Impact of Molecular Testing on First-Line Treatment Decisions in NSCLC

Published Online: Friday, October 18, 2013
During an OncLive Peer Exchange video roundtable discussion held in the spring of 2013, the following five lung cancer experts discussed recent advances and current issues surrounding the treatment of non-small cell lung cancer (NSCLC): David R. Gandara, MD, director of the Thoracic Oncology Program at University of California Davis Cancer Center; Corey J. Langer, MD, director of Thoracic Oncology at Abramson Cancer Center of the University of Pennsylvania; Alan B. Sandler, MD, principal medical director at Genentech (formerly at Oregon Health & Science University); Mark A. Socinski, MD, director of the Lung Cancer Section at University of Pittsburgh; and Anne S. Tsao, MD, director of the Thoracic Chemo-Radiation Program at The University of Texas MD Anderson Cancer Center. In part one of this series, the faculty discussed several issues surrounding the impact of molecular testing on upfront treatment decisions for patients with advanced NSCLC.
Dr. David R. Gandara

David R. Gandara, MD

Professor of Medicine Division of Hematology and Oncology Director, Thoracic Oncology Program, Associate Director, Clinical Research, UC Davis Cancer Center Sacramento, CA

Concurrent or Sequential Molecular Testing?

Dr Gandara: Corey, I know you raised the issue about concurrent versus sequential testing. Our thinking is evolving for symptomatic patients with stage IV disease, because if you test first for EGFR mutation and then wait for the results, and then have to test for EML4-ALK, etc, a lot of time can go by. How do you decide on an individual patient basis whether you will test concurrently or sequentially?

Dr Langer: We routinely perform molecular testing concurrently for at least EGFR and EML4-ALK. The big issue is the timing. We ideally like to get these results within 1 to 2 work weeks. If patients are highly symptomatic and very ill with a declining performance status and the test results are not back yet, I’ll start them on chemotherapy. For these patients, we don’t really have the luxury of waiting.

Stay the Course With Chemotherapy or Switch to EGFR Inhibition?

Dr Langer: The big dilemma, of course, is what to do after these patients have received a cycle or two of chemotherapy and their disease has stabilized or improved, and the test results are positive for EGFR mutation. Should we switch to erlotinib at that point or should we see them through the course of chemotherapy and then perhaps use erlotinib as a maintenance approach or even integrate it later on in the second-line setting? I don’t think we have a firm grasp on the optimal approach.

Dr Gandara: What would you do?

Dr Langer: If patients are doing well on chemotherapy, I will actually maintain them on chemotherapy for 4 to 6 cycles and then go on to maintenance therapy. Depending on the nature of their response, how symptomatic they were at presentation, and how well they’re tolerating the chemotherapy, I will choose either switch maintenance (use of an agent for maintenance that was not used in the first-line setting) or continuation maintenance (use of a component of the first-line agents for maintenance). If they’ve had a tough time with the chemotherapy, I’ll typically go on to erlotinib maintenance. Certainly, the SATURN trial showed a major progression-free survival (PFS) advantage for erlotinib maintenance in patients with EGFR-mutated disease (see NSCLC trials).1,2 That hazard ratio is down around 0.1,2 which is really one of the most striking results I’ve ever seen. Therefore, deciding how to treat patients in this situation is a big dilemma, but it’s a better dilemma to have than we have had in the past (ie, before the advent of erlotinib, bevacizumab, pemetrexed, crizotinib, and afatinib). Dr Sandler:I would echo that. I am a firm believer that you should complete the chemotherapy evaluation, at least to 2 cycles. The response rate for EGFR inhibition in EGFR-mutated disease is approximately 70%,3 but if your patient responds, that’s 100% for that patient and, prognostically, patients with EGFR-mutated disease do better with chemotherapy than those with EGFR-wild-type disease (see NSCLC trials sidebar— IPASS).4 So, I get those 2 cycles in and then if they’re doing well, I continue as I would without knowing their EGFR mutation status and then I would make that same assessment you did, Corey, and would probably use erlotinib as maintenance.

Important NSCLC Trials of EGFR Inhibitors

SATURN trial:A phase III trial that examined the addition of maintenance erlotinib after first-line chemotherapy with a platinum doublet in patients with advanced NSCLC. Median progression-free survival (PFS) was significantly but modestly longer with erlotinib than with placebo (12.3 weeks vs 11.1 weeks; hazard ratio [HR] = 0.71; P < .0001).1 However, in the EGFR mutation-positive subgroup, erlotinib had a profound predictive effect on PFS compared with placebo (HR = 0.10; P < .001).2
IPASS trial: A phase III trial that compared gefitinib to carboplatin/paclitaxel in previously untreated patients in East Asia with advanced adenocarcinoma. The gefitinib group showed a PFS advantage compared with the chemotherapy group (HR = 0.74; P < .001).4 Among the patients with EGFR-mutated disease, PFS was significantly longer for gefitinib compared with chemotherapy (HR = 0.48; P < .001).4 Compared with EGFR-wild-type disease, those patients with EGFR-mutated disease had a higher response rate to chemotherapy (47.3% vs 23.5%).4
EURTAC trial: A phase III trial that compared first-line erlotinib to doublet chemotherapy in patients with advanced EGFR-mutated (exon 19 or exon 21) NSCLC. Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the chemotherapy group (HR = 0.37; P < .0001).5 First-line erlotinib produced a grade 1/2 rash in 67% of patients and grade 3 rash in 13% of patients.5
LUX-Lung 3 trial: A phase III trial that compared afatinib with cisplatin/pemetrexed in patients with advanced EGFR-mutated adenocarcinoma. Based on its PFS advantage over cisplatin/pemetrexed (HR = 0.58; P = .0004),13 afatinib recently earned FDA approval for patients with EGFR-mutated disease. When only patients with the common exon 19 and 21 mutations were examined, the HR was 0.47.13
Dr Langer: It’s intriguing. If you look at survival from the EURTAC trial in the setting of EGFR mutation, whether erlotinib was used first- or second-line after chemotherapy failed, the survival was essentially the same (see NSCLC trials sidebar).5 This echos prior data from Rosell et al published in NEJM, where survival seemed to be identical whether EGFR TKIs were given first- or second-line.
 
Dr Socinski: And I think part of the art of managing advanced NSCLC now is not abandoning prematurely therapies that are working. For a patient with a very nice symptomatic, radiographic response to chemotherapy, I would have no problem continuing that treatment, followed by some form of maintenance. Then, as shown by the EURTAC results,5 you have a very good second-line treatment—erlotinib—for that particular patient. So, I don’t think getting an EGFR-positive test result necessarily mandates that you switch to erlotinib. Remember, erlotinib is a convenient drug, but it has its share of toxicities (see NSCLC trials sidebar—EURTAC).5 Dr Langer: I agree, it can be quite toxic. I just saw a patient yesterday who had a grade 3 rash. He’s thrilled because his disease is essentially in complete remission, but, to be frank, he’s had a bit more toxicity on erlotinib than he had on prior chemotherapy.

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