Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non–Small-Cell Lung Cancer in CheckMate 227

Author(s): Julie R. Brahmer, MD¹; Jong-Seok Lee, MD, PhD²; Tudor-Eliade Ciuleanu, MD, PhD³; Reyes Bernabe Caro, MD, PhD⁴; Makoto Nishio, MD, PhD⁵; Laszlo Urban, MD⁶; Clarisse Audigier-Valette, MD⁷; Lorena Lupinacci, MD⁸; Randeep Sangha, MD⁹; Adam Pluzanski, MD, PhD¹⁰; Jacobus Burgers, MD, PhD¹¹; Mauricio Mahave, MD¹²; Samreen Ahmed, MD¹³; Adam J. Schoenfeld, MD¹⁴; Luis G. Paz-Ares, MD, PhD¹⁵; Martin Reck, MD, PhD¹⁶; Hossein Borghaei, DO, MS¹⁷; Kenneth J. O’Byrne, MD, PhD¹⁸; Ravi G. Gupta, MD¹⁹; Judith Bushong, BS¹⁹; Li Li, MS, DPH¹⁹; Steven I. Blum, MBA¹⁹; Laura J. Eccles, PhD¹⁹; and Suresh S. Ramalingam, MD²⁰

Source: DOI: 10.1200/JCO.22.01503 Journal of Clinical Oncology 41, no. 6 (February 20, 2023) 1200-1212.

Dr. Maen Hussein's Thoughts

Combination immunotherapy beats chemotherapy, there is no data to compare against a chemo immunotherapy combination, but is an option for patients who may not tolerate chemotherapy.

PURPOSE

We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status.

METHODS

Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life.

RESULTS

At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed.

CONCLUSION

With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer.

Author Affiliations

¹Johns Hopkins Kimmel Cancer Center, Baltimore, MD;²National University Bundang Hospital, Seongnam, Republic of Korea;³Institutul Oncologic Prof Dr Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania;⁴Hospital Universitario Virgen Del Rocio, Instituto de Biomedicina de Seville, Seville, Spain;⁵Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan;⁶Matrai Gyogyintezet, Mátraháza, Hungary;⁷Orientation Oncologique, Hôpital Sainte Musse, Toulon, France;⁸Hospital Italiano De Buenos Aires, Buenos Aires, Argentina;⁹Cross Cancer Institute, Edmonton, AB, Canada;¹⁰Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland;¹¹Netherlands Cancer Institute, Amsterdam, the Netherlands;¹²Instituto Oncológico Fundación Arturo López Pérez, Santiago, Chile;¹³University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester, United Kingdom;¹⁴Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY;¹⁵Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Clinical Research Unit, Universidad Complutense & CiberOnc, Madrid, Spain;¹⁶Airway Research Center North, German Center for Lung Research, Lung Clinic, Grosshansdorf, Germany;¹⁷Fox Chase Cancer Center, Philadelphia, PA;¹⁸Princess Alexandra Hospital, Translational Research Institute and Queensland University of Technology, Brisbane, Queensland, Australia;¹⁹Bristol Myers Squibb, Princeton, NJ;²⁰Winship Cancer Institute, Emory University, Atlanta, GA

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The combination therapy demonstrated improved overall survival (a 25% reduction in mortality) but was associated with increased toxicity, including skin rash and venous thromboembolic events (VTEs). Single-agent osimertinib may lose its role as monotherapy for EGFR-mutated NSCLC, as the FLAURA2 trial showed that combining osimertinib with chemotherapy yielded better outcomes than osimertinib alone.

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.