Investigating Atezolizumab, Varlilumab With or Without Cobimetinib for Previously Treated BTC

A randomized, phase 2 study investigated the efficacy of atezolizumab with varlilumab (CDX-1127), an anti-CD27 human antibody, with or without the addition of cobimetinib, a MEK inhibitor (MEKi), in patients with previously treated and unresectable biliary tract cancer (BTC).

At the 2024 American Society of Clinical Oncology Annual Meeting, Thatcher Ross Heumann, MD, MPH, presented the results of this study to determine which combination provides better clinical outcomes in this patient population.

Results of a previous trial demonstrated significantly improved progression-free survival (PFS) in patients with advanced BTC after receiving first-line chemotherapy who were treated with combined MEKi and PD-L1 blockades over PD-L1 monotherapy.

While MEKi can boost tumor immunogenicity, it impairs host T-cell activation. The addition of immune agonists such as anti-CD27 antibodies can boost T-cell function when administered with systemic MEKi in vivo and may optimize the immunomodulatory potential of MEKi when used in combination.

The trial enrolled 57 patients with unresectable, previously treated BTC. Patients received either intravenous (IV) atezolizumab 840 mg on days 1 and 15 plus IV varlilumab 3 mg/kg on days 1 and 15 (AV), or oral cobimetinib 60 mg on days 1-21 (off on days 22-28) with atezolizumab and varlilumab (CAV).

There were 29 patients in the CAV treatment arm and 28 in the AV arm. A total of 67% of patients had intrahepatic cholangiocarcinoma, and 33% had received previous PD-L1. Both treatment combinations were well-tolerated, with no new safety signals.

The co-primary end points were overall response rate (ORR) and PFS. The primary correlative outcomes were treatment-related changes in CD8+ infiltrating T cells.

The trial was closed early, as a preplanned interim analysis of ORRs did not meet the threshold for continuance in either treatment arm.

The addition of CDX-1127 did not provide a meaningful increase in immunotoxicity beyond the established PD-L1 toxicity profiles. With a median follow-up time of 6.2 months, the median PFS rates were 2.2 in the CAV arm and 1.8 in the AV arm (hazard ratio [HR], 0.71 [0.40-1.25]), while ORR was 0% and 4%, respectively.

In PDL1-experienced patients, the median PFS was 3.6 months in the CAV arm and 1.7 months in the AV arm (HR, 0.44 [0.14-1.33]); the median OS was 10.2 and 6.1 months, respectively (HR, 0.76 [0.37-1.55]). In the same patient population, the median OS was 6.4 (CAV) and 4.4 (AV) months (HR, 0.68 [0.19-0.42]).

The combination treatment of atezolizumab and varlilumab with or without cobimetinib was safe but did not improve clinical outcomes in patients with advanced-stage BTC treated in later lines. Treatment with CAV provided slightly more favorable PFS and OS rates compared with AV among immunotherapy-experienced patients.