Pembrolizumab retreatment effective in patients with advanced or metastatic NSCLC who experienced disease progression

At IASLC WCLC 2022, a pooled analysis of outcomes with second-course pembrolizumab across five phase III studies of non-small-cell lung cancer (NSCLC) was presented. A second course of pembrolizumab monotherapy was feasible, associated with antitumour activity and clinically meaningful benefit, with manageable safety in patients with advanced or metastatic NSCLC who experienced disease progression after completing first-course pembrolizumab with or without chemotherapy. These data support pembrolizumab retreatment upon disease progression.

Pembrolizumab as monotherapy and in combination with chemotherapy substantially prolongs overall survival (OS) and progression-free survival (PFS) versus chemotherapy alone in patients with previously untreated advanced or metastatic non-small cell lung cancer (NSCLC) without EGFR/ALK alterations. In the clinical trial setting, patients whose disease progresses after completing 35 cycles (⁓2 years) of pembrolizumab have the potential to receive a second course of pembrolizumab monotherapy for 17 additional cycles (⁓1 year). Limited data from individual studies indicate antitumour activity in patients who began second-course pembrolizumab. At IASLC WCLC 2022, Prof. Rodriguez-Abreu presented outcomes from an exploratory pooled analysis of clinical trials in patients with advanced or metastatic NSCLC who received second-course pembrolizumab. Cohort 1 of the analysis included patients treated with pembrolizumab monotherapy in the first course while cohort 2 included patients treated with pembrolizumab plus chemotherapy in the first course.

Study design

This analysis pooled patients with advanced or metastatic NSCLC treated with pembrolizumab monotherapy (cohort 1) in the KEYNOTE-024, KEYNOTE-042, and KEYNOTE-598 studies, and pembrolizumab plus chemotherapy (cohort 2) in the KEYNOTE-189 and KEYNOTE-407 studies. Patients included in this analysis received second-course pembrolizumab (up to 17 cycles) following disease progression after either completing 35 cycles of pembrolizumab (with/without chemotherapy) with stable disease or better or stopping pembrolizumab before 35 cycles due to complete response. Efficacy was analysed in the intention-to-treat (ITT) population and safety in the as-treated population.

Results

In cohort 1, among 123 patients who completed 35 cycles of pembrolizumab and experienced disease progression, 57 patients received second-course pembrolizumab and were included in this analysis. Cohort 2 included 14 of 57 patients who completed 35 cycles of pembrolizumab (as part of pembrolizumab plus chemotherapy), experienced disease progression, and received second-course pembrolizumab. In total, 32% of patients in cohort 1 and 50% of patients in cohort 2 had squamous histology and 81% and 36%, respectively, had PD-L1 tumour proportion score (TPS) ≥50%. Median (range) time from stopping first-course pembrolizumab to starting second course was 12.0 (3.8 - 35.6) months in cohort 1 and 5.4 (0.9 – 18.2) months in cohort 2. Median duration on second course was 8.3 months in cohort 1 and 7.6 months in cohort 2, with an estimated 62.8% and 55.0%, respectively, remaining on second course at six months.

The objective response by investigator review during second-course pembrolizumab was 19.3% in cohort 1 and 0% in cohort 2, with a disease control rate of respectively 73.7% and 50.0%. The median duration of response in cohort 1 was not reached.  Median OS was 27.5 months in cohort 1 and not reached in cohort 2. Corresponding 6-month OS rates were 85.1% in both cohorts. Median PFS was 10.3 months for patients in cohort 1 and 7.7 months for patients in cohort 2. The 6-month PFS rates were respectively 60.8% and 54.5%. In total, 14 patients (25%) in cohort 1 and 4 (29%) in cohort 2 experienced treatment-related adverse events (AEs) on or after second course, of which 3 (5%) and 1 (7%) were grade 3-4, respectively. None were grade 5. Immune-mediated adverse events were reported in six patients in cohort 1 (of which one was of grade 3), and in no patients from cohort 2.

Conclusion

A second course of pembrolizumab monotherapy was feasible and associated with clinically meaningful benefit. In addition, safety was manageable during the second course of pembrolizumab with no treatment-related grade 5 AEs. These data support pembrolizumab retreatment upon disease progression in patients with advanced or metastatic NSCLC after completing 35 cycles (~2 years) of first-course pembrolizumab with or without chemotherapy.

Reference

Rodriguez-Abreu D, Wu L, Boyer M, et al. Pooled Analysis of Outcomes With Second-Course Pembrolizumab Across Five Phase 3 Studies of Non–Small-Cell Lung Cancer. Presented at IASLC WCLC 2022; Abstract OA15.06.