Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer

Author(s): Heather Wakelee, M.D., Moishe Liberman, M.D., Ph.D., Terufumi Kato, M.D., Masahiro Tsuboi, M.D., Ph.D., Se-Hoon Lee, M.D., Ph.D., Shugeng Gao, M.D., Ke-Neng Chen, M.D., Ph.D., Christophe Dooms, M.D., Ph.D., Margarita Majem, M.D., Ph.D., Ekkehard Eigendorff, M.D., Gastón L. Martinengo, M.D., Olivier Bylicki, M.D., Delvys Rodríguez-Abreu, M.D., Ph.D., Jamie E. Chaft, M.D., Silvia Novello, M.D., Ph.D., Jing Yang, Ph.D., Steven M. Keller, M.D., Ayman Samkari, M.D., and Jonathan D. Spicer, M.D., Ph.D. for the KEYNOTE-671 Investigators*

Source: DOI: 10.1056/NEJMoa2302983

Dr. Anjan Patel's Thoughts

Neoadjuvant Pembro+chemo followed by surgery and adjuvant pembro had a superior PFS and pCR rate compared to neoadjuvant chemo followed by surgery. PCR rates were 30 vs. 11%, and PFS rates at 24 months were 62 vs. 41%, in the chemoIO vs. chemo alone groups, respectively. Still, OS was not significantly different, and this has yet to make it onto NCCN.

BACKGROUND

Among patients with resectable early-stage non–small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.

METHODS

We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety.

RESULTS

A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P=0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P=0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P=0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events.

CONCLUSIONS

Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.)

Author Affiliations

From Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA (H.W.); Centre Hospitalier de l’Université de Montréal (M.L.) and McGill University Health Centre (J.D.S.) — both in Montreal; Kanagawa Cancer Center, Yokohama (T.K.), and National Cancer Center Hospital East, Kashiwa (M.T.) — both in Japan; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (S.-H.L.); the National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (S.G.), and Beijing Cancer Hospital, Peking University (K.-N.C.) — both in Beijing; University Hospitals Leuven, Leuven, Belgium (C.D.); Hospital de la Santa Creu i Sant Pau, Barcelona (M.M.), and Hospital Universitario Insular de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas (D.R.-A.) — both in Spain; Zentralklinik Bad Berka, Bad Berka, Germany (E.E.); Sanatorio Parque, Cordoba, Argentina (G.L.M.); Hôpital d’Instruction des Armées Sainte-Anne, Toulon, France (O.B.); Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York (J.E.C.); the Department of Oncology, University of Turin, Azienda Ospedaliero-Universitaria San Luigi Gonzaga di Orbassano, Turin, Italy (S.N.); and Merck, Rahway, NJ (J.Y., S.M.K., A.S.).

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.