Q&A: Cervical Cancer

Medscape

19 hours ago

Maurie Markman, MD
Dr Maurie Markman, an internationally recognized medical oncologist and president of medicine and science at City of Hope, specializes in gynecologic malignancies. In this interview, he discusses the transformative role of immunotherapy in advanced and recurrent cervical cancer treatment. He also addresses practical management considerations for special populations, immunotherapy toxicity profiles, surveillance strategies, resistance mechanisms, and the field's future directions.
How has immunotherapy transformed the landscape for recurrent and metastatic cervical cancer, and what defines the current standard of care?
The transformation has been nothing short of remarkable. Before immunotherapy, we were essentially offering patients with cervical cancer single-agent cisplatin with awful toxicity and minimal response rates; it was a pretty dismal situation. The introduction of pembrolizumab in the first-line setting has been a true game-changer.
Based on the KEYNOTE-826 trial results, pembrolizumab — combined with platinum-based chemotherapy, with or without bevacizumab — significantly prolonged both progression-free and overall survival compared to chemotherapy alone.[1,2] This has become our standard approach for PD-L1-positive disease.[3] In practice, this means that patients who previously had almost no effective therapy options now have a regimen that produces meaningful tumor responses and substantial survival gains. We're talking about dramatically improved outcomes where none existed before.
The current standard involves simultaneous administration of all agents from cycle 1. For patients who are candidates for triple therapy, we give pembrolizumab on day 1 with cisplatin or carboplatin plus paclitaxel and add bevacizumab at its usual dose and schedule if there are no contraindications.[3] The beauty is that pembrolizumab toxicities don't meaningfully interact with chemotherapy or bevacizumab; the immune-related adverse events occur independently of vascular toxicities. We only withhold bevacizumab for patient-specific reasons like recent major surgery or active fistula, not because of immunotherapy concerns.
Walk us through PD-L1 testing and biomarker strategies. What should oncologists know about patient selection?
Every patient with recurrent or metastatic cervical cancer should undergo PD-L1 testing using an FDA-approved assay; this is nonnegotiable.[3] The score is reported as a combined positive score (CPS), which is the number of PD-L1-staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. A CPS of 1 or more is considered PD-L1-positive based on FDA definition and KEYNOTE-826 data. Essentially, if at least 1% of cells are PD-L1-positive based on this formula, the tumor qualifies for pembrolizumab-based therapy.[1,2]
But we don't stop there. While PD-L1 remains the primary biomarker, we routinely obtain comprehensive genomic testing because other features can influence the treatment strategy. NCCN (National Comprehensive Cancer Network) recommends testing for MSI/MMR in recurrent disease.[3] Although MSI-H is uncommon in cervical cancer, any patient with MSI-H or high tumor mutational burden would be eligible for pembrolizumab on a tumor-agnostic basis.
We also recommend comprehensive panel testing, including HER2 amplification/overexpression and NTRK fusions.[3] These markers may not predict pembrolizumab response per se, but they identify other targeted therapies if immunotherapy fails. For example, HER2 overexpression opens the door to trastuzumab deruxtecan later in the treatment course.
How do targeted therapies like trastuzumab deruxtecan and tisotumab vedotin fit into the treatment paradigm?
This is where things get exciting for the small subset of patients with specific molecular targets. HER2 overexpression occurs in roughly 2%-6% of cervical cancers, but it's clinically significant when these are present. The DESTINY-PanTumor02 trial included a cervical cancer cohort and showed impressive activity; the confirmed objective response rate was about 50% overall, and in the subset with IHC 3+ tumors, it reached 75%.[4]
Based on these results, NCCN now recommends routine HER2 testing (IHC with FISH reflex) in recurrent/metastatic disease and lists trastuzumab deruxtecan as a category 2A, second-line option for HER2-positive tumors (IHC 3+ or 2+).[3] So, while only a minority of patients have HER2-positive disease, those who do have access to an active ADC (antibody-drug conjugate) therapy after first-line treatment.
Tisotumab vedotin represents another significant advance. This tissue factor-directed ADC received full FDA approval in April 2024 for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, and it's now the only NCCN category 1 preferred option for second-line therapy.[3,5] What's particularly interesting is the ongoing innovaTV 205 (GOG-3024) trial combining tisotumab vedotin with pembrolizumab in the first-line setting; the NCCN guidelines already note this combination as an option for PD-L1-positive patients based on encouraging phase 2 activity.[3]
The rationale behind these ADCs is compelling: They can target tumor cells independent of the PD-1 pathway, potentially overcoming immunotherapy resistance mechanisms.
How do you approach treatment in special populations such as elderly patients, those with poor performance status, and PD-L1-negative disease?
This requires individualized decision-making and honest conversations about goals of care. Age alone is never a contraindication; we don't refuse immunotherapy solely because of chronological age. However, older patients often have more comorbidities that can amplify even low-grade toxicities. Before treating such patients, we carefully assess overall health, lab values, and organ function.[6]
For truly frail patients or those with poor performance status (ECOG [Eastern Cooperative Oncology Group] ≥ 2) due to disease burden, we discuss goals of care candidly. Sometimes we choose single-agent chemotherapy or best supportive care instead of full triple therapy. For moderately impaired patients who seem reasonably functional, we may proceed with chemo-immunotherapy but with closer monitoring and potentially modified dosing.
The key is vigilant follow-up; these patients need frequent labs and clinic visits to catch toxicity early. We personalize the approach: full regimen if they can tolerate it, otherwise a modified strategy.
For PD-L1-negative disease, pembrolizumab isn't indicated, so we revert to traditional approaches: platinum-based chemotherapy plus bevacizumab when feasible, followed by second-line agents like topotecan or irinotecan.[3] We still ensure broad molecular profiling since targets like NTRK fusions or microsatellite instability could open second-line options, but immunotherapy is reserved for PD-L1-positive cases per label.
What are the key principles for managing immunotherapy-related toxicities, and are there cervical cancer-specific considerations?
Toxicity management for pembrolizumab in cervical cancer follows the same principles as other tumors. There are no cervical cancer-specific immune toxicities. We monitor for the usual immune-related adverse events (thyroid function tests, skin checks, GI symptoms) and treat according to standard guidelines like steroids for grade ≥ 2 colitis and hormone replacement for hypothyroidism.
The main caveat is that many patients with cervical cancer have had extensive prior therapy (eg, radiation, cisplatin) and may have compromised organ function or poor performance status at baseline. This means that even the same immune side effect could be more clinically challenging. For example, a patient with heavy tumor burden and GI involvement might not tolerate low-grade colitis as well as someone with good performance status.[6]
We apply common sense; patients with multiple comorbidities or moderate ECOG 2-3 status require very close monitoring since any grade 3-4 immune-related adverse event could tip the balance. In practice, we treat most patients with PD-L1-positive disease regardless of age or mild frailty, but we have a lower threshold to hold therapy and manage side effects aggressively in vulnerable populations.
What does surveillance look like during and after immunotherapy, and what emerging resistance mechanisms concern you?
Unlike some other cancers, we don't have reliable tumor markers to follow in cervical cancer. There's no CA-125 equivalent. We rely entirely on imaging, typically CT scans every 3 months or as clinically indicated by symptoms. For patients with visceral disease, we image the chest, abdomen, and pelvis together.[3]
We continue therapy as long as patients derive benefit (response or stable disease) without prohibitive toxicity. The surveillance schedule is similar to other metastatic cancers: every 2-3 cycles (6-8 weeks) for the first 6 months and then every 3 months if stable.
Regarding resistance mechanisms, this is an active area of research that keeps me up at night. We know from other cancers that tumors can evade immunotherapy through several routes: downregulating antigen presentation machinery, upregulating alternative checkpoints like LAG-3 or TIM-3, or creating an immunosuppressive microenvironment. In cervical cancer specifically, these mechanisms haven't been fully elucidated.
What's clear is our need for effective second-line strategies. This is where ADCs become particularly attractive; they target tumor cells independent of the PD-1 pathway.[4,5] Beyond HER2-targeted and tissue factor-directed ADCs, new conjugates targeting novel antigens are in development. The field is also exploring combination strategies adding other checkpoint inhibitors or stimulatory agents and novel approaches like therapeutic vaccines.
What developments in earlier-stage disease and emerging trials should we be watching?
Immunotherapy is rapidly moving upstream, and this trend will likely accelerate. Pembrolizumab was recently approved in combination with definitive chemoradiation for high-risk locally advanced cervical cancer (FIGO 2014 stage III–IVA) based on the ENGOT-cx11/GOG-3047 (KEYNOTE-A18) trial.[7] This trial showed that adding pembrolizumab after chemo-RT improves outcomes, and NCCN guidelines now include this as a category 1 recommendation.[3]
Whether to extend immunotherapy to even earlier stages remains to be proven. For bulky stage IB or IIA disease, we'd need to weigh benefits against long-term toxicity and cost. The current priority is optimizing use in high-risk settings where relapse rates are significant, rather than treating early-stage patients we already cure with surgery or chemoradiation.
Several trials deserve attention. The innovaTV 205 (GOG-3024) study combining tisotumab vedotin with pembrolizumab in first-line treatment is particularly intriguing; the rationale is that tisotumab vedotin may provide synergy with PD-1 blockade.[3] Other ongoing trials are testing combinations of PD-1 inhibitors with CTLA-4 inhibitors or novel immunomodulators.[8,9,10]
Looking ahead, ADC combinations and additional checkpoint combinations represent the major themes. We're also seeing movement toward incorporating immunotherapy into adjuvant settings for high-risk patients. The goal is to build on our success in metastatic disease and prevent recurrences before they occur.
Of course, while we're making these therapeutic advances, we can't forget that prevention through HPV vaccination and screening remains our best strategy for reducing cervical cancer incidence overall.