Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non–Small Cell Lung Cancer

Abstract

plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non-small cell lung cancer (NSCLC).OBJECTIVE To evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTSThe phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled.INTERVENTIONS Patients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m 2 ), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m 2 ) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m 2 ), pemetrexed (500 mg/m 2 ), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab. MAIN OUTCOMES AND MEASURESCoprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis. RESULTS A total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score Ն1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score Ն1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B.Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively. CONCLUSIONS AND RELEVANCEThe findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.

Dosimetric Risk Factors for Acute Radiation Pneumonitis in Patients With Prior Receipt of Immune Checkpoint Inhibitors

“…First, patients herein received full courses of ICIs prior to RT initiation, whereas in other studies ( 11 – 16 ) most patients did not have as high of a degree of immune system galvanization prior to commencing RT. KEYNOTE-799 (which delivered ICIs before RT) observed a <10% rate of grade ≥3 pneumonitis, but that trial delivered a median of 1 cycle of pembrolizumab/chemotherapy prior to RT (as compared to a median of 4 cycles herein) ( 18 ). The higher level of immune activation prior to starting RT in this cohort could have predisposed these patients to develop RP more frequently and with greater severity than patients in the aforementioned publications, but this notion requires further corroboration.…”

Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)

“…This led to the FDA approval of atezolizumab as the adjuvant therapy for this patient population. Similarly, in the phase 2 KEYNOTE-799 trial, pembrolizumab plus concurrent chemoradiation therapy demonstrated objective response rates of 71% in locally advanced, stage III NSCLC ( Jabbour et al, 2021 ). Because our case was a locally advanced dMMR/MSI-H tumor, we were also interested in the efficacy of adjuvant immunotherapy in this setting.…”

Bladder-Sparing Chemoradiotherapy Combined with Immune Checkpoint Inhibition for Locally Advanced Urothelial Bladder Cancer—A Review

“…Van den Ende et al showed the feasibility of concurrent ICI use with CRT in a neoadjuvant setting before resectioning of esophageal carcinoma [ 44 ]. Furthermore, a recent nonrandomized phase II trial of pembrolizumab concurrent to CRT in patients with locally advanced stage III NSCLC demonstrated objective response rates of 70% [ 45 ]. Although toxicity in this regime was relatively high, with 58% of patients experiencing any grade 3–5 AEs leading to treatment discontinuation in 26%, this seems acceptable considering the historical response rates of CRT between 35.9 and 54.5% [ 46 , 47 , 48 ].…”