Phase II randomized trial of first-line pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Final results.

person Andreas Nicholas Saltos Moffitt Cancer Center, Tampa, FL info_outline Andreas Nicholas Saltos, Tawee Tanvetyanon, Ben C. Creelan, Michael Rahman Shafique, Scott Joseph Antonia, Eric B. Haura, Hong Zheng, Xiaoqing Yu, James Joseph Saller, Sebastian Viracacha, Ram Thapa, Theresa A. Boyle, Dung-Tsa Chen, Amer A Beg, Jhanelle Elaine Gray

Authors person Andreas Nicholas Saltos Moffitt Cancer Center, Tampa, FL info_outline Andreas Nicholas Saltos, Tawee Tanvetyanon, Ben C. Creelan, Michael Rahman Shafique, Scott Joseph Antonia, Eric B. Haura, Hong Zheng, Xiaoqing Yu, James Joseph Saller, Sebastian Viracacha, Ram Thapa, Theresa A. Boyle, Dung-Tsa Chen, Amer A Beg, Jhanelle Elaine Gray Organizations Moffitt Cancer Center, Tampa, FL, Duke Cancer Institute, Durham, NC Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Merck Sharp & Dohme LLC, Department of Defense Background: Histone deacetylase inhibitors enhance tumor immunogenicity through various mechanisms including induced expression of MHC and T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in advanced/metastatic (m)NSCLC was well tolerated with signals of activity in ICI-pretreated pts. To further investigate the combination, we conducted a first-line, phase II trial. Methods: Pts with treatment-naïve mNSCLC and tumor PD-L1 expression ≥ 1% were eligible. Pts were randomized, open-label, 1:1 to receive P 200 mg IV q3 wk as monotherapy [Arm A] vs P 200 mg IV q3 wk plus V 400 mg PO daily [Arm B]. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for exploratory correlative analysis including gene expression and changes in the tumor microenvironment. Results: Between 7/2017 – 2/2022, 86 pts were enrolled, with 83 pts evaluable for response (40 in Arm A and 43 in Arm B). Median age was 69 (range 44 - 87), 47% female, and ECOG PS 0/1 in 9%/91%. PD-L1 TPS was ≥50% in 20/40 (50%) of pts in Arm A, and in 23/46 (50%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (15%) and fatigue (10%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included fatigue (41%), nausea (44%), diarrhea (35%) and increased creatinine (33%). 3 pts in Arm B experienced grade ≥ 3 irAE (2 grade 3 pneumonitis and 1 grade 4 myopericarditis). In Arm B, 22/45 (49%) of pts had a dose-reduction in vorinostat, most commonly due to grade 2-3 fatigue or nausea. Efficacy results by intention-to-treat are summarized in the Table below. For evaluable patients only, ORR was 44% in Arm B (19/43) and 28% in Arm A (11/40) (p=0.18). RNA-sequencing of a subset of patients showed a significant increase in interferon-γ pathway activity in both Arms. However, between the two Arms, interferon-γ pathway activity was enhanced to greater extent in Arm B, which may have contributed the higher overall response rate. Conclusions: To our knowledge, this is the first randomized trial investigating the combination of HDAC inhibition and anti-PD1 therapy in NSCLC. Although the combination arm had a numerically higher ORR compared to P monotherapy, the result did not meet the primary endpoint for significance. While there were no new safety signals with the combination therapy, reduction or interruption in V dose occurred frequently, which may have contributed to lack of survival differences between arms. Clinical trial information: NCT02638090. Best response: Arm A N= 40 Arm B N = 46 P value PR/CR 11 (28%) 19 (41%) p=0.266 SD 15 (38%) 15 (33%) PD 14 (35%) 9 (20%) NE 3 (7%) DCR 26 (65%) 34 (74%) p=0.508 Median PFS 4.5 mo 4.3 mo p = 0.8

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