Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation
Another KRAS G12C inhibitor. Congrats to FCS Director of Drug Development Manish Patel, MD, one of the authors. Durable responses with less adverse events.
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.).Related Articles
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Neoadjuvant chemotherapy trial with post op nivolumab for 6 months shows promising results.
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Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non–Small-Cell Lung Cancer
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Perioperative Nivolumab and Chemotherapy in Stage III Non–Small-Cell Lung Cancer
The NADIM-II study looked at perioperative Nivo+chemo vs. chemo alone in stIIIA – stIIIB NSCLC. High pCR rates with chemoIO are again seen, as in the Checkmate 816 and NADIM-I study, they were even higher in this cohort (37%), suggesting higher-stage patients derive the biggest benefit from neoadjuvant chemoIO. Pretty impressive results, however, I still must point out that this was a phase II study with a small sample size, OS benefits have not been demonstrated and this has yet to make it on to NCCN.
