rationale: Combinations with FOLFOX+bevacizumab and trifluridine/tipiracil+bevacizumab: Paired biopsy data from the ongoing FOG-001 trial indicate that FOG-001 drives reduction in markers of stemness and upregulation of the angiogenesis pathway, pointing to potentially greater susceptibility to both chemotherapy and bevacizumab. Preclinical studies employing patient-derived xenograft (PDX) mouse models indicate FOG-001 can significantly deepen and extend the benefit of both chemotherapy backbone agent 5-FU and bevacizumab. A second combination regimen, pairing FOG-001 with PD-1 checkpoint inhibitors, is supported by paired biopsy data from the ongoing trial indicating that FOG-001 induces the Merck tumor inflammation signature in otherwise immunologically 'cold' tumors. Preclinical studies in MC38 mouse models suggest this potential, demonstrating synergistic combination efficacy between FOG-001 and PD-1 checkpoint inhibitors. These observations indicate that FOG-001 could improve CRC responses to immunotherapy, which currently has minimal to no monotherapy efficacy in MSS-CRC. ASCO poster information: Title: 'A Phase 1/2 study of FOG-001, a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer (CRC) and other locally advanced or metastatic solid tumors' Abstract Number: TPS3169 Date and Time: June 2, 2025, 1:30-4:30 p.m. CDT Session: Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology Location: Hall A – Posters and Exhibits ESMO GI poster information: Title: 'FOG-001 – a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer (CRC) and other locally advanced or metastatic solid tumors: Phase 1/2 study design' Presentation Number: 145TiP Date and Time: July 3, 2025, 3:30-4:30 p.m. CET Session: Poster display session Location: Foyer About FOG-001 FOG-001 is an investigational first-in-class competitive inhibitor of β-catenin interactions with the T-cell factor (TCF) family of transcription factors, and is currently in clinical development. By directly targeting the β-catenin TCF4 protein-protein interaction, FOG-001 is intended to block the Wnt signaling pathway irrespective of the various APC and beta-catenin mutations that typically drive disease. FOG-001 combines key features that distinguish it from previously reported Wnt/β-catenin pathway modulators: FOG-001 acts inside the cell where it binds directly to the key oncogenic driver β-catenin; and FOG-001 blocks the Wnt pathway at the most downstream node, disrupting the interaction between β-catenin and the transcription factor TCF, thereby abrogating the signal transmission by which Wnt pathway mutations are believed to drive oncogenesis. FOG-001 is currently being evaluated in a first-in-human Phase 1/2 clinical trial in patients with locally advanced or metastatic solid tumors. About Parabilis Medicines Parabilis Medicines is a clinical-stage biopharmaceutical company dedicated to creating extraordinary medicines for people living with cancer. Through its Helicon discovery platform, Parabilis is engineering precisely tuned, stabilized helical peptide therapeutics that have the potential to unlock a large number of traditionally undruggable targets. This versatile platform enables applications for Helicons across three main areas: functional inhibitors of intracellular protein-protein interactions, targeted protein degraders, and targeted radiopharmaceuticals. Parabilis is advancing a pipeline of first-in-class programs across these three domains, led by FOG-001, its clinical-stage β-catenin TCF4 inhibitor. Parabilis is headquartered in Cambridge, Mass., and is well-capitalized, with more than $500 million raised to date from leading life sciences investors. For more information, please visit:
Business Wire
3 days ago
- Health
- Business Wire
Ontada Unveils Comprehensive Data on Social Determinants of Health and Outcomes of Early-Onset Colorectal Cancer at ASCO
BOSTON--(BUSINESS WIRE)-- Ontada ®, a leader in real-world oncology data and insights, is proud to present its latest research findings in a pivotal oral presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting. The study, titled, "Real-world Social Determinants of Health and Outcomes of Early-onset Colorectal Cancer: An Analysis of a Large Nationally Representative US Community Oncology Network," provides critical data on the impact of social determinants on the outcomes of early-onset colorectal cancer (EO-CRC) patients, and offers one of the largest studies of EO-CRC to date. Over 104,000 patients with CRC were studied, including nearly 15,000 patients with early-onset CRC. Key Data Findings Racial and ethnic disparities: A higher burden of EO-CRC was observed among patients of Black and American Indian/Alaskan Native race and Hispanic/Latino ethnicity. Obesity as a risk factor: There was a 5% higher prevalence of obesity among patients with early-onset CRC versus average onset CRC. More advanced stage at diagnosis for EO-CRC: Patients with EO-CRC have an 11% greater likelihood of diagnosis at Stage III or IV disease as compared to average-onset disease. Poorer survival associated with advancing age: At each cancer stage, patients with EO-CRC had a longer overall survival as compared to patients with average-onset CRC, reflecting existing knowledge about cancer survival decreasing with advancing age. Importance of screening and earlier diagnosis: Among all patients with CRC, including early-onset diagnosis, disease stage at diagnosis was the strongest predictor of overall survival, reflecting the importance of earlier detection and screening programs for all. 'Understanding the complex interplay between social factors and cancer incidence and outcomes is crucial for developing effective, patient-centered care strategies, and this research underscores the importance of understanding and then intervening on social determinants of health to improve care for patients with EO-CRC,' said Jessica K. Paulus, ScD, senior director, Real-World Research, Ontada. 'Ontada's data provides a clear and compelling picture of the impact of social determinants on the outcomes of patients with EO-CRC. By leveraging our unique data emanating from the nationally representative The US Oncology Network and our measures of social determinants at scale, we can drive meaningful changes in clinical practice and policy, ultimately improving patient care and outcomes.' Study Methodology This retrospective observational cohort study examined adult CRC patients within The US Oncology Network and non-Network practices, encompassing over 2,700 community-based providers treating more than 1.4 million patients annually. All patients diagnosed with CRC between 2000 and 2024 were included; patients were categorized as EO-CRC if they were <50 years at first diagnosis and average-onset (AO)-CRC otherwise. Over 104,000 patients with CRC were studied, including nearly 15,000 patients with early-onset CRC. Patient characteristics were sourced from iKnowMed, an oncology-specific electronic health record system, and descriptively summarized. Overall Survival (OS) was assessed from diagnosis using Kaplan-Meier methods. Other Research at ASCO 2025 Ontada is showcasing its research capabilities at ASCO with 12 accepted abstracts on topics such as using large language models to extract cancer data, accelerating Phase 2 clinical development with real-world data in HER2-positive metastatic breast cancer, validating real-world event-free survival in early-stage triple negative breast cancer, analyzing outcomes of BRAF-mutated melanoma patients, and providing a descriptive epidemiology of Waldenström Macroglobulinemia. 'At Ontada, we are at the forefront of transforming cancer care through the power of real-world data and insights,' said Christine Davis, president, Ontada. 'Our extensive research at ASCO 2025 underscores our commitment to driving meaningful advancements in oncology. This research will not only highlight the critical role of real-world evidence in improving patient outcomes but also demonstrate our dedication to addressing the complex challenges faced by cancer patients and healthcare providers.' Ontada is a part of McKesson, which has an unmatched portfolio of oncology businesses and partners that provide research, insights, technologies, and services that are helping address barriers and improve cancer and specialty care. At ASCO, McKesson-supported businesses including The US Oncology Network, Ontada, and Sarah Cannon Research Institute (SCRI), are part of approximately 170 accepted abstracts and presentations. These are inclusive of oral and poster presentations, educational sessions, late-breaking studies, and early-phase studies. For a comprehensive list of Ontada abstracts and presentations, visit Ontada's ASCO 2025 Site. Additionally, visit the Ontada Booth (#35093) at the McCormick Place Convention Center from May 30 – June 3 to explore the data presented at ASCO 2025 and experience Ontada's solutions firsthand. About Ontada ® Ontada is an oncology technology and insights business dedicated to transforming the fight against cancer. Part of McKesson Corporation, Ontada was founded on the core belief that precise insights – delivered exactly at the point of need – can save more patients' lives. We connect the full patient journey by combining technologies used by The US Oncology Network and other community oncology providers with real-world data and research relied on by all top 15 global life sciences companies. Our work helps accelerate innovation and powers the future of cancer care. For more information, visit About McKesson Oncology and Specialty Solutions It's an unprecedented time for patients living with cancer as life sciences companies race to create new, cutting-edge therapies. With cancer care becoming more targeted, providers, life sciences companies, and payers face a multitude of challenges and complexity in the development of new treatments and making them accessible to patients in need. At McKesson, our unmatched portfolio of oncology businesses and partners provide research, insights, technologies, and services that are helping to address these hurdles and improve cancer and specialty care. McKesson is fueling discovery by helping patients participate in cutting-edge clinical trials closer to home through its joint venture with Sarah Cannon Research Institute. The US Oncology Network and McKesson Provider Solutions are advancing specialty care and high-quality cancer care in the communities where patients live by supporting the practices of thousands of independent, community-based providers. Ontada ®, a McKesson business dedicated to oncology, generates real-world data (RWD) and real-world evidence (RWE), and provides clinical education and provider technology to inform and improve cancer care. As a leading distributor of oncology and specialty medicines, we are ensuring medicines make their way to those who are counting on them. And through CoverMyMeds, Biologics by McKesson, and GPO services, our work continues to help patients access, afford, and adhere to their medicines.
Business Recorder
4 days ago
- Politics
- Business Recorder
Disputes involving kids: Mediation offers a mutually beneficial solution: SC
ISLAMABAD: The Supreme Court has ruled that in matters involving children, such as custody, guardianship, and family disputes, the courts must recognise that a strictly adversarial approach often exacerbates conflict, delays resolution, and undermines the child's sense of stability and security. 'In contrast, Alternative Dispute Resolution (ADR), particularly mediation, offers a more collaborative, efficient, and child-sensitive mechanism for resolving such dispute. While the CRC does not explicitly reference the term ADR, its spirit and structure clearly support its use,' said a two-judge bench comprising Justice Syed Mansoor Ali Shah and Justice Aqeel Ahmed Abbasi's verdict in children custody case. The bench gave children custody to their mother. The bench directed that all courts, particularly Family Courts and judges of the District Judiciary that 'the voice of the child must be heard and respected in every custody and guardianship matter'. The 12-page judgment, authored by Justice Mansoor, said that properly designed ADR mechanisms reduce the psychological burden on children, promote parental cooperation, and lead to faster, more sustainable outcomes that support the child's long-term welfare. Accordingly, Family Courts and Guardianship Tribunals must prioritise mediation as a first recourse, particularly where parties demonstrate a willingness to engage in good faith. Adjudication should be pursued only when mediation fails or is deemed unsuitable due to concerns of safety, coercion, or imbalance of power. It said that the principles enshrined in Articles 3 and 12 of the CRC, the primacy of the child's best interests and the right to be heard find clear constitutional resonance in Articles 9, 14, 25 and 34 of the Constitution. Article 9 guarantees the right to life, which includes the right to a healthy, secure, and meaningful life. Article 14 protects the inherent dignity of every person, including children. Article 25 enshrines equality before the law and nondiscrimination, and Article 34 obligates the State to ensure the protection of motherhood and childhood. It noted that collectively, these provisions establish a strong constitutional foundation for child justice and child-centered adjudication, aligning Pakistan's constitutional values with its international obligations under the CRC and other international instruments it has ratified16. The Constitution further reinforces these obligations. Article 25(3) empowers the State to enact special provisions for the protection of children, including measures that may favorably differentiate them from adults. The judgment underscored that courts are bound to approach all matters involving children through the lens of a dedicated child-centered and child justice framework, a judicial philosophy grounded in both legal and moral obligations to safeguard, nurture, and empower children within the justice system. The concept of child justice is broad and inclusive. It encompasses not only children in conflict with the law, who require rehabilitative and restorative processes rather than punitive sanctions, but also children in contact with the law, including those involved in custody and guardianship disputes and other civil proceedings who must be treated with dignity, heard, protected, and empowered throughout judicial proceedings. As custodians of justice, courts bear a heightened responsibility to prioritise the best interests of the child in all decisions affecting them. This principle, central to international child rights jurisprudence, demands that the judiciary transcend procedural formalism and engage substantively with each child's unique vulnerabilities, developmental needs, and future potential. Such an approach requires judicial sensitivity, active participation of children in proceedings (where appropriate), and the creation of child-sensitive courtroom environments that respect their dignity and ensure their voices are not only heard but meaningfully considered. Copyright Business Recorder, 2025
