Highlights
- •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.
Abstract
Background
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).
Results
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.
Conclusion
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.
Graphical Abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: February 07, 2023
Accepted:
January 31,
2023
Received in revised form:
January 30,
2023
Received:
October 23,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
