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Ipilimumab-nivolumab combo as 2L does not improve survival for immunotherapy naive NSCLC

Checkpoint inhibitors have become a mainstay in treatment of lung cancer, especially due to the use of biomarker testing in patients. Recently, the combination of nivolumab and ipilimumab was demonstrated to be superior to platinum-based chemotherapy in treatment naïve NSCLC in Checkmate 227 [1]. Furthermore, in CheckMate 9LA, nivolumab plus ipilimumab with two cycles of chemotherapy significantly improved overall survival compared to chemotherapy alone [2].

Designed as a biomarker-driven study, the Lung Cancer Master Protocol (Lung-MAP) aims to quickly and efficiently evaluate the benefit of molecularly targeted therapies for advanced non-small cell lung cancers (NSCLC). It is the first precision medicine trial in lung cancer to be supported by the National Cancer Institute (NCI). Additionally, it is the first major NCI trial to utilize an “umbrella” design in which multiple treatments are being evaluated concurrently. Patients enrolled in the study complete a genomic profile to determine if they have any alterations or mutations and are then matched to a treatment based on their profile. If a patient does not have a genomic match to any of the trials, they are given the option to receive the immunotherapy treatments that are being evaluated in the trials.

The second sub-study within Lung-MAP (NCT02785952) was for patients who did not qualify for a “matched trial. It aimed to determine if the same combination of nivolumab-ipilimumab vs. nivolumab alone would improve overall survival as second-line therapy in patients with recurrent stage IV squamous cell lung cancer and no biomarker matched trials. The results of the study were recently published in JAMA Oncology. At the time the study began, nivolumab had not yet approved as initial therapy in patients with advanced NSCLC.

252 patients enrolled in the Phase 3 trial from 58 institutions in the US through the National Clinical Trial network and were randomized 1:1 to nivolumab or the combination of nivolumab-ipilimumab. The median follow-up in surviving patients in both groups was 29.5 months (95% CI, 26.0-32.8 months). The primary endpoint of overall survival was not significantly different between groups (HR, 0.87; 95% CI, 0.66-1.16; P = .34). The median survival was 10 months (95% CI, 8.0-14.4 months) for the nivolumab-ipilimumab combination and 11 months (95% CI, 8.6-13.7 months) for nivolumab alone. Median investigator assessed progression-free survival was 3.8 months (95% CI, 1.8-4.0 months) for the combination and 2.9 months (95% CI, 1.8-4.0 months) for nivolumab alone. The combination had a median response duration of 28.4 months (95% CI, 4.9 months to not reached) compared to 9.7 months (95% CI, 4.2-23.1 months) for nivolumab alone. 39.5% of patients who received the combination had a grade 3 or higher treatment-related events compared to 33.3% in the nivolumab. Additionally, 25% of patients receiving the combination discontinued due to toxic effects compared to 15% in receiving nivolumab only.

Biomarker analysis from PD-L1 expression and tumor sequencing did not identify any tumor characteristics that would predict a benefit from the combination therapy. The study did find, however, that patients with no tumor PD-L1 expression and high TMB would have a benefit from the combination therapy.

While the study does admit the question posed for the trial is no longer relevant given that most patients with advanced NSCLC will be given first-line immunotherapy, they do discuss the need to understand the differences between each of the PD-1 inhibitors and whether utilizing combination therapy with anti-CLTA-4 agents could provide benefit in first-line treatment.

At MEDSIR, we are also evaluating combination immunotherapy approaches in lung cancer with our LUPER study of lurbinectedin and pembrolizumab in patients with relapsed small cell lung cancer. To learn more about our exciting trials in lung cancer and more, contact us!


1. M.D. Hellmann, L. Paz-Ares, R. Bernabe Caro, B. Zurawski, Kim SW, Carcereny Costa, K, Park, A, Alexandru, L. Lupinacci, E. de la Mora Jimenez, H. Sakai, I. Albert, A. Vergnenegre, S. Peters, K. Syrigos, F. Barlesi, M. Reck, H. Borghaei, J.R. Brahmer, K.J. O’Byrne, W.J. Geese, P. Bhagavatheeswaran, S.K. Rabindran, R. S and SSR. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381:2020–2031.

2. L. Paz-Ares, T.E. Ciuleanu, M. Cobo, M. Schenker, B. Zurawski, and J. Menezes. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. The Lancet. 2021. DOI:



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