Abstract CT182: The anti-PD-1 antibody spartalizumab (PDR001) in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600-mutant melanoma: First efficacy, safety, and biomarker findings from the part 2 biomarker cohort of COMBi-i
Authors: Dummer Reinhard , Schadendorf Dirk , Nathan Paul , Tawbi Hussein , Robert Caroline , Ascierto Paolo A. , Ribas Antoni , Lebbé Celeste , Mandala Mario , Yamazaki Naoya , Richtig Erika , Miller Wilson H. , Gasal Eduard , Kaper Mathilde , Brase Jan C. , Mookerjee Bijoyesh , Long Georgina V. 
Published: August 2018

Abstract
Introduction: The phase 3 COMBI-i study (NCT02967692) is evaluating spartalizumab (S; PDR001) in combination with dabrafenib + trametinib (D+T) in treatment-naive patients (pts) with BRAF V600–mutant metastatic melanoma. COMBI-i comprises 3 parts: (1) safety run-in; (2) biomarker part; and (3) double-blind, randomized, placebo-controlled part. In part 1, 9/9 pts had confirmed responses (Dummer et al. ASCO-SITC 2018). The primary objective for part 2 is to evaluate changes in PD-L1 levels and CD8+ cells after treatment with S+D+T. Here, we report first efficacy, safety, and biomarker data for part 2.
Methods: In the biomarker cohort, tissue samples were collected at baseline (BL) and, if visible lesions were present, after 2-3 wk, after 8-12 wk, and at disease progression. CD8 and PD-L1 (using DAKO 28-8 assay) were examined by IHC. Any remaining tumor material was analyzed for additional biomarkers (eg, LAG3, TIM3, FOXP3, CD163). Peripheral blood mononuclear cells and plasma samples were collected at several time points for flow cytometry, ctDNA analysis, and cytokine profiling.
Results: At the data cutoff (27 Oct 2017) 23 pts received S 400 mg Q4W + D 150 mg BID + T 2 mg QD. 13 pts had completed 8 wk of treatment and median follow-up was 2.0 mo (range, 0.1-3.5). At study entry, median age was 62 y. 20 pts (87%) had stage IV disease and 3 had unresectable stage III disease; 8/9 pts with stage IV M1c had elevated LDH. Adverse events (AEs) of any grade occurred in 91% of pts; 22% (n=5) were grade 3/4. No AEs led to discontinuation. Any-grade AEs occurring in ≥ 15% of pts included pyrexia (n=14, 61%), arthralgia, fatigue, rash, and vomiting (n=4 each, 17%). The only grade 3/4 event occurring in &gt; 1 pt was pyrexia (n=2, 8.7%), which was managed with dose interruption. All 7 pts evaluable for response at first post-BL assessment at wk 12 had an unconfirmed partial response; no pts had progressive disease. In preliminary analyses of matched paired BL and on-treatment tumor samples (n=9), 4/9 tumors had no intratumoral CD8+ cells and 5/9 had very few intratumoral CD8+ cells at BL. After 2-3 wk of S+D+T treatment, 8/9 pts had an increase in intratumoral CD8+ cells; most increases were substantial. CD8+/PD-L1 and other tissue-specific and circulating biomarkers will be presented in a larger set of samples.
Conclusions: Although follow-up was limited and pt numbers were small, initial data support use of the anti–PD-1 antibody S with D+T in pts with BRAF V600–mutant unresectable or metastatic melanoma. The manageable safety profile and promising efficacy are consistent with part 1 findings from COMBI-i. Initial biomarker data suggest that S+D+T has a beneficial effect on the tumor immune microenvironment, particularly on enhancing intratumoral CD8+ T-cell infiltration.
Citation Format: Reinhard Dummer, Dirk Schadendorf, Paul Nathan, Hussein Tawbi, Caroline Robert, Paolo A. Ascierto, Antoni Ribas, Celeste Lebbé, Mario Mandala, Naoya Yamazaki, Erika Richtig, Wilson H. Miller, Eduard Gasal, Mathilde Kaper, Jan C. Brase, Bijoyesh Mookerjee, Georgina V. Long. The anti-PD-1 antibody spartalizumab (PDR001) in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600-mutant melanoma: First efficacy, safety, and biomarker findings from the part 2 biomarker cohort of COMBi-i [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT182.