EGFR+ NSCLC: Experts Weigh Risk vs Reward at ASCO 2025

Medscape

4 hours ago

This transcript has been edited for clarity.
Coral Olazagasti, MD: Hello. My name is Coral Olazagasti, and I'm a thoracic oncologist at Sylvester Comprehensive Cancer Center at the University of Miami. Joining me today is my friend and colleague, Maria Velez, a clinical instructor at UCLA, and also my other friend and colleague, Ana Velázquez Mañana, who's an assistant professor of medicine at UCSF.
Today we are super excited because we are speaking about the ASCO 2025 Annual Meeting here in Chicago. We just came out from the oral abstracts for the metastatic setting for non-small cell lung cancer and we want to share some of the data that we learned. We want to start the discussion here today about EGFR -mutant disease in the second-line setting.
We're going to start with Maria. Do you want to tell us a little bit about the HERTHENA-Lung02 study?
Maria A. Velez, MD, MS: Sure. HERTHENA-Lung02 was a study that evaluated HER3-DXd, which is an antibody-drug conjugate (ADC), in the second-line setting for patients with previously treated EGFR -sensitizing mutations.
It was an open-label study where patients received either the HER3-DXd or the investigator's choice chemotherapy, and the primary endpoint was median progression-free survival.
The results showed that the median progression-free survival for patients who received HER3-DXd was 5.8 months whereas the median for the chemotherapy arm was 5.4 months. Even though it was a statistically significant difference, it was not a very clinically meaningful difference, with a huge implication that 100% of the patients in this study had treatment-related adverse events and some patients experienced interstitial lung disease (ILD).
All in all, taking these data into account, even though there's a huge need in the treatment landscape for second-line EGFR -mutant patients, I think this ADC did not really show a substantial enough clinically meaningful benefit and had a large amount of toxicity.
Olazagasti: Not to say that this study didn't show any overall survival (OS) benefit. We're talking about a drug that's not really giving patients a longer life and is also giving many side effects, like you mentioned — a large amount of discontinuation due to ILD, and so much toxicity without that benefit there. I think we'll table that regimen for now. Do you agree?
Velez: I agree.
Ana I. Velázquez Mañana, MD, MSc: I agree. Clearly, it's disappointing to see the results of not beating chemotherapy in the second-line setting, but I do think that potentially there is a role in the third line or afterwards. We know that patients are going to be getting chemotherapy and amivantamab in the second-line setting. There is a need for further drugs and interventions in the third line if patients don't have other AGAs [actionable oncogenic alterations] or other drivers that we can use targeted therapies for.
I am hesitant to give up completely on the drug. I do agree it's quite toxic and very disappointing to unfortunately see these results in the second line.
Olazagasti: I agree. Moving on to the next study — Ana, do you want to talk to us about the SACHI study?
Velazquez Mañana: The SACHI study was an open-label, randomized trial of savolitinib plus osimertinib vs platinum doublet chemotherapy in patients who, post EGFR TKI, had progressed in the second line and had a MET amplification. We know that MET amplifications are an extremely common mechanism of resistance to EGFR TKI-targeted therapies.
Interestingly, in this study, which brings a little bit of heterogeneity, they included patients treated with first- and second-generation EGFR TKIsas well as those treated with third-generation TKIs like osimertinib, which would be our standard of care. They did look to make sure those were T790M negative, those treated with earlier generations.
Interestingly, the results on the primary endpoint of progression-free survival (PFS) showed a benefit of 8.2 months in the combination vs 4.5 months in patients treated with doublet chemotherapy. That [benefit] was maintained in both patients treated with earlier-generation TKIs as well as those treated with third-generation TKIs. It also had some efficacy data and overall response rates of 63.2% vs 36.2%.
Definitely, as we know, using a MET-targeted therapy is helpful. We already know from the United States that they use an approval in the second line of chemotherapy and amivantamab. That approach leads to responses in patients after EGFR TKIs. I think it's an interesting approach, obviously, to think of sparing patients from chemo in that second line and combining two TKIs, but we have to see if that is better than chemo with amivantamab would've been, which would've been our standard of care here.
With savolitinib, we know what the adverse events are. It's a drug that's been approved in China now for years. It's not used in the United States, but I think, based on these studies, it's interesting to see what other studies will come in the future and whether this is a potential approach for us to use.
Olazagasti: Definitely it's interesting. I feel like EGFR is the cool kid on the block now. We have so many options and so many studies looking into it, and it's just interesting to see what the future holds and what else is going to come into play.
Continuing down the line of the EGFR second-line studies, I'm going to talk about the OptiTROP-Lung03 study. This study uses sacituzumab tirumotecan. It's a phase 3 study of EGFR mutants. Patients had to receive not only TKI but also platinum therapy, and they were randomized into using sacituzumab tirumotecan — we're going to call it sac-TMT because this is very hard to pronounce — vs docetaxel.
The primary endpoints of the study were overall response rates, and secondary endpoints were PFS and OS. The study showed that the overall response rate was 45.1% vs 15.6% in the docetaxel arm. Also, there was a PFS benefit. The median PFS was 6.9 compared to only 2.8 in the chemo arm.
Even though the median OS is still ongoing, with the median not reached yet, at 12 months there was an OS of 72.8% compared to 43.2%. I think this drug has been approved in China, and I know that in December it received breakthrough FDA designation in the United States. We'll see, again, what the future holds.
Do you have any thoughts about this?
Velazquez Mañana: We've been seeing from the different TROP2 ADCs that clearly they have a role in EGFR -driven lung cancer. I think it's exciting to see another one. Unfortunately, there are drugs that have many toxicities, so they are hard to manage for patients.
Again, on this one I am a little bit conflicted with what the comparator arm is, and one that not necessarily would be our current standard of care. So we are having a large amount of new development and newer drugs, but because of how long it takes to run trials and the newer approvals that come, it's hard to make comparisons and decisions of which ones you should select and the timing of them. Hopefully, we'll get more data in the future.
Olazagasti: I think that's the general consensus. And the dilemma that we have right now in the EGFR space, because we have so many approved options, is that there's really not a great sequential treatment. It's not really a one-size-fits-all approach.
Some people use osimertinib alone in the first line. Some people use the FLAURA2 study with osimertinib and chemo. Some people prefer the MARIPOSA regimen. These are all pretty decent options, and so bringing these other drugs into the second- and third-line setting, how do we do the sequencing? I think that's really where the dilemma and the problems are going to come about.
Institutions may have different orders and different preferences, but I think in these situations it's also important to take each patient into consideration individually because, like we have already mentioned, it's not only about the treatment and then the benefits, but also the side-effect profile.
This one in particular didn't have any ILDs compared to in HERTHENA where they had a high rate, but we have to really look into toxicities because it's not only survival for patients and PFS; it's really about quality of life, too.
With this great discussion, I think we're going to wrap up for today. Thank you to my friends and colleagues for joining me. Again, this is Coral Olazagasti, speaking from the 2025 ASCO Annual Meeting here in Chicago.