Nivolumab/Ipilimumab Plus Two Cycles of Histology-Based Chemotherapy: Another Option in First-Line Metastatic NSCLC

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Introduction of immunotherapy has revealed a paradigm shift in the management of patients with metastatic non–small cell lung cancer (NSCLC) that does not harbor a therapeutically targetable driver mutation. Over the past 5 years, several trials have informed treatment decisions, based on disease characteristics such as histology and tumor PD-L1 expression. We have come a long way from prescribing a platinum-doublet chemotherapy regimen to all. In fact, the question today for our patients is not who should get immunotherapy, but rather who can avoid chemotherapy.

“The question today for our patients is not who should get immunotherapy, but rather who can avoid chemotherapy.”

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As reported in The Lancet Oncology by Paz-Ares and colleagues,1 and reviewed in this issue of The ASCO Post, the CheckMate 9LA trial evaluated nivolumab plus ipilimumab with two cycles of chemotherapy in patients with metastatic NSCLC. It is the latest front-line trial to show a significant improvement in overall survival vs chemotherapy alone. Patients with squamous and nonsquamous histologies were included and received only two cycles of chemotherapy upfront combined with dual checkpoint blockade followed by maintenance nivolumab and ipilimumab until disease progression. This regimen has now been approved by the U.S. Food and Drug Administration (FDA) and is included in national treatment guidelines.

New Treatment Paradigm for Select Patients

Although this regimen has not been compared in a head-to-head fashion with other chemoimmunotherapeutic approaches in this setting (such as pembrolizumab plus chemotherapy in KEYNOTE-189 and KEYNOTE-407 or atezolizumab plus chemotherapy in IMpower130 and IMpower150) or single-agent immunotherapy approaches (such as pembrolizumab in KEYNOTE-24 and atezolizumab in IMpower110), combining distinct immunotherapies with complementary mechanisms of action does represent a new strategy and perhaps a new treatment paradigm for a select subgroup of patients.

For starters, this regimen may be best suited for patients who express a desire to pursue a “chemotherapy-free” intervention or do not wish to sustain the long-term side effects of chemotherapy. Surely, such an approach already exists: The CheckMate 227 trial demonstrated an overall survival benefit for nivolumab plus ipilimumab compared with chemotherapy and was approved by the FDA as a first-line treatment option in patients with NSCLC with PD-L1 expression of at least 1%. However, the addition of an abbreviated chemotherapy course upfront may offer early disease control, as was evident in the initial separation of curves seen in the CheckMate 9LA trial and not seen on the CheckMate 227 trial.

Whether this will translate into a long-term benefit remains to be seen. It is important to remember that ‘chemotherapy free’ does not necessarily translate into “toxicity free,” as immunotherapy combinations can be associated with significant toxicities, including autoimmune-related hepatic toxicity, acute renal failure, and pneumonitis. These effects can be fatal when not quickly identified and managed.

We have made significant advances in the management of patients with NSCLC. However, to maximize the benefits of these therapies, we simultaneously need to develop biomarkers that can help us select patients and personalize their first-line immunotherapy regimen. 

Dr. Aggarwal is Associate Professor for Lung  Cancer Excellence the Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

DISCLOSURE: Dr. Aggarwal has served as a consultant or advisor to AstraZeneca, Blueprint Genetics, Celgene, Daiichi Sankyo/AstraZeneca, Genentech, Lilly, Merck, and Shionogi; has an immediate family member who has participated in a speakers bureau for AstraZeneca and Roche/Genentech; and has received institutional research funding from AstraZeneca/MedImmune, Genentech/Roche, Incyte, MacroGenics, and Merck Sharp & Dohme.


1. Paz-Ares L, Ciuleanu TE, Cobo M, et al: 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. Lancet Oncol 22:198-211, 2021.

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