Original Study|Articles in Press

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study

Published:February 07, 2023DOI:


      • 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.

      Graphical Abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Lung Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Siegel RL
        • Miller KD
        • Fuchs HE
        • Jemal A
        Cancer Statistics, 2021.
        CA Cancer J Clin. 2021; 71: 7-33
        • Juarez-Garcia A
        • Sharma R
        • Hunger M
        • Kayaniyil S
        • Penrod JR
        • Chouaid C
        Real-world effectiveness of immunotherapies in pre-treated, advanced non-small cell lung cancer patients: A systematic literature review.
        Lung Cancer. 2022; 166: 205-220
        • Lee HT
        • Lee JY
        • Lim H
        • et al.
        Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab.
        Sci Rep. 2017; 7: 5532
        • Pawelczyk K
        • Piotrowska A
        • Ciesielska U
        • et al.
        Role of PD-L1 expression in non-small cell lung cancer and the prognostic significance according to clinicopathological factors and diagnostic markers.
        Int J Mol Sci. 2019; 20: 824
        • Govindan R
        • Aggarwal C
        • Antonia SJ
        • et al.
        Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lung cancer and mesothelioma.
        J Immunother Cancer. 2022; 10e003956
        • Botticella A
        • Mezquita L
        • Le Pechoux C
        • Planchard D
        Durvalumab for stage III non-small cell lung cancer patients: clinical evidence and real-world experience.
        Ther Adv Respir Dis. 2019; 13: 1-10
        • Paz-Ares L
        • Dvorkin M
        • Chen Y
        • et al.
        Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.
        Lancet. 2019; 394: 1929-1939
        • Antonia SJ
        • Villegas A
        • Daniel D
        • et al.
        Overall survival with durvalumab after chemoradiotherapy in Stage III NSCLC.
        N Engl J Med. 2018; 379: 2342-2350
        • Johnson M
        • Cho BC
        • Luft A
        • et al.
        Durvalumab+/- tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the Phase 3 POSEIDON study.
        J Thorac Oncol. 2021; 16: PL02.01
        • Mottamal M
        • Zheng S
        • Huang TL
        • Wang G
        Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents.
        Molecules. 2015; 20: 3898-3941
        • Roy DM
        • Walsh LA
        • Chan TA
        Driver mutations of cancer epigenomes.
        Protein Cell. 2014; 5: 265-296
        • Cao LL
        • Song X
        • Pei L
        • Liu L
        • Wang H
        • Jia M
        Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer: A meta-analysis.
        Medicine (Baltimore). 2017; 96: e7663
        • Minamiya Y
        • Ono T
        • Saito H
        • et al.
        Expression of histone deacetylase 1 correlates with a poor prognosis in patients with adenocarcinoma of the lung.
        Lung Cancer. 2011; 74: 300-304
        • Giaginis C
        • Damaskos C
        • Koutsounas I
        • et al.
        Histone deacetylase (HDAC)-1, -2, -4 and -6 expression in human pancreatic adenocarcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival.
        BMC Gastroenterol. 2015; 15: 148
        • Mamdani H
        • Jalal SI
        Histone deacetylase inhibition in non-small cell lung cancer: hype or hope?.
        Front Cell Dev Biol. 2020; 8: 582370
        • Zhou N
        • Moradei O
        • Raeppel S
        • et al.
        Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
        J. Med. Chem. 2008; 51: 4072-4075
        • Fournel M
        • Bonfils C
        • Hou Y
        • et al.
        MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo.
        Mol. Cancer Ther. 2008; 7: 759-768
        • Batlevi CL
        • Crump M
        • Andreadis C
        • et al.
        A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma.
        Br J Haematol. 2017; 28: 2047-2049
        • Chan E
        • Chiorean EG
        • O'Dwyer PJ
        • et al.
        Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors.
        Cancer Chemother Pharmacol. 2018; 81: 355-364
        • Grivas P
        • Mortazavi A
        • Picus J
        • et al.
        Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes.
        Cancer. 2019; 125: 533-540
        • Younes A
        • Oki Y
        • Bociek RG
        • et al.
        Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial.
        Lancet Oncol. 2011; 12: 1222-1228
        • Pathak R
        • Pharaon RR
        • Mohanty A
        • Villaflor VM
        • Salgia R
        • Massarelli E
        Acquired resistance to PD-1/PD-L1 blockade in lung cancer: mechanisms and patterns of failure.
        Cancers (Basel). 2020; 12: 3851
        • Fujiwara Y
        • Mittra A
        • Naqash AR
        • Takebe N
        A review of mechanisms of resistance to immune checkpoint inhibitors and potential strategies for therapy.
        Cancer Drug Resist. 2020; 3: 252-275
        • Jenke R
        • Ressing N
        • Hansen FK
        • Aigner A
        • Buch T
        Anticancer therapy with HDAC inhibitors: mechanism-based combination strategies and future perspectives.
        Cancers (Basel). 2021; 13: 634
        • Briere D
        • Sudhakar N
        • Woods DM
        • et al.
        The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy.
        Cancer Immunol Immunother. 2018; 67: 381-392
        • Ji Y
        • Wang SJ
        Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 design for practical phase I trials.
        J Clin Oncol. 2013; 31: 1785-1791
        • Lee JJ
        • Liu DD
        A predictive probability design for phase II cancer clinical trials.
        Clin Trials. 2008; 5: 93-106
        • Antonia SJ
        • Balmanoukian A
        • Brahmer J
        • et al.
        Clinical activity, tolerability, and long-term follow-up of durvalumab in patients with advanced NSCLC.
        J Thorac Oncol. 2019; 14: 1794-1806
        • Garassino MC
        • Cho B-C
        • Kim J-H
        • et al.
        Durvalumab as third-line or later treatment for advanced non-small cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.
        Lancet Oncol. 2018; 19: 521-536
        • Martell R
        • Younes A
        • Ewer M
        • et al.
        Clinical development of MGCD0103, an isotype-selective HDAC inhibitor: Pericarditis/pericardial effusion in the context of overall safety and efficacy.
        Blood. 2009; 114: 4756
        • Boumber Y
        • Younes A
        • Garcia-Manero G
        Mocetinostat (MGCD0103): a review of an isotype-specific histone deacetylase inhibitor.
        Expert. Opin. Investig. Drugs. 2011; 20: 823-829
        • Sampat K
        • Rossi A
        • Garcia-Gutierrez V
        • et al.
        Characteristics of pericardial effusions in patients with leukemia.
        Cancer. 2010; 116: 2366-2371
        • Habibian J
        • Ferguson BS
        The crosstalk between acetylation and phosphorylation: emerging new roles for HDAC inhibitors in the heart.
        Int J Mol Sci. 2018; 20: 102
        • Fujita K
        • Yamamoto Y
        • Kanai O
        • et al.
        Retreatment with anti-PD-1 antibody in non-small cell lung cancer patients previously treated with anti-PD-L1 antibody.
        Thorac Cancer. 2020; 11: 15-18
        • Kitagawa S
        • Hakozaki T
        • Kitadai R
        • Hosomi Y
        Switching administration of anti-PD-1 and anti-PD-L1 antibodies as immune checkpoint inhibitor rechallenge in individuals with advanced non-small cell lung cancer: Case series and literature review.
        Thorac Cancer. 2020; 11: 1927-1933
        • Watanabe H
        • Kubo T
        • Ninomiya K
        • et al.
        The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer.
        Jpn J Clin Oncol. 2019; 49: 762-765
        • Leighl NB
        • Redman MW
        • Rizvi N
        • et al.
        Phase II study of durvalumab plus tremelimumab as therapy for patients with previously treated anti-PD-1/PD-L1 resistant stage IV squamous cell lung cancer (Lung-MAP substudy S1400F, NCT03373760).
        J Immunother Cancer. 2021; 9e002973
        • Reckamp KL
        • Redman MW
        • Dragnev KH
        • et al.
        Phase II randomized study of ramucirumab and pembrolizumab versus standard of care in advanced non-small cell lung cancer previously treated with immunotherapy: Lung-MAP S1800A.
        J Clin Oncol. 2022; 40: 2295-2306
        • Niu J
        • Maurice-Dror C
        • Lee DH
        • et al.
        First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small cell lung cancer.
        Ann Oncol. 2022; 33: 169-180
        • Gray JE
        • Saltos A
        • Tanvetyanon T
        • et al.
        Phase I/Ib Study of pembrolizumab plus vorinostat in advanced/metastatic non-small cell lung cancer.
        Clin Cancer Res. 2019; 25: 6623-6632
        • Hellmann MD
        • Janne PA
        • Opyrchal M
        • et al.
        Entinostat plus pembrolizumab in patients with metastatic NSCLC previously treated with anti-PD-(L)1 therapy.
        Clin Cancer Res. 2021; 27: 1019-1028
        • Syn NL
        • Teng MWL
        • Mok TSK
        • Soo RA
        De-novo and acquired resistance to immune checkpoint targeting.
        Lancet Oncol. 2017; 18: e731-e741
        • Center for Drug Evaluation and Reserach [CDER]
        Clinical pharmacology and biopharmaceuticals review: durvalumab.
        US FDA. 2017;
        • Rizvi NA
        • Brahmer JA
        • Ignatius S-H, Ou
        • et al.
        Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC).
        Journal of Clinical Oncology. 2015; 33: 8032
        • Rebelatto M
        • Mistry A
        • Sabalos C
        • et al.
        Development of a PD-L1 companion diagnostic assay for treatment with MEDI4736 in NSCLC and SCCHN patients.
        Journal of Clinical Oncology. 2015; 33: 8033
        • Paz-Ares L
        • Spira A
        • Raben D
        • et al.
        Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small cell lung cancer in the PACIFIC trial.
        Ann Oncol. 2020; 31: 798-806