Perioperative Nivolumab in Resectable Lung Cancer

Author(s): Tina Cascone, M.D., Ph.D., Mark M. Awad, M.D., Ph.D., Jonathan D. Spicer, M.D., Ph.D., Jie He, M.D., Ph.D., Shun Lu, M.D., Ph.D., Boris Sepesi, M.D., Fumihiro Tanaka, M.D., Ph.D., Janis M. Taube, M.D., Robin Cornelissen, M.D., Ph.D. https://orcid.org/0000-0002-4289-3092, Libor Havel, M.D., Nina Karaseva, M.D., Jaroslaw Kuzdzal, M.D., Ph.D., Lubos B. Petruzelka, M.D., Ph.D., Lin Wu, M.D., Jean-Louis Pujol, M.D., Ph.D., Hiroyuki Ito, M.D., Ph.D., Tudor-Eliade Ciuleanu, M.D., Ph.D., Ludmila de Oliveira Muniz Koch, M.D., Annelies Janssens, M.D., Ph.D., Aurelia Alexandru, M.D., Sabine Bohnet, M.D., Fedor V. Moiseyenko, M.D., Ph.D., Yang Gao, M.D., Ph.D., Yasutaka Watanabe, M.D., Ph.D., Cinthya Coronado Erdmann, M.D., Padma Sathyanarayana, Ph.D., Stephanie Meadows-Shropshire, Ph.D., Steven I. Blum, M.B.A., M.A., and Mariano Provencio Pulla, M.D., Ph.D., for the CheckMate 77T Investigators†

Source: DOI: 10.1056/NEJMoa2311926

Dr. Anjan Patel's Thoughts

Perioperative nivolumab (Nivo) showed a 20% 18-month EFPS improvement. This is another option to consider for your patients with stage IIA-IIIB NSCLC. Of note, the study arm received chemo + Nivo x 4 cycles preoperatively, then 12 months of Nivo therapy, and toxicities were as expected.

BACKGROUND

Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non–small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes.

METHODS

In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety.

RESULTS

At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group.

CONCLUSIONS

Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.)

Author Affiliations

From the University of Texas M.D. Anderson Cancer Center, Houston (T.C., B.S.); Dana–Farber Cancer Institute, Boston (M.M.A.); McGill University Health Centre, Montreal (J.D.S.); the National Cancer Center–National Clinical Research Center for Cancer–Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (J.H.), Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (S.L.), and Hunan Cancer Hospital (L.W.) and Xiangya Hospital, Central South University (Y.G.), Changsha — all in China; the University of Occupational and Environmental Health, Kitakyushu (F.T.), Kanagawa Cancer Center, Yokohama (H.I.), and Saitama Cancer Center, Saitama (Y.W.) — all in Japan; Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore (J.M.T.); Erasmus MC Cancer Institute, Rotterdam, the Netherlands (R.C.); Thomayer Hospital (L.H.) and Charles University (L.B.P.) — both in Prague, Czech Republic; St. Petersburg State Budgetary Healthcare Institution, Clinical Oncology Dispensary (N.K.), and St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (F.V.M.) — both in St. Petersburg, Russia; Jagiellonian University Collegium Medicum, John Paul II Hospital, Krakow, Poland (J.K.); Montpellier Regional University Hospital, Montpellier, France (J.-L.P.); Prof. Dr. Ion Chiricuta and Universitatea de Medicina si Farmacie Iuliu Hatieganu, Cluj-Napoca (T.-E.C.), and Institutul Oncologic București Prof. Dr. Alexandru Trestioreanu, Bucharest (A.A.) — both in Romania; Hospital Israelita Albert Einstein, São Paulo (L.O.M.K.); Antwerp University Hospital, Edegem, Belgium (A.J.); Universitätsklinikum Schleswig-Holstein, Lübeck, Germany (S.B.); Bristol Myers Squibb, Princeton, NJ (C.C.E., P.S., S.M.-S., S.I.B.); and Hospital Universitario Puerta de Hierro, Madrid (M.P.P.).

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.