Although many commentaries on studies featured in The ASCO Post call for scrutiny of the fine points, this is not the case for the recent report by Antonia et al in The Lancet Oncology (reviewed in the current issue of The ASCO Post).1 This article serves as a well-deserved victory lap for the authors and anyone who cares for patients with non–small cell lung cancer (NSCLC).
One of the reasons the lung cancer research community refused to abandon the idea of immunotherapy despite persistent failure of the approach in clinical trials—prior to the advent of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/L1) inhibitors—was the promise of durable benefit. The initial reports evaluating PD-L1 inhibitors showed impressive response rates, but the durability of the responses could not be fully appreciated based on the limited follow-up.2-4
These data prove that the theoretical idea that a patient’s immune system could keep a tumor at bay for a prolonged period… is no longer theoretical.— Edward B. Garon, MD
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We have now seen a 5-year survival rate of more than 15% with both nivolumab5 and pembrolizumab.6 Yet these reports looked at single-arm studies, leading to potential bias in patient selection and the inability to definitively demonstrate that the benefit was due to the drug. The report by Antonia et al documents the longest follow-up among patients treated with nivolumab. The long-term data from the original nivolumab trial have been previously reported,5 and the additional follow-up data on the single-arm trial of nivolumab in multiply previously treated squamous cell carcinoma7 add marginally to available data. The power of this report is that we now for the first time see long-term data among 854 patients randomly assigned to nivolumab vs chemotherapy (docetaxel).
Durable Responses: Not Merely the Result of Patient Selection
Although the follow-up time and overall survival percentage among nivolumab-treated patients in the randomized trials are numerically marginally lower than previous reports from single-arm studies, the results are clearly similar. Therefore, the durable responses seen in single-arm trials are not merely the result of patient selection.
More important, the inclusion of patients randomly assigned to a control arm definitively show that the long-term survival is a direct result of treatment with nivolumab. The 4-year survival of patients randomly assigned to docetaxel is 5%, in the range of what would have been expected prior to these trials. The 4-year survival among nivolumab-treated patients, in both the total analyzed population as well as among patients randomly assigned to nivolumab vs docetaxel, is 14%. Among radiographic responders, the median survival exceeded 5 years, and 19% of patients with stable disease at 6 months remained alive with 4 years of follow-up.
Patient selection remains an important issue for PD-L1 inhibitors. The PD-L1 assessment (even at the cut point of 1% expression) identified that patients randomly assigned to nivolumab with PD-L1 expression were more than twice as likely as those without PD-L1 expression (20% vs 9%) to be alive after 4 years of follow-up.
No Longer a Theoretical Idea
This has been a time of rapid incorporation of PD-1 and PD-L1 inhibitors into clinical practice. At least in the United States, the data from this manuscript do not directly help us in the management of the majority of our patients, as PD-L1 inhibitors are generally used in combination with chemotherapy in treatment-naive advanced disease8-10 or as monotherapy in treatment-naive patients with PD-L1 expression.11,12 Yet these data prove that the theoretical idea that a patient’s immune system could keep a tumor at bay for a prolonged period, analogous to what is done with pathogens, is no longer theoretical.
The benefits of immunotherapy in NSCLC are no longer anecdotal and are not limited to single-arm studies with the potential for selection bias. This report by Antonia et al confirms what we already knew. Although there is tremendous work ahead of us—our clinics after nivolumab and similar agents have changed, and while the cause of that change was quite clear prior to this publication—this report definitively identifies the overwhelming driver of that change. ■
DISCLOSURE: Dr. Garon disclosed financial ties with Dracen Pharmaceuticals, Merck, Genentech, AstraZeneca, Novartis, Lilly, Bristol-Myers Squibb, Mirati Therapeutics, Dynavax, Iovance Biotherapeutics, EMD Serono, and Neon Therapeutics.
REFERENCES
1. Antonia SJ, Borghaei H, Ramalingam SS, et al: Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: A pooled analysis. Lancet Oncol 20:1395-1408, 2019.
2. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.
3. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.
4. Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563-567, 2014.
5. Gettinger S, Horn L, Jackman D, et al: Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: Results from the CA209-003 study. J Clin Oncol 36:1675-1684, 2018.
6. Garon EB, Hellmann MD, Rizvi NA, et al: Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: Results from the phase I KEYNOTE-001 study. J Clin Oncol 37:2518-2527, 2019.
7. Rizvi NA, Hellmann MD, Brahmer JR, et al: Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 34:2969-2979, 2016.
8. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078-2092, 2018.
9. Paz-Ares L, Luft A, Vicente D, et al: Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379:2040-2051, 2018.
10. Socinski MA, Jotte RM, Cappuzzo F, et al: Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288-2301, 2018.
11. Reck M, Rodríguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823-1833, 2016.
12. Mok TSK, Wu YL, Kudaba I, et al: Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 393:1819-1830, 2019.
Dr. Garon is Associate Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles.
