A phase II trial cohort of nivolumab plus ipilimumab in patients (Pts) with recurrent/metastatic adenoid cystic carcinoma (R/M ACC).

Abstract

6084 Background: R/M ACC is a malignant neoplasm most commonly of salivary gland origin with no standard treatment. The impact of combined PD-1/CTLA-4 checkpoint blockade in R/M ACC is unknown. Methods: In a two-stage minimax phase II trial, pts with progressive R/M ACC (non-salivary primaries allowed) were enrolled and treated with nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (1 cycle = 6 weeks). Imaging, using RECIST v1.1 response assessment, was scheduled to be performed approximately every 12 weeks. The primary endpoint was overall response rate (ORR = complete response [CR]+partial response [PR]) per RECIST v1.1. To detect a difference between an unacceptable ORR of 5% and a desirable ORR of 20% (one-sided type I error of 10%, power of 90%), at least 1 in the first 18 pts required an observed response. At least 4 responses of 32 total pts were needed to meet the primary endpoint. Treatment beyond progression of disease (PD) was allowed at the discretion of the investigator. A second cohort of pts with non-ACC salivary cancer is still accruing for separate analysis. Results: From 6/12/2017-6/20/2018, 32 pts were enrolled and evaluable for the primary endpoint. There was 1 confirmed PR in the first 18 pts, therefore enrollment of the second stage continued. ORR was 6% (2/32). One additional pt had an unconfirmed PR (-31% regression before CNS PD). For best overall response, there were 2 PRs, 15 SD, and 11 PD. Four pts never reached a first disease assessment: 3 due to death from clinical PD and 1 was removed for toxicity. Six pts discontinued the trial for toxicities (Grade 4 (G4) neutropenia/sepsis and G3 adrenal insufficiency (1), G2 hypophysitis (2), G3 arthritis > 7 days (1), G3 colitis (1), and G3 hepatitis/G4 creatinine kinase (CK) elevation (1)). The 2 confirmed PRs consisted of -73.1% and -58.4% regressions, with a duration of therapy of 18.4 and 7.8 months, respectively (treatment ongoing for both). Conclusions: The study did not meet its primary endpoint, though the responses observed were dramatic. Paired biopsy and peripheral blood samples will be analyzed to elucidate insights into mechanisms of response and resistance to dual checkpoint blockade. Clinical trial information: NCT03172624.

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

“…In the ACC cohort, an ORR of 8.7% was observed (4/46 patients) (53). The combination of ipilimumab and nivolumab was initially thought to improve outcomes; however, only 2 out of 32 patients treated achieved a partial response, with a median PFS of 19.3 weeks in a prospective study (96). As previously stated, ACC appears to lack immune infiltration and harbors a lower mutation burden, being unlikely to benefit from immunotherapy (50).…”

Antitumor Activity and Treatment-Related Toxicity Associated With Nivolumab Plus Ipilimumab in Advanced Malignancies: A Systematic Review and Meta-Analysis

“…Four hundred sixty four studies and 452 abstracts were initially retrieved from PubMed search and from 2019 ASCO annual meeting abstracts, respectively. After applying our study selection criteria, 24 clinical trials including 13 trials from PubMed (Wolchok et al, 2013; Antonia et al, 2016b; Hodi et al, 2016; Hammers et al, 2017; Hellmann et al, 2017; Wolchok et al, 2017; D’Angelo et al, 2018; Hellmann et al, 2018; Long et al, 2018; Motzer et al, 2018; Omuro et al, 2018; Overman et al, 2018; Tawbi et al, 2018) and 11 trials from ASCO annual meeting (Bazhenova et al, 2019; Emamekhoo et al, 2019; Fischer et al, 2019; Klein et al, 2019; McGregor et al, 2019; Mielgo et al, 2019; Pelster et al, 2019; Singh et al, 2019; Tchekmedyian et al, 2019; Yau et al, 2019; Zer et al, 2019) were finally included in this meta-analysis. The detailed study selection flow diagram can be seen in Figure 1 .…”

Lymphocyte activation gene 3 (LAG3) protein expression on tumor-infiltrating lymphocytes in aggressive and TP53-mutated salivary gland carcinomas

“…Previous studies have demonstrated that SGCs express PD-L1, PD-L2 and CTLA at varying frequencies of up to 86% [ 12 , 13 , 15 , 16 ]. Also, checkpoint inhibitor therapy leads to dramatic responses in some patients [ 18 , 20 ]. Together with the mentioned results, our findings suggest that inhibition of immune-checkpoint molecules could be an option for systemic therapy.…”

“…Another comparable phase II study reported a slightly higher response rate of 16% for SGC (only partial responses) [ 19 ]. Also recently, a phase II trial demonstrated encouraging effectiveness of the PD-1 inhibitor nivolumab in combination with CTLA-4 inhibitor ipilimumab in SGC [ 20 ]. Another study which evaluates the therapeutic use of nivolumab alone is ongoing (NCT03132038).…”