Future Directions for Precision Medicine in Advanced NSCLC - Episode 5
Transcript:Benjamin P. Levy, MD: We talked a lot about targeted therapies in the advanced stage setting. It’s been impressive to see the improvements in outcome, PFS [progression-free survival]. Now we see OS [overall survival], and perhaps underrated in some of these trials, is quality of life improvement. But we’re not curing patients. I think that’s important. We’re making huge strides in the advanced setting. The question is, can we use these same drugs to cure patients or help cure patients, specifically for early stage lung cancer patients. We had a trial recently, a phase II trial. MJ [Mohammad Jahanzeb, MD, FACP], do you want to walk us through that trial—the adjuvant gefitinib [Iressa] versus cisplatin-based chemotherapy for surgically resected EGFR-mutant lung cancer?
Mohammad Jahanzeb, MD, FACP: Sure. So, this was a Chinese multicenter study, reported by Dr [Wenzhao] Zhong [MD, PhD]. And, in that study, they randomly assigned patients to adjuvant therapy with gefitinib instead of chemotherapy—that’s a basic difference—or 4 cycles of adjuvant platinum-based chemotherapy. So, this is very different from some of the studies where everybody got 4 cycles of chemotherapy and then were randomized to observation, versus TKI [tyrosine kinase inhibitor therapy such as in the RADIANT trial. The other major difference with RADIANT, was it was unselected patients, and they had to do a subset analysis of EGFR-positive subset. So, in this mutated population, the 2 main EGFR mutations—exon del 19 and L858R—these patients got gefitinib for 2 years; so a predefined duration, or they got the standard cisplatin-based chemotherapy.
The main endpoint was time to relapse, and there was a 10-month difference—18 months to 28 months in favor of gefitinib. However, what happens after you stop it 2 years later, we don’t know yet. There is no mature overall survival data yet, so I don’t think this is a practice-changing result so far, but intriguing. In the United states, as we all know, we have the ALCHEMIST trial and that is different because everybody gets 4 cycles of chemotherapy. And then according to the mutation, whether it’s EGFR or ALK, they get targeted therapy for 2 years or observation.
Benjamin P. Levy, MD: Is anyone using adjuvant TKI off a clinical trial, in EGFR-mutated lung cancer?
Lyudmila A. Bazhenova, MD: No.
Anne S. Tsao, MD: No.
Benjamin P. Levy, MD: OK. I briefly want to go back. We talked a lot about sensitizing mutations and drugs that work against sensitizing mutations. But there are also uncommon EGFR mutations that do occur, and we have some data emerging that osimertinib [Tagrisso] may be active with uncommon EGFR mutations. Lyudmila, do you want to briefly walk us through that?
Lyudmila A. Bazhenova, MD: Yes. So, we know that not all EGFR mutations are the same. What we have been discussing up to this point is data or products which work for sensitizing mutations; which are del 19 and L858R. However, there are other mutations which comprise approximately 12% of all EGFR mutations which mostly happen in codon 18, and those are L851Q, G719X, and C7681. We know, based on the preclinical data, that traditional first-generation EGFR tyrosine kinase inhibitors do not work very well for those mutations, and you need higher concentrations to inhibit cell lines with those mutations. We also know from preclinical data that afatinib [Gilotrif] seems to require lower concentrations to inhibit those mutations and so does osimertinib. Afatinib currently has an approval for patients with atypical EGFR mutations based on a combined analysis of LUX-Lung trials, which showed overall response rate of approximately 71%. And it’s interesting also that those 3 different mutations that I just mentioned, they actually have differential sensitivity to afatinib.
There is one mutation, which is L861Q, which seems to be more sensitive to osimertinib in the preclinical data, and that was the reason to do an osimertinib study in atypical mutations. And it showed efficacy. It was a small number of patients, about 36. The overall response rate was about 50%. The progression-free survival was slightly over the 9 months. But the mutation that had the most activity with osimertinib was L861Q with a response rate of 77%. Other mutations had a response rate between 30[%] and 50%.
So, the practical point is, when you’re looking at your molecular testing report, don’t just say EGFR mutation is detected. You need to know which EGFR mutation is detected. Because if it’s atypical mutation, I definitely would not use gefitinib or erlotinib. Before, I used to use afatinib, but now with the data on osimertinib—and we know for those of us who’ve actually given both drugs—it is a little bit better tolerated than afatinib. So, now I think this presentation that was presented at [the IASLC 19th] World [Conference on] Lung [Cancer] makes me want to switch from my afatinib go-to drug for atypical mutations, to osimertinib.
Transcript Edited for Clarity