Good anti-tumor activity and manageable safety profile seen

When added to concurrent chemoradiation therapy (cCRT), pembrolizumab—a highly selective humanized monoclonal anti-PD-1 antibody—showed promising antitumor activity in patients with untreated, locally advanced stage III non-small cell lung cancer (NSCLC), according to results from the phase III KEYNOTE-799 nonrandomized trial, published in JAMA Oncology.

Roughly 70% of patients in each treatment group experienced an objective response, with 75% of this group experiencing an objective response for at least 12 months.

The standard of care for patients with NSCLC with tumor stages IIIA to IIIC was platinum-doublet chemotherapy given concurrently with cCRT. In 2018, durvalumab—also a monoclonal antibody against PD-L1—was approved by the FDA for NSCLC patients irrespective of their PD-L1 expression, explained Salma K. Jabbour, MD, of Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, and fellow researchers of the KEYNOTE-799 trial.

“However, approximately 22% to 30% of patients with unresectable stage III NSCLC who begin cCRT experience disease progression (PD) or toxic effects and are unable to complete the prescribed cCRT. This substantial patient population does not meet the criteria for durvalumab as consolidative therapy. We postulated that administration of concurrent anti-programmed cell death 1 (PD-1) therapy and cCRT as initial therapy may provide treatment benefit to a greater proportion of patients with locally advanced, unresectable, stage III NSCLC,” they added.

Indeed, pembrolizumab has been shown to increase long-term survival and have durable clinical benefits when used “as first-line treatment in patients with advanced or metastatic NSCLC with PD-L1 tumor proportion score (TPS) 1% or greater as monotherapy and in combination with chemotherapy in patients with advanced or metastatic NSCLC irrespective of PD-L1 expression,” Jabbour et al noted.

For this global, two-cohort, open-label study, they included 214 patients from 52 academic facilities and community-based institutions across 10 countries. Patients were randomized into two cohorts:

  • The first (cohort A), was comprised of 112 patients (median age: 66.0 years; 67.9% male; 58.9% with PD-L1 greater than or equal to 1%; 65.2% squamous NSCLC), who were treated with 1 cycle of carboplatin (3 weeks; AUC: 6 mg/mL/min), paclitaxel (200 mg/m2), and pembrolizumab (200 mg). This was followed by carboplatin (AUC: 2 mg/mL/min) and paclitaxel (45 mg/m2) weekly for 6 weeks and two cycles of pembrolizumab plus standard thoracic radiotherapy.
  • The second group (cohort B) included 102 patients (median age: 64.0 years; 60.8% male; 39.2% with PD-L1 score ≥1%; 100% squamous NSCLC). These patients were treated with three cycles of cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and pembrolizumab (200 mg) every 3 weeks, and thoracic radiotherapy during cycles 2 and 3.

In cohort A, 58.9% of patients had PD-L1 tumor proportion score (TPS) of 1% or greater, as did 39.2% of cohort B. Not all tumor samples, however, could be assessed for PD-L1 expression.

The primary endpoints were objective response rate (ORR) per RECIST v1.1 and the incidence of grade 3-5 pneumonitis. Patients in cohort A were followed for a median of 18.5 months, and those in cohort B, for 13.7 months.

In cohort A, the ORR was 70.5% (95% CI: 61.2%-78.8%) compared with 70.6% (95% CI: 60.7%-79.2%) in cohort B. Although both groups failed to reach the median duration of response, 79.7% and 75.6%, respectively, had responses lasting ≥12 months. Death occurred in 28.6% of patients in cohort A and in 14.7% of those in cohort B.

In all, 8.0% of patients in cohort A had grade 3 or higher pneumonitis, compared with 6.9% of those in cohort B. Finally, treatment-related adverse events (TRAEs) occurred in 93.8% of patients in cohort A, and in 97.1% of those in cohort B. Grade 3-5 TRAEs occurred in 64.3% and 50.0% of patients, respectively, the most common of which was neutropenia in both groups (16.1% versus 9.8%).

“To our knowledge, KEYNOTE-799 is the largest trial to date of concurrent anti–PD-(L)1 therapy plus cCRT in patients with previously untreated, locally advanced, stage III NSCLC. In this study, pembrolizumab plus cCRT demonstrated robust antitumor activity with a manageable safety profile,” concluded Jabbour and colleagues.

Study limitations included its nonrandomized, phase 2 design and limited follow-up in patients in cohort B.

  1. Results from the phase II KEYNOTE-799 trial suggest that pembrolizumab plus concurrent chemoradiation therapy (cCRT) has robust antitumor activity with manageable safety and may be a promising therapy in patients with previously untreated, locally advanced, stage III NSCLC.
  2. Pembrolizumab plus cCRT demonstrated objective response rates of 70.5% in cohort A and 70.6% in cohort B.

Liz Meszaros, Deputy Managing Editor, BreakingMED 

This study was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

Jabbour reported receiving grants, personal fees, and nonfinancial support from Merck & Co during the conduct of the study; and receiving grants from the National Cancer Institute and grants to institution from Merck & Co outside the submitted work.


Cat ID: 24

Topic ID: 78,24,730,24,192,65,925