- •Mocetinostat plus durvalumab was investigated in non-small cell lung cancer patients.
- •Responses were seen in patients with disease refractory to prior checkpoint inhibitors.
- •Clinical activity was modest in other patient cohorts.
- •Mocetinostat plus durvalumab was generally well tolerated.
Histone deacetylase (HDAC) inhibitors have potential to augment the effectiveness of immune checkpoint inhibitors and overcome treatment resistance. This dose-escalation/expansion study (NCT02805660) investigated mocetinostat (class I/IV HDAC inhibitor) plus durvalumab in patients with advanced non-small cell lung cancer (NSCLC) across cohorts defined by tumor programmed death-ligand 1 (PD-L1) expression and prior experience with anti-programmed cell death protein-1 (anti-PD-1) or anti-PD-L1 regimens.
Patients and Methods
Sequential cohorts of patients with solid tumors received mocetinostat (starting dose: 50 mg TIW) plus durvalumab at a standard dose (1500 mg Q4W) to determine the recommended phase II dose (RP2D: phase I primary endpoint), based on the observed safety profile. RP2D was administered to patients with advanced NSCLC across 4 cohorts grouped by tumor PD-L1 expression (none or low/high) and prior experience with anti-PD-L1 /anti-PD-1 agents (naïve, clinical benefit: yes/no). The phase II primary endpoint was objective response rate (ORR, RECIST v1.1).
Eighty-three patients were enrolled (phase I [n = 20], phase II [n = 63]). RP2D was mocetinostat 70 mg TIW plus durvalumab. ORR was 11.5% across the phase II cohorts, and responses were durable (median 329 days). Clinical activity was observed in NSCLC patients with disease refractory to prior checkpoint inhibitor treatment: ORR 23.1%. Across all patients, fatigue (41%), nausea (40%), and diarrhea (31%) were the most frequent treatment-related adverse events.
Mocetinostat 70 mg TIW plus durvalumab at the standard dose was generally well tolerated. Clinical activity was observed in patients with NSCLC unresponsive to prior anti-PD(L)1 therapy.
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Published online: February 07, 2023
Accepted: January 31, 2023
Received in revised form: January 30, 2023
Received: October 23, 2022
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