TY - JOUR
T1 - Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC
T2 - Results From a Phase I/II Study
AU - Johnson, Melissa L.
AU - Strauss, James
AU - Patel, Manish R.
AU - Garon, Edward B.
AU - Eaton, Keith D.
AU - Neskorik, Tavette
AU - Morin, Josée
AU - Chao, Richard
AU - Halmos, Balazs
N1 - Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
KW - Checkpoint inhibitor
KW - HDAC
KW - Histone deacetylase inhibitor
KW - PDL1
KW - Programmed death-ligand 1
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UR - http://www.scopus.com/inward/citedby.url?scp=85150025861&partnerID=8YFLogxK
U2 - 10.1016/j.cllc.2023.01.013
DO - 10.1016/j.cllc.2023.01.013
M3 - Article
C2 - 36890020
AN - SCOPUS:85150025861
SN - 1525-7304
VL - 24
SP - 218
EP - 227
JO - Clinical lung cancer
JF - Clinical lung cancer
IS - 3
ER -