Advances in Targeted Therapies for Non-Small Cell Lung Cancer - Episode 8

First- and Second-Line Treatment Options for Patients with mNSCLC and an EGFR Exon 20 Mutation

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The panel reviews the first- and second-line treatment options for the patient in the presented case, before and after knowing her molecular testing results.

Joel Neal, MD, PhD: Let's say this patient was feeling symptomatic, anxious, something happened to the tissue and the liquid biopsy was negative as it is, somewhere around 10% to 20% of the time for an actual biomarker so we have to say, let's wait for the NGS for a few weeks. The decision was made to start treatment with carboplatin and pemetrexed. Zosia, what would the first-line treatment option be for this patient if they were symptomatic in your opinion?

Zosia Piotrowska, MD: I would agree with this decision. Even with high PD-L1, I think the biggest risk that we run into in these patients, and the reason truthfully that we're so eager to wait for the molecular testing is when we use upfront immunotherapy for patients and then find them to have an oncogene driver and make try to make the switch to a targeted therapy. We know from a variety of different targeted therapy agents, Osimertinib being the most commonly cited one where we know that there's a higher risk of autoimmune toxicities and specifically pneumonitis when Osimertinib is given to patients immediately following immunotherapy. We've also seen similarly, for example, with crizotinib and increased rates of hepatitis, and I think we'll see higher rates of toxicities when we use many TKIs after immunotherapy. The key thing is, even despite the high PD-L1, in this case, until I have the NGS back, I would do everything I can to wait to initiate immunotherapy. I think the way to do that is to initiate chemotherapy where you may ultimately find that you have something that you think is more likely to be effective for this patient, but you probably won't have shot yourself in the foot in terms of being able to pivot to that if the NGS testing does come back with an oncogene driver. For those reasons, I think starting with carboplatin, pemetrexed can be a great way to initiate therapy. Patients who are symptomatic and who need to start, we will often do that. Withhold the immunotherapy from cycle 1, wait for that NGS testing to result, which usually can happen within the three weeks before they come back for cycle 2. Then if they don't have a targetable oncogene, you can feel comfortable then adding in the immunotherapy with cycle 2.

Joel Neal, MD, PhD: Absolutely. For this patient, wouldn't you know it, the day after we start chemotherapy, the testing comes back and shows an EGFR Exon-20 insertion. Even though we were hoping or wanted to explain that we were profiling for everything actionable, but maybe secretly hoping for one of those classic sensitizing EGFR mutations, the EGFR Exon 20 insertion is a different kind of mutation overall. These were described at the same time as we used to do sequencing across the whole EGFR gene but unlike EGFR Exon-19 deletions and the common L858R mutation in Exon-21, the Exon-20 insertions are not generally sensitizing to those TKIs that we have. The first, the second, and the third generation EGFR TKIs with some exceptions that we'll get into for the data. Michelle, how often do you see these EGFR Exon-20 insertions across molecular profiling? Are they easy to detect from a molecular pathology point of view?

S. Michelle Shiller, DO, AP/CP, MGP: With respect to targetable mutations in EGFR in non-small cell lung cancer, largely adenocarcinoma, the vast majority are going to be your L858R mutation in your Exon-19 deletion. That's going to represent upwards of 80% of the alterations you're going to see. Then you have a whole host of other less common EGFR alterations. Exon-20 insertion is one of those. As you said, it doesn't tend to respond to those first, second, and third-generation tyrosine kinase inhibitors and so it permits a need for a different approach. With respect to testing approach, PCR-based assays are prone to potentially miss 50% of your Exon-20 insertions because PCR-based assays can only answer specific questions that are asked. If the question is broader and there's a lot of different types of Exon-20 insertions, it's like if you understand, and all of these biomarkers have their own personality, so that's another interesting thing in this whole space. But ALK, we know the ALK gene is, as they say, in fidelitous with its rearrangement partners or the NTRK family of genes. To make a PCR-based assay that could cover all of those possibilities would be very, very complex and require an enormous amount of tissue. That's where next-generation sequencing, which can sequence through those regions is going to be more sensitive and more likely to detect your Exon-20 insertion and not miss something versus a PCR-based assay.

Joel Neal, MD, PhD: This patient was started on chemotherapy. Now that we know that the patient has a tumor with an EGFR Exon-20 insertion, 769, 770 insertion mutation, what do we think about, Lauren in terms of treatment options? Should we switch from chemotherapy, go to other agents, or stay the course for now?

Lauren Welch, MSN, NP-C, AOCNP: Well, I think it's a unique question given the answer would be different if it was a different EGFR mutation. I think since this is an Exon-20 insertion mutation and our two approved therapies in this space are after platinum chemotherapy, we probably would proceed with that second cycle of chemotherapy if they were tolerating it well and see if they're responding and kind of reserve our Exon-20 insertion targeted therapies to time of progression. I think in this patient's case, it sounds like they're on the right track.

Joel Neal, MD, PhD: I'm a big fan of the, let's stay the course and scan early, maybe around six weeks and see if it's actually working. In this case, the patient did, and after six weeks of treatment total of carboplatin-pemetrexed, the tumor was shrinking pretty dramatically, 50% reduction in all the areas, symptoms were getting better. Then this EGFR Exon-20 mutation was observed.