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

Abstract

9567 Background: Histone deacetylase inhibitors may enhance tumor immunogenicity through various mechanisms including induced expression of T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in mNSCLC was well tolerated with signals of activity in ICI-pretreated pts. We initiated a randomized trial in the first-line setting with the primary objective to determine if the combination had superior ORR compared to pembrolizumab monotherapy. Methods: Pts with treatment-naïve mNSCLC and 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] or 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 analysis of CD8+ TIL, scored using a 0-3 scale in tumor beds. Here we report results after a preplanned interim analysis for efficacy, with accrual ongoing to a planned total of 39 patients per arm. Results: Between 7/2017 – 1/2019, 49 pts were enrolled, with 47 pts evaluable for response (24 in Arm A and 23 in Arm B). Median age was 69 (range 47 - 87), 49% female, ECOG PS 0/1 in 11%/89%. PD-L1 TPS was ≥50% in 13/24 (54%) of pts in Arm A, and in 13/23 (57%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (13%), fatigue (8%), and pruritus (8%). 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 anorexia (43%), fatigue (43%), nausea (35%) and increased creatinine (35%). 1 pt in Arm B experienced grade ≥ 3 irAE (1 grade 3 pneumonitis). Pre-treatment CD8+ TIL were not significantly different between Arm A and Arm B (p = 0.85) with the majority of tumors in both arms having a low TIL score of 1 (65% Arm A and 73.7% Arm B). A significant increase from pre-treatment to on-treatment TIL scores was seen in both Arm A (p = 0.001) and Arm B (p = 0.002). The ORR in Arm B pts with low pre-treatment TIL (score = 1) pts was substantially higher (66.7%) than in Arm A (33.3%), suggesting the combination may be especially beneficial against low TIL tumors. Conclusions: The combination arm had a considerably higher ORR compared to pembrolizumab monotherapy, with a manageable toxicity profile. The combination of pembrolizumab plus vorinostat in mNSCLC warrants further investigation. Clinical trial information: NCT02638090 . [Table: see text]

Combining immunotherapy with an epidrug in squamous cell carcinomas of different locations: rationale and design of the PEVO basket trial

“…The ORR was significantly higher in the combination arm for patients with a low TIL level at baseline (70% versus 33%). 50 An ORR of 32% was reported with this combination in 25 patients with recurrent and/or metastatic HNSCC, 51 which is substantially higher than reported with single-agent pembrolizumab.…”

“… 49 Preliminary results from a randomized phase II trial comparing this combination with pembrolizumab alone in PD-L1 TPS > 1% metastatic NSCLC patients showed a higher ORR in the combination arm (48% versus 25%, P = 0.026). 50 Of note, eight patients (35%) in the experimental arm experienced an increase in creatinine levels. No other safety alert was reported.…”

“…The combination of an HDACi and an anti-PD-1 agent has been shown to be safe in early-phase clinical trials. 49 , 50 , 51 Ongoing trials are summarized in Table 2 .…”

“… 49 II ORR = 48% Saltas et al. 50 Pembrolizumab 02538510 HNSCC, salivary gland tumors Any II HNSCC: ORR = 32% Saltas et al. 50 Entinostat Pembrolizumab 02909452 Advanced solid tumors Any I Ongoing Gandhi et al.…”

“… 50 Pembrolizumab 02538510 HNSCC, salivary gland tumors Any II HNSCC: ORR = 32% Saltas et al. 50 Entinostat Pembrolizumab 02909452 Advanced solid tumors Any I Ongoing Gandhi et al. 52 Pembrolizumab 02437136 NSCLC >1 Ib/II Prior progression on anti-PD-1/PD-L1 therapy ORR = 9% Pembrolizumab Ipilimumab (anti-CTLA4) 02453620 Advanced solid tumors Any I Ongoing Nivolumab Pembrolizumab ±Azacitidine (DNMTi) 01928576 02437136 NSCLC Melanoma 2 or 3 II II Ongoing Prior progression on anti-PD-1/PD-L1 therapy ORR = 19% Rodriguez et al.…”