Malignant plural mesothelioma is a rare, incurable cancer with limited treatment options and poor prognosis. First-line treatment with cisplatin plus pemetrexed is the standard of care, but this is associated with an overall survival (OS) of only 12.1 months. Addition of bevacizumab to this chemotherapy regimen further improves survival in pleural mesothelioma and may be a reasonable option for appropriately selected patients. After progression on first-line therapy, there are no FDA approved treatment options; however, single-agent chemotherapy (eg, gemcitabine, vinorelbine, pemetrexed) are often used, though these agents have limited activity. In recent years, immunotherapy with antibodies targeting PD-1 and PD-L1 have become a mainstay of cancer treatment across tumor types and disease stages. The PD-1 inhibitors pembrolizumab and nivolumab (with and without ipilimumab) have both shown promising activity in advanced, pretreated mesothelioma. The phase 1b JAVELIN Solid Tumor trial evaluated the safety and activity of the PD-L1 inhibitor avelumab in a cohort of 53 patients with advanced unresectable mesothelioma that had progressed on prior treatment with platinum and pemetrexed chemotherapy.
Treatment with avelumab resulted in a confirmed objective response in 5 patients (ORR 9%), including a complete response in 1 patient and partial response in 4 patients. The disease control rate was 58%, and 50% of patients experienced a reduction in tumor size. The median duration of response was 15.2 months, with responses ongoing in 3 of 5 patients at data cut-off. Twelve-month rates of progression-free survival (PFS) and OS were 17.4% and 43.8%, respectively. The median OS was 10.7 months.
Responses occurred more commonly in patients with PD-L1-positive tumors than in patients with PD-L1-negative tumors (19% vs 7%). PD-L1 expression was also associated with a prolonged PFS (5.3 months vs 1.7 months) and OS (20.2 months vs 10.2 months) compared to patients who have tumors that did not express PD-L1.
Treatment-related adverse events (AEs) of any grade occurred in 81% of patients and were consistent with the known safety profile of avelumab. Grade 3/4 treatment-related AEs occurred in 5 patients (9%), and only 3 patients (6%) experienced a grade 3 or greater immune-related AE (pneumonitis, colitis, and diabetes type 1). The most common treatment-related AEs of any grade were infusion-related reactions (36%), chills (15%), fatigue (15%), and pyrexia (11%).
The authors concluded that avelumabis safewith durable clinical activity in heavily pretreated patients with advanced mesothelioma and may represent an attractive alternative to chemotherapy in patients progressing on first-line, platinum-based chemotherapy. Further studies of avelumab and other PD-1/PD-L1 inhibitors as single agents and in combinations are warranted.