A Combination of Atezolizumab and Varlilumab (CDX-1127) With or Without the Addition of Cobimetinib in Previously Treated Unresectable BTC: A Randomized Phase 2 Study

The combination of MEK inhibition (MEKi) and PD-L1 blockade has demonstrated a significant improvement in progression-free survival (PFS) compared with PD-L1 monotherapy in patients with advanced biliary tract cancer (BTC) after initial chemotherapy (NCT03201458). By introducing immune agonists such as a CD27 agonist, it is possible to restore T-cell function in the presence of systemic MEKi. This approach may serve as an effective strategy to maximize the immunomodulatory capabilities of MEKi when used alongside checkpoint blockade.

A phase 2 randomized trial (NCT04941287) was carried out to assess the efficacy of atezolizumab in combination with the CD27 immune agonist (CDX-1127 [varlilumab]), with or without the addition of MEKi (cobimetinib), in patients with unresectable, previously treated, BTC. The study included adults with confirmed BTC, who had undergone at least 1 prior line (but no more than 2) of systemic therapy, had measurable disease, and an ECOG performance status ≤1. Patients who had previously received PD-[L]1 were also considered eligible. The trial aimed to enroll 64 evaluable subjects in a 1:1 ratio, stratified by BTC site, into either the AV (atezolizumab [840 mg intravenously on days 1 and 15] + varlilumab [3 mg/kg intravenously on days 1 and 15]) or CAV (cobimetinib [60 mg orally daily days 1-21, off days 22-28] + atezolizumab + varlilumab) group. The co-primary end points were the overall response rate (ORR) and PFS, with the primary correlative outcome focusing on treatment-related changes in CD8+ infiltrating T cells. The secondary end points included overall survival (OS) and safety.

Following a preplanned interim analysis based on ORRs, it was determined that neither treatment arm met the required threshold for continuation, resulting in the premature closure of the trial due to futility. The study included a total of 57 patients, with 26 in the CAV group and 27 in the AV group. Among the participants in the AV group, 60.7% had intrahepatic cholangiocarcinoma (iCCA), and 25.0% had previously undergone PD-L1 treatment. Among the participants in the CAV group, 72.4% had iCCA, and 37.9% had previously undergone PD-L1 treatment. The ORR was 0% for CAV and 3.8% for AV. The median PFS was 2.40 months for CAV and 1.8 months for AV, with a hazard ratio (HR) of 0.67. In patients with prior PD-[L]1 experience, the median PFS was 3.62 months for CAV and 1.84 months for AV (HR, 0.54). The median OS was 7.96 months for CAV and 6.08 months for AV (HR, 0.96). For PD-[L]1–experienced patients, the median OS was 6.36 months for CAV and 4.44 months for AV (HR, 0.56). The most common treatment-related adverse events of any grade included rash (acneiform) (CAV, 53.8% vs AV, 0), diarrhea (CAV, 53.8% vs AV, 7.4%), fatigue (CAV, 38.5% vs AV, 22.2%), and rash (maculopapular) (CAV, 34.6% vs AV, 18.5%). There were no treatment-related deaths.

Atezolizumab and varlilumab, with or without cobimetinib, were found to be safe when used in combination, but did not show any improvement in clinical outcomes for advanced-stage BTC patients in later lines of treatment. Although the difference was not statistically significant, the treatment with CAV showed a numerically favorable PFS and OS compared with AV among patients who had previous experience with immunotherapy.

Source:

Heumann TR, Yarchoan M, Murray J, et al. A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without addition of cobimetinib in previously treated unresectable biliary tract cancer. Chicago, IL, & online: presented at 2024 ASCO Annual Meeting; abstract 4017.