Even, Caroline , Wang, Hung-Ming , Li, Shau-Hsuan, Ngan, Roger , Dechaphunkul, Arunee , Zhang, Li , Yen, Chia Jui , Chan, Po Chung , Chakrabandhu, Somvilai , Ma, Brigette , Tanasanvimon, Suebpong , Lee, Victor , Lou, Pei-Jen , Li, Zujun , Spira, Alexander , Sukari, Ammar , Guigay, Joël , McCune, Steve , Wan-Teck Lim, Darren , Yongjian , Sun, Szpakowski, Sebastian, Yao, Yao, Fan, Oliver and Manenti, Luigi Phase II study of spartalizumab (PDR001) vs chemotherapy in patients with recurrent/metastatic nasopharyngeal cancer.

Abstract

Background: Nasopharyngeal cancer (NPC) is a common malignancy in South East Asia. Currently, there are no standard treatment options for patients (pts) with platinum refractory, recurrent metastatic (R/M) NPC. Spartalizumab (sparta) is a humanized anti-PD-1 IgG4 mAb that blocks interaction with PD-L1 and PD-L2. This is the first randomized phase II study to evaluate the efficacy and safety of sparta vs chemotherapy (CT) in NPC.

Methods: In this phase II open-label study, pts with non-keratinizing locally advanced R/M NPC who had progressed on or after platinum-based CT and received up to 2 systemic therapies, were randomized (2:1) to receive sparta or CT, per investigator’s choice. Sparta was dosed at 400 mg every 4 weeks intravenously. Pts in CT arm could crossover to receive sparta if progression was confirmed by RECIST v1.1, based on independent central review. Primary endpoint was progression free survival (PFS) and secondary endpoints included overall response rate (ORR), based on central review by RECIST v1.1, duration of response (DOR), overall survival (OS), safety and pharmacokinetics. Correlation between efficacy and expression of immunological biomarkers and immune-related genes was also studied.
Results: In total, 76 pts were randomized in sparta arm and 37 pts in CT arm (median age: 51 years, ECOG performance status: 0–2). As of Jan 31, 2018, 18/76 (23.7%) sparta-treated pts, 8/37 (21.6%) CT-treated pts and 4/20 (20.0%) pts in the crossover group were ongoing. Discontinuation rates were similar between the two arms, mainly due to progressive disease in both arms (67% each). Median PFS (95% CI) was 1.9 mo (1.8, 3.5) in sparta arm vs 6.6 mo (3.7; 9.2) in CT arm; primary endpoint was not met (HR:1.53 [95% CI 1.02, 2.27]). The ORR (95% CI) was 18.4% (10.5; 29.0) vs 32.4% (18.0; 49.8) in sparta vs CT arm, respectively and 5.0% (0.1, 24.9) in the crossover group. ORR for pts treated with monotherapy CT was 19.2% (5/26) and for those treated with CT doublet/triplet was 63.3% (7/11). The Kaplan–Meier estimate of DOR rate at 12 mo in responding sparta-treated pts was 61.0% (95% CI: 20.2, 85.8). In the CT arm, 11/12 pts either progressed or discontinued at 12 mo; at data cut-off, 1 pt remained responding for 3.61 mo. The safety profile of sparta was largely consistent with results obtained from other sparta single agent studies. Overall, treatment-related grade 3/4 adverse events were reported in 18.4% of sparta-treated pts and 40.5% of CT-treated pts. No treatment-related deaths occurred. RNA sequencing analyses of tumors revealed a correlation between response to sparta and IFNγ signature, TIM3 and LAG3 gene expression; this correlation was not observed in pts treated with CT.

Conclusions: Sparta was well tolerated and despite the study not reaching its primary endpoint, long-lasting tumor responses were observed in a subset of sparta-treated pts with NPC. Biomarker analysis is ongoing.

Item Type:	Article
Keywords:	PDR001, NPC, Spartalizumab
Date Deposited:	17 Dec 2019 00:45
Last Modified:	17 Dec 2019 00:45
URI:	https://oak.novartis.com/id/eprint/39304