Pembrolizumab Plus Lenvatinib Elicits Positive Clinical Activity in Recurrent Pleural Mesothelioma

The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) generated promising clinical activity with a manageable safety profile in pretreated patients with malignant pleural mesothelioma (MPM), according to data from the phase 2 PEMMELA trial (NCT04287829) presented at the 2022 World Conference on Lung Cancer.

The objective response rate (ORR) was 58% and 76% of patients required dose reductions, according to investigators.

“This study met its primary end point, showing promising clinical activity of pembrolizumab plus lenvatinib in patients with recurrent MPM who progressed after chemotherapy, with remarkable but no unexpected toxicity,” said Li-Anne Douma, a PhD candidate at The Netherlands Cancer Institute in Amsterdam who presented the results.

In patients with MPM, there is a large unmet need for effective second-line treatment options. The PD-1 receptor blocker, pembrolizumab, has shown a response rate up to 20% as monotherapy whereas lenvatinib, a multiple tyrosine kinase inhibitor with mostly vascular endothelial growth factor receptor blocking properties, has synergistic interactions with PD-1 blocking agents in other tumors.

Because of this, investigators sought to evaluate the clinical activity and toxicity of the 2 agents in combination as treatment for patients with recurrent MPM in the phase 2 single-arm, open-label study.

Thirty-eight eligible patients received intravenous pembrolizumab given at a dose of 200 mg once every 3 weeks plus lenvatinib at 20 mg orally once a day in patients with MPM who progressed after chemotherapy.

Enrollment was open to patients aged 18 years or older with histologically proven MPM. Patients had an ECOG performance status of 0 or 1, measurable disease according to the modified RECIST version 1.1, and had received prior chemotherapy. Those enrolled remained on treatment for up to 2 years, until unacceptable toxicity or disease progression evaluated by CT-scan every 6 weeks.

ORR was defined as the proportion of patients with complete response (CR), or partial response (PR), with secondary end points including safety of the treatment combination, disease control rate (DCR) at month 3 and 6, ORR, and progression free survival.

A total of 38 participants were eligible and included in the trial between March 5, 2021 and January 31, 2022. Of the 38 patients, 33 were male (86.8%), 19 (50%) had an ECOG performance status of 0, and the median age was 70.5 years (range, 36-83). A majority of the patients (89.5%) presented with epithelioid MPM, 5.3% had non-epithelioid mesothelioma, and the other 5.3% were mixed. In regard to PD-L1 status, 18 patients (47.4%) were PD-L1 positive, 17 (44.7%) were PD-L1 negative, and 3 (7.9%) had undetermined status.

At data cutoff of March 31, 2022, 22 of the 38 patients had reached PR as best overall response (HR 58%; 95% CI, 41%-74%; P < .0001), and 15 of these patients had confirmed PR (39.5%; 95% CI, 24%-57%; P = .07). Among the 7 patients who had unconfirmed PR, 3 can still reach confirmed PR.

In regard to safety, most of the AEs were deemed grade 1/2 and consisted of fatigue (n = 21), hoarseness (n = 21), anorexia (n = 13), diarrhea (n = 13), hypertension (n = 5), and elevated alanine aminotransferase/ aspartate transaminase levels (n = 5).

Grade 3/4 treatment-related adverse events (TRAEs) were observed in 26 patients with the most common grade 3 TRAEs being hypertension in 8 patients (24%) and anorexia in 3 (18%). Additionally, there were 2 patients with grade 4 myositis and 10 patients with 13 treatment-related serious adverse events.

Dose reductions or permanent discontinuation of lenvatinib treatment were required by 76% of all patients due to toxicity concerns. For pembrolizumab, 2 of the 38 patients (8%) resulted in permanent discontinuation on the trial.

Overall, these data demonstrate the promising clinical activity observed with treatment consisting of pembrolizumab plus lenvatinib in patients with recurrent MPM who progressed after chemotherapy.

Reference

1. Douma LA, de Gooijer CJ, Noort V, et al. PEMbrolizumab plus lenvatinib in second and third line malignant pleural mesothelioma patients: A single arm phase II study (PEMMELA. Presented at the 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract OA04.06.