Platinum-based chemoradiotherapy plus pembrolizumab for unresectable, stage III NSCLC

Updated results of the phase II Keynote-799 trial, confirm the clinical potential of pembrolizumab in combination with concurrent chemoradiotherapy (cCRT) as a treatment modality for patients with unresectable, locally advanced, stage III NSCLC. The treatment induced a response in 70% of patients, regardless of PD-L1 expression and tumor histology. At the 1-year landmark 4 out of 5 patients were still alive.

Introduction

The current standard of care for patients with unresectable stage III NSCLC consists of cCRT followed by consolidation therapy with the immune checkpoint inhibitor durvalumab in patients without disease progression after at least 2 cycles of cCRT. The fact that durvalumab is only used in patients without progression after 3 cycles of cCRT excludes a substantial proportion of patients (20-30%) from the potential benefit of immune checkpoint inhibition. To address this issue, the nonrandomized, phase II Keynote-799 trial assesses a combination of cCRT with pembrolizumab in patients with previously untreated, unresectable, stage IIIA-C NSCLC.

Study design

Cohort A of this trial enrolled both squamous and non-squamous patients and treated them with pembrolizumab (200 mg Q3W) plus paclitaxel (200 mg/m² Q3W) and carboplatin (AUC6 Q3W) in cycle 1, followed by two cycles of pembrolizumab (200 mg/m² Q3W) in combination with paclitaxel (45 mg/m² Q3W), carboplatin (AUC2 Q3W) and thoracic radiotherapy and an additional 14 cycles of pembrolizumab monotherapy (200mg Q3W). Cohort B only included patients with a non-squamous histology. Treatment consisted of a first cycle of pembrolizumab (200mg Q3W) combined with pemetrexed (500mg/m² Q3W) and cisplatin (75mg/m² Q3W), two cycles of the same regimen in combination with thoracic radiotherapy and 14 subsequent cycles of pembrolizumab monotherapy. Previous results of this trial indicated an overall response rate (ORR) of 67% in cohort A and 56.6% in cohort B. During this initial analysis, grade ≥3 pneumonitis was seen in 8% and 5.5% of cohorts A and B patients, respectively. During WCLC 2020, updated results with an additional follow-up of 6 months were presented.

High rate of durable responses with pembrolizumab + cCRT

At the time of the analysis, 38.4% of the 112 patients in cohort A had completed their treatment and therapy was ongoing in 1.8%. As such, 59.8% had discontinued their therapy, mainly as a result of adverse events (36.6%) and disease progression (12.5%). In cohort B (N=101), the treatment was complete in 23.8% and ongoing in 40.6%. Also in this cohort the main reasons for treatment discontinuation (35.6% in total) consisted of toxicity (16.8%) and disease progression (10.9%). The primary efficacy population of cohort B included 61 patients in total.

The ORR reported in this updated analysis was very similar between both cohorts at 69.6% in cohort A and 70.5% in cohort B. In both cohorts, the median duration of response was not yet reached, with the majority of patients having a response duration of ≥12 months (82.2% in cohort A, 72.1% in cohort B). No difference in ORR was seen between patients with a PD-L1 tumor proportion score (TPS) of <1 and ≥1 in both cohorts. In cohort A, the ORR was also similar in patients with a squamous and non-squamous histology. The median progression-free survival was not yet reached in the two cohorts. At 12 months, respectively 67.7% and 65.2% of cohort A and B patients were alive and free of progression. The overall survival rates were 81.2% in cohort A and 88.0% in cohort B.

The incidence of grade ≥3 pneumonitis was reported at 8% in cohort A and 7.9% in cohort B. Overall, grade 3-5 adverse events (AEs) were seen in 64.3% of patients treated with paclitaxel-carboplatin chemotherapy as compared to 46.5% in cohort B patients who received pemetrexed-cisplatin. Als the incidence of immune-mediated AEs was higher in cohort A compared to cohort B at 52.7% and 35.6%, respectively (grade 3-5: 16.1% vs. 9.9%).

Conclusions

In this updated analysis of Keynote-799, pembrolizumab plus cCRT continues to show promising antitumor activity in patients with unresectable, locally advanced, stage III NSCLC, regardless of PD-L1 TPS and tumor histology. The regimen induced an ORR of 70%, with an estimated response duration of more than 12 months in most patients. At 1 year, 80% of patients was still alive. The observed toxicity profile was consistent with established toxicity profiles of cCRT for stage III NSCLC and pembrolizumab monotherapy. The 8% incidence of grade ≥3 pneumonitis is within the expected range for immunotherapy combined with cCRT.

Reference

M. Reck, et al. Pembrolizumab Plus Platinum Chemotherapy and Radiotherapy in Unresectable, Locally Advanced, Stage III NSCLC: KEYNOTE 799. Presented at WCLC 2020; Abstract OA02.04.