Future Directions for Precision Medicine in Advanced NSCLC - Episode 4

Frontline Chemo and TKI Combination in EGFR+ NSCLC

Transcript:Benjamin P. Levy, MD: Let’s talk about some combination approaches in the EGFR space. I’ve always believed that we should be using targeted therapies and sparing our patients chemotherapy, which was the whole concept behind precision medicine. But we had some very interesting data at ASCO [American Society of Clinical Oncology Annual Meeting] this year looking at the combination of chemotherapy with a TKI versus TKI alone in patients with EGFR mutation.

Shirish M. Gadgeel, MD: This study, the NEJ009, is a cooperative group from Japan, with Dr Nakamura as the principal investigator. They presented a phase III study comparing gefitinib monotherapy versus gefitinib plus carboplatin and pemetrexed—a triplet combination in patients with EGFR mutations. I was most impressed with this study because of the unexpected results: Patients who had EGFR mutations—sensitive mutations exon del19, L858R, and 21—were randomized to gefitinib or gefitinib plus chemotherapy, standard doses of all 3 agents, and there were no dose interruptions in the triplet combination.

The primary endpoint was overall survival, unlike most studies similar to this one, designed for a progression-free survival benefit. They also had 2 other endpoints: a consideration of progression-free survival 1—the time to progression from treatment initiated to first documented progression—and progression-free survival 2—the point after the first progression and whichever treatment they received subsequently. In the gefitinib arm, they had to receive carboplatin/pemetrexed; they assessed the progression-free survival as well.

Concerning the primary endpoint, the study yielded an improvement in overall survival with a hazard ratio that translated to about 0.7.

Shirish M. Gadgeel, MD: [It was] 0.69, which translated to a median progression-free survival of 20 months with the combination of gefitinib and chemotherapy and only 10 months with patients taking gefitinib. What was most interesting, however, was, when looking at the progression-free survival 1 and progression-free survival 2, the progression-free survival 1 exhibited the difference with the triplet combination compared with gefitinib. Once the patient progressed, the second progression-free survival was equivalent within the 2 arms, indicating a need for a more complete therapy in the beginning, to produce an improvement in overall survival. By giving the triplet therapy, I presume, you’re targeting multiple different clones that may not be as well targeted by a single-agent EGFR TKI—hence the survival improvement.

In the single-agent gefitinib, the median survival rate was as expected, at about 38 months, whereas with the triplet combination, the median was 52 months, suggesting a profound improvement.

Anne S. Tsao, MD: This made huge waves, right? My argument is that this is using gefitinib.

Shirish M. Gadgeel, MD: Correct.

Anne S. Tsao, MD: It is not comparing or using osimertinib, which we now largely use as our standard of care. While I understand that yes, it’s a positive trial, I have a hard time thinking that this can be implemented in the United States.

Mohammad Jahanzeb, MD, FACP: Are you going to take the leap of faith and use osimertinib with carboplatin/pemetrexed?

Anne S. Tsao, MD: No.

Shirish M. Gadgeel, MD: I completely agree. At present, these are certainly interesting data. One has to at least consider the medians; they are no different [from what] one would see with osimertinib alone. I’d rather give a single pill and IV [intravenous] chemotherapy; however, it raises 2 two prospects: (1) that maybe we will see even better outcomes if you combine chemotherapy with osimertinib and (2) that there may also be value in combination treatments and a better understanding of the biology of the tumor—identifying good partners beyond chemotherapy to improve upon the current standard of care.

Lyudmila A. Bazhenova, MD: It certainly opens our options for more trials. But I agree with Anne that at this point, I don’t think this changes my practice. Should there be a trial knocking on my door, however, randomizing patients to osimertinib versus osimertinib to chemotherapy, I would certainly consider it as an option.

Benjamin P. Levy, MD: I’m torn by these data: I am overwhelmed by the survival medians and seeing that type of difference, which is meaningful for patients. However, philosophically, are we moving backward by adding chemotherapy to everything? We’ve learned in [KEYNOTE]-189 to just add chemotherapy. This is not the topic that we’re going to handle with immunotherapy but rather: Is adding chemotherapy to targeted therapy showing improvement? It runs against, to a degree, the precision medicine paradigm. But it does highlight what we’re extracting from tumor biology, tumor heterogeneity, and subclonal events that are happening up front, which may be wiped out by chemotherapy and touched by the targeted therapy.

Anne S. Tsao, MD: My argument, again, is that we don’t know with osimertinib: It may be totally fine, and then [we] introduce chemotherapy later when they progress and you put those clones down. We shouldn’t make any extrapolations here.

Mohammad Jahanzeb, MD, FACP: We are at least sure about 1 clone that suppresses T790M, in addition to the EGFR-sensitive populations.

Benjamin P. Levy, MD: The common message is that osimertinib still remains the standard. Considering clinical trials, chemotherapy should not be added to this drug but rather in a sequential fashion.

Transcript Edited for Clarity