Q&A with Lead ALCHEMIST Investigator, Dr. Ramaswamy Govindan

Dr. Ramaswamy Govindan

Posted: May 27, 2019

ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) is a large umbrella trial evaluating patients with early-stage NSCLC who have undergone complete tumor resection. As a whole, the trial will examine the role of erlotinib for those patients with EGFR mutations, crizotinib for those patients who have ALK rearrangements, and nivolumab for patients with no EGFR mutations or ALK rearrangements. Ramaswamy Govindan, MD, Anheuser Busch Endowed Chair in Medical Oncology, professor of medicine in the Division of Oncology, and director of the Section of Medical Oncology at Washington University School of Medicine, spoke with the IASLC Lung Cancer News regarding ALCHEMIST’s trial design in comparison with other, similar trials in Asia, as well as the optimal duration of therapy in this setting. Dr. Govindan, who is the lead investigator of the EGFR portion of ALCHEMIST, highlights unanswered questions and controversies, as well as recent accrual statistics.

Q: SELECT—part of the rationale for ALCHEMIST—showed promising PFS, but a sharp drop-off after 2 years when the study drug was stopped. The same was true in a RADIANT subset analysis of patients with EGFR mutations and in a Canadian trial evaluating gefitinib in the adjuvant setting. This all leads to the question of whether 2 years of a TKI is sufficient in the adjuvant setting. Your thoughts?
A: That’s a great question. The problem is that compliance is always a challenging issue in patients who have undergone a major surgery like thoracotomy. These patients go through not only surgery but also, most of the time, receive adjuvant chemotherapy with or without radiation. We feel that the longer duration of therapy would result in poor compliance. At some point, we have to just pick a duration; I think 2 years is a reasonable starting point. Much like what happened with endocrine therapy in breast cancer, no one knows what the optimal duration is at this point. In reality, however, these therapies have long-term side effects, such as malaise and dermatologic toxicities. If you can get patients to take 2 years of therapy, I think it’s a good place to start. Future studies may have to address the question of the optimal duration of therapy. Let us crawl before we can walk. ALCHEMIST will be the first randomized trial to really look at the role of EGFR TKIs following standard therapy.

Q: Are EGFR TKIs effective when there is disease relapse, particularly after prior exposure in the adjuvant or neoadjuvant setting?
A: I think that we know, to some extent, that if patients relapse after adjuvant therapy, they may still benefit from EGFR TKIs based on the limited data we have. But post-ALCHEMIST, we will probably know a lot more about this. I suspect that (the potential benefit) will have to a lot to do with the interval time off therapy and what resistance mechanisms exist. For example, if a patient has a EGFR T790 mutation at the time of relapse, he or she will not respond well to erlotinib; if no EGFR T790 mutation is present, patients may respond well.

Q: In ALCHEMIST, is a tissue or liquid biopsy performed at the time of relapse and, if so, what molecular events are being examined?
A: We are collecting those specimens whenever possible, but we cannot mandate them for various reasons. At the time of disease progression, we encourage physicians to get tissue biopsies. If there is a sufficient amount of tissue in a specimen, we can do a comprehensive unbiased whole-exome analysis. When patients experience disease progression, they come off the study, so there is no way to mandate their cooperation regarding biopsies and lab results unless there is a follow-up study on which the patient can enroll.

Q: No study to date of an EGFR TKI in the adjuvant setting has demonstrated an OS advantage. Investigators in Japan and China are conducting several trials, but they are substituting TKIs for chemotherapy, which may be a misguided approach. Is there really a role for TKIs in the adjuvant setting, or are we studying them correctly?
A: In my opinion, the studies are somewhat overlapping and provide useful information at different levels. In general, the studies out of Asia have randomized patients after surgery to chemotherapy or EGFR TKI, whereas in ALCHEMIST we are building on our previous (modest) success with chemotherapy. I think there are two different models to test: one asks what EGFR TKIs can add on top of the proven adjuvant, chemotherapy; the other model asks whether TKIs can replace chemotherapy. I’m actually somewhat agnostic as to what is the best approach. We may also learn a lot about the side effects of EGFR TKI, tolerance, and compliance in these two different populations.

Q: As part of ALCHEMIST, the TKI components of the trial are accruing slowly, so its feasibility is in question. In stark contrast, ANVIL, which is also part of ALCHEMIST and which compares nivolumab to observation in EGFR wild-type NSCLC, is accruing “like gangbusters.” Your thoughts?
A: A patient cannot go on the ANVIL study if they have EGFR mutation or ALK rearrangement. It is important to keep in mind that there are many more patients who do not have EGFR mutations or ALK rearrangements in early-stage NSCLC. As of January 4, 2019, the number of patients registered to the ALCHEMIST screening trial was 4,092; the number of patients registered to the EGFR portion was 248. ALK registration included 79 patients. This study has been open at more than 1,000 centers in the United States, and I am incredibly impressed and grateful to the leadership at the National Cancer Institute for supporting this study even when accrual was going slowly. We recently crossed the halfway mark for enrollment and are very encouraged by the pace of enrollment now.

Q: Finally, ALCHEMIST uses “yesterday’s” drugs; if we had started the trial today, we’d have used osimertinib in lieu of erlotinib and alectinib in lieu of crizotinib. So, even if the trial demonstrates positive results, one wonders how relevant they are; if the results are negative, might we have done better with newer, more effective, less toxic agents. Comments?
A: This is the reality of drug development and clinical trials. ALCHEMIST trial was conceived nearly 10 years ago. At that time, erlotinib was the only approved drug for EGFR-mutated lung cancer. It took some years to get the trial approved through various agencies, during which time newer drugs came along. We debated a few times whether we should continue the current strategy or change the study drug. We decided, I think correctly, that we will complete the study based on the original design. The same applies for the ALK study as well. There will be industry-led studies looking at osimertinib in the adjuvant setting. In addition, we are conducting a number of scientific studies— for example, the whole-genome and whole-exome analyses of the resected specimens as part of the ALCHEMIST screening—and we will learn quite a bit from those as well. ✦