Opinion
Video
Navigating Post-Afatinib Progression: Treatment Sequencing Strategies in NSCLC
Expert insights on sequencing treatment options for patients with uncommon EGFR mutations who have progressed on afatinib, emphasizing clinical trial considerations, biomarker testing, and emerging therapeutic approaches.
Transcript:
Charu Aggarwal, MD, MPH: Let’s say a patient comes in with an EGFR uncommon mutation, as we are calling them on this program. We started them on afatinib. I would just like to go around the room and think about what sequencing treatment options may look like. I’ll start with you, Kaushal [Parikh], how are you sequencing treatment with those who have progressed on afatinib?
Kaushal Parikh, MD: I think that this has been the tragedy for EGFR inhibitors in general. We’ve developed very good first-line drugs for a few years now, and second line, I think now we are starting to see some newcomers, especially amivantamab. A patient with an uncommon EGFR mutation is progressing on afatinib. So far, my second-line treatment has been chemotherapy. I have not seen evidence that patients who become resistant to afatinib with an uncommon EGFR mutation and do not develop a T790M mutation have any benefit with osimertinib.
We do routinely send all patients at resistance for a biopsy as well as in NGS [next-generation sequence] testing. It would be very unfortunate to find a small cell inflammation, but we have even uncommon mutations. Outside of a study, chemotherapy, and doublet chemotherapy is a standard of care for me. I’m not sure if you can extrapolate this, but I’d be happy to because amivantamab again is, it’s almost a mutation-agnostic agent since it acts extracellularly at the receptor level. I wonder if there’s the ability to use amivantamab plus chemotherapy in these patients on progression.
Charu Aggarwal, MD, MPH: A great point. [Dr Dietrich], what are you doing in your practice?
Martin Dietrich, MD, PhD: Well, it depends. The question is, why is a first-line agent no longer working? And obviously, the retesting is part of it. One IHC [immunohistochemistry] that I think is going to be critical based on the data we’ve seen at ASCO [the American Society of Clinical Oncology’s annual meeting] is MET. At the usefulness of amivantamab in the second-line setting in MET overexpressing patients, even MET amplified patients, with the dramatic impact from the response rate by itself of about 60%. So, I think MET is a secondary factor in addition to the mutation. I think the MARIPOSA-2 [NCT04988295] study shows usefulness upon progression on osimertinib, at least in the first-line setting; I think this is now probably the all-comers go-to, which is similar to what you said. If it’s not a T790M, it should probably be chemotherapy.
I think after ESMO [the European Society for Medical Oncology’s annual meeting], it should be chemotherapy plus amivantamab for all-comers. I think that’s the only phase 3–based data. But I think others are coming. I think petitumab had some very good data with very nice response rates in the second-line setting, about 30% had responses. I think we’ve seen some data with datopotamab, even in the first-line setting now, including some of the driver mutations that were very helpful. I think sacituzumab has data in the second-line setting. So the antibody-drug conjugate [ADC] certainly capitalizes on the chemosensitivity of EGFR disease in a broader setting.
Ideally, I would like to understand on a molecular level what is happening and tailor treatment accordingly. But oftentimes that’s not possible. I think MET is currently the only large subgroup that I’m interested in. But we do get at the very least a liquid biopsy. Now with the immunocytochemistry and the markers being so important, I think we need to just acknowledge that even in the second-line setting, the evolving nature of biomarkers does require tissue biopsy, and immunochemistry and tissue is going to reclaim some of the importance from liquid biopsy. I’m not playing them against each other. I think they both have a complementary role. But I think we do need biopsies in the second-line setting for the most optimal treatment.
Unfortunately, MARIPOSA2, like MARIPOSA [NCT04487080], didn’t have a lot of good molecular work yet. I think we’re eagerly awaiting the information as to how patients are responding. Who are those that have the best benefit in the next-line setting? One thing I think that was very surprising to us, the combination of lazertinib and amivantamab didn’t have improved outcomes. For us, the question [of] should we continue a brain-active TKI [tyrosine kinase inhibitor] in the later-line setting kind of got a little bit of a reduced enthusiasm there. I think looking at the ADCs, there’s a brain-active agent that we’ve seen with patritumab and now also with amivantamab, and also gives us some food for thought for the treatment selection in the second-line setting.
Charu Aggarwal, MD, MPH: You’ve highlighted a few very good studies that have just been reported. While they don’t technically call out specifically on common mutations, I think as the molecular data emerges, it will be very informative of our treatment approaches in the future. Dr [Nagashree] Seetharamu, do you do anything differently? Chemotherapy, clinical trial, what’s your preference after afatinib failure?
Nagashree Seetharamu, MD: If there is a clinical trial that would take precedence, I think this is an unmet need. We all, I think, agree with that. But tissue biopsy is critical. Tissue and liquid biopsy is critical. Again, to look at transformation, but look at ISCs [intestinal stem cells], which are not typically, the NGS [next-generation sequencing] just provides us the genomic information. At the protein level, it’s also important to get immunohistochemistry, which was discussed earlier. The sites of progression, I mean, is it possible? If it’s oligoprogression, can we continue on the same agent and address it locally? Is there something extremely important to make sure that we don’t miss that opportunity to just treat the resistant clone at the site where it’s occurring and then continue on the same TKI?
If a clinical trial is not available, if there are no other mutations like MET that was discussed, I add chemotherapy, but I tend to continue the TKI alongside. That’s my practice.
Charu Aggarwal, MD, MPH: I think it’s so important to call out that if it’s oligoprogression, I think many of us use it in our clinic, but I think it’s important to just highlight to use other modalities such as radiation therapy and then think about brain penetration. Dr [Tarek] Mekhail, your thoughts here on progression post afatinib?
Tarek Mekhail, MD, MSc, FRCSI, FRCSEd: I wanted to clarify the discussion because I think we mixed 2 things up during this section. We’re talking about progression after afatinib, and I imagine you’re referring to the uncommon mutations. So, because a lot of the discussion, the focus of the MARIPOSA or the CHRYSALIS [NCT02609776] with amivantamab, lazertinib or amivantamab, plus chemo, plus or minus lazertinib, these are patients for delection-19 or exon-21 or progressing on osimertinib. That’s not what we’re talking about, even though I agree with everything that has been said. But for the patients with uncommon mutations, we actually don’t have much data. We have hardly anything with this new data that were presented, unless I missed something. The CHRYSALIS or the MARIPOSA did not include the uncommon mutations. So, does amivantamab work in these patients? Well, I would go back and about 300% would try to identify the mechanism of resistance.
Conceptually, if you find MET overexpression in one of these patients, I would not argue against using amivantamab, even in the uncommon mutations. But it is actually a data-free zone. I don’t think there are any data in this area. But please correct me if I’m wrong, before the conference call ends. So, understanding the mechanism of resistance is goal, No. 1. And in the absence of clinical trial, I’ve used chemotherapy plus antiangiogenic as a second line, if I don’t have any of the other clinical trials that could target and acquire mechanism resistance. Granted...oligoprogression, etc, I think these things are very, very important to know. Retesting liquid biopsy might give you an indication [of] even either an acquired mechanism of resistance or even transformation. We sometimes see a convolution of TP53, and RB1 and all these might indicate a different histology, including small cell [cancer]. I think trying to understand the mechanism of disease every step of the way is the way to go.
Charu Aggarwal, MD, MPH: Absolutely. I think that sums up our practices, looking at the pattern of progression, how symptomatic the patient may be, where is the progression occurring, as well as rebiopsy and getting as much molecular information as we can; of course, chemotherapy is our default option. But I do think that data for clinical trials, especially with ADCs, and those patients with uncommon mutations who have already been enrolled in these clinical trials, will greatly inform our treatment strategies as these agents become available in the clinic.
Transcript edited for clarity.
