Pembrolizumab plus chemotherapy holds promise for recurrent EGFR-mutant non-small cell lung cancer
Treatment options for metastatic non-small cell lung cancer (NSCLC) harbouring an EGFR mutation or an ALK rearrangement with disease recurrence on first line tyrosine kinase inhibitor therapy are limited. Results of a phase II trial presented at WCLC 2021 now suggest that a combination of pembrolizumab and carboplatin-based chemotherapy might be of benefit in patients with recurrent EGFR-mutant metastatic NSCLC. The 42% response rate with a median progression-free and overall survival of 8.3 and 22.2 months, respectively warrant further study of this regimen in this setting.
Despite recent advances in the management of patients with EGFR- or ALK-positive metastatic non-small cell lung cancer (NSCLC), the median progression free survival (PFS) for these patients remains suboptimal at 10-19 months for patients with an EGFR mutation and 10-34 months for patients harbouring an ALK rearrangement. Moreover, at the time of relapse the therapeutic options for patients are limited. For example, the use of platinum-based chemotherapy following recurrence on an EGFR/ALK targeting tyrosine kinase inhibitor (TKI) only induces a response in approximately 30% of patients, with a median PFS of 4-5 months. Also results with single-agent immune checkpoint inhibition in ALK or EGFR-positive patients are disappointing with response rates below 5%. In an attempt to address the existing medical need in recurrent EGFR/ALK-positive metastatic NSCLC patients, the presented phase II study assessed whether the addition of pembrolizumab to platinum-based chemotherapy would result in a better outcome for these patients.
Study design
In order to be eligible for the study, patients had to have an EGFR mutation (i.e., deletion 19, exon 21 L858R or L861Q, exon 18 G719X or S781) or harbour an ALK-rearrangement and they had to be pre-treated with an appropriate TKI. Patients who received more than one prior cycle of platinum-based chemotherapy for their advanced disease were excluded. Patients with asymptomatic brain metastases were allowed to enter the study. Patients were treated with a combination of pembrolizumab and carboplatin/pemetrexed (4 cycles followed by pemetrexed and pembrolizumab maintenance for up to 2 years). The primary endpoint of the trial was response rate, with PFS and overall survival (OS) as key secondary objectives. Of note, the trial was stopped early due to a slow patient accrual (mainly due to the availability of this regimen in the general practice and due to the COVID-19 crisis).
Results
In total, 26 patients with an EGFR-mutation were enrolled in addition to 7 patients with an ALK rearrangement. Of the EGFR patients, 46% had brain metastases while this was the case for 28% in the ALK group. Sixty one percent of patients in the EGFR cohort received the study drug in 2nd line, while this was the case for 71% in the ALK group. Finally, 85% of EGFR-mutant patients received prior osimertinib.
Among EGFR-mutant patients, a response rate of 42.3% (11/26) was reported, while in the ALK group 28.6% (2/7) of patients responded to pembrolizumab plus chemotherapy. The median PFS in this study reached 8.3 months in the EGFR cohort as compared to 2.9 months among patients with recurrent ALK-positive disease. The corresponding 12-month PFS rates were reported at 29% and 14%, respectively. With respect to OS, the study revealed a median OS of 22.2 months for EGFR-mutant patients with 76% of patients being alive at this landmark. For ALK-positive patients this was much lower at 2.9 months and 14%, respectively. No difference in PFS or OS was observed when the investigators assessed these outcomes in function of the PD-L1 expression (PD-L1 0% vs. ≥ 1%). Similarly, also changes in the level of circulating tumour cells among EGFR mutant patients did not show a significant association with OS.
The most common adverse events were fatigue, nausea, cytopenias, cough and dyspnoea. The most common ≥ grade 3 toxicities were neutropenia, thrombocytopenia, thromboembolism, and AST/ALT elevation. One patient developed pneumonitis.
Conclusion
Pembrolizumab in combination with chemotherapy demonstrated a response rate of 42% and median survival of 22 months among patients with recurrent EGFR-mutated NSCLC. Results in recurrent ALK-positive patients were more modest although the interpretation of these findings is hampered by the low patient number (only 7 patients). As such, the investigators concluded that these findings warrant further evaluation of this combination in patients with recurrent EGFR-mutant, metastatic NCLC.
Reference
Gadgeel S et al. Pembrolizumab in Combination With Platinum-Based Chemotherapy in Recurrent EGFR/ALK-Positive Non-Small Cell Lung Cancer (NSCLC). Presented at the 2021 World Conference on Lung Cancer; Abstract OA09.03.
