Patients with recurrent EGFR/ALK-positive non-small cell lung cancer (NSCLC) obtained durable remissions with the combination of pembrolizumab (Keytruda) and chemotherapy, a small prospective study showed.
The immuno-oncology (IO) combination led to a median progression-free survival (PFS) of 8.3 months in EGFR-mutant NSCLC and overall survival (OS) of 22.2 months. The combination had limited activity in seven patients with recurrent ALK-positive disease, reported Shirish M. Gadgeel, MD, of the Henry Ford Cancer Institute in Detroit, at the virtual World Conference on Lung Cancer (WCLC).
“The results observed in the EGFR population warrant further evaluation of pembrolizumab plus chemotherapy in patients with recurrent EGFR mutation-positive non-small cell lung cancer,” said Shirish M. Gadgeel, MD, of the Henry Ford Cancer Institute in Detroit.
During a post-presentation discussion, Gadgeel acknowledged that ALK-positive NSCLC typically has more favorable outcomes as compared with EGFR-positive disease. The reasons for the lack of activity (objective responses in two of seven patients) are unclear, he added, emphasizing the caveats associated with so few patients.
Patients with recurrent EGFR/ALK-positive NSCLC have few options beyond additional treatment with targeted tyrosine kinase inhibitors (TKIs). Most patients receive platinum-based chemotherapy, which has limited efficacy following TKIs, Gadgeel said. In the post-TKI setting, chemotherapy typically leads to an overall response rate (ORR) of about 30% and median PFS of 4 to 5 months.
Single-agent immunotherapy with anti-PD1/L1 agents has limited activity in EGFR/ALK-positive NSCLC, he continued. A trial of immunotherapy plus chemotherapy showed improvement in response rate, PFS, and OS in nonsquamous NSCLC and no EGFR/ALK mutations.
Investigators in a multicenter trial extended the evaluation of pembrolizumab and chemotherapy into the setting of recurrent EGFR/ALK-positive NSCLC. They enrolled a total of 33 patients, 26 with EGFR-mutant NSCLC and seven with ALK-positive disease.
Eligibility criteria included histology-proven NSCLC associated with EGFR exon 19 deletion, exon 21 L858R or L861Q, exon 18 G719X, S7681, or ALK rearrangement. The trial had no limit on prior number of TKI therapies, but most had received only one prior targeted TKI, said Gadgeel. No more than one prior line of platinum-based chemotherapy for advanced NSCLC was allowed. Correlative studies included PD-L1 expression, circulating tumor cells (CTCs), and whole-exome sequencing.
Treatment consisted of pembrolizumab plus four cycles of carboplatin/pemetrexed chemotherapy, followed by maintenance pembrolizumab for 2 years. The primary endpoint was ORR by RECIST criteria, and PFS and OS were key secondary endpoints. The trial had a target accrual of 42 patients, but ended early because of slow enrollment, said Gadgeel.
Overall, 13 of 33 (39.4%) patients had objective responses, including 11 of 26 (42.3%) in the EGFR-positive subgroup and two of seven (28.6%) of patients with ALK rearrangement. In addition to the median PFS of 8.3 months, the EGFR cohort had a 12-month PFS of 29%. Median PFS in the ALK cohort was 2.9 months with a 12-month PFS of 14%.
The patients with EGFR mutations had a 12-month OS of 76%, in addition to the median OS of 22.2 months. Median and 12-month OS values for the ALK subgroup were 2.9 months and 14%, respectively.
PD-L1 expression status was available for 30 patients, 13 who had PD-L1-negative tumors (
No new or unexpected adverse events (AE) occurred during the study, said Gadgeel. Gastrointestinal and skin toxicities, as well as cytopenias, were the most commonly reported AEs (all grades).
The trial comprised a heterogeneous patient population with both common and uncommon mutations, said WCLC invited discussant Charu Aggarwal, MD, of the University of Pennsylvania and Abramson Cancer Center in Philadelphia. Patients with oncogene-addicted tumors represent distinct populations that should be studied separately.
‘There’s no clear role, at least based on the data we saw, for chemoimmunotherapy in patients with ALK-rearranged non-small cell lung cancer,” said Aggarwal. “We cannot generalize outcomes across all subtypes of patients with actionable mutations, and further research is needed.”
The study was supported by Merck.
Gadgeel disclosed relationships with Merck, Genentech/Roche, AstraZeneca, Bristol Myers Squibb (BMS), Pfizer, Mirati, Lilly, Janssen, Blueprint, and Novartis.
Aggarwal disclosed relationships with AstraZeneca, BMS, Blueprint, Celgene, Merck, Roche, Daiichi-Sankyo, Novartis, and Xencor.