Phase 1b study of ABBV-368, tilsotolimod, budigalimab, and nab-paclitaxel in patients with recurrent/metastatic head and neck squamous cell carcinoma

BACKGROUND: ABBV-368 is a humanized monoclonal antibody that targets the costimulatory receptor OX40. Here, we investigate a treatment strategy with ABBV-368 combined with the investigational toll-like receptor 9 agonist tilsotolimod, the programmed cell death 1 inhibitor budigalimab, and nab-paclitaxel in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). To our knowledge, this is the first clinical study in this setting to investigate chemotherapy combined with three immunotherapy agents, aiming to overcome failure of prior immune checkpoint inhibition and chemotherapy. METHODS: This phase 1b, multicenter, open-label study (NCT04196283) enrolled adult patients with R/M HNSCC into one of three treatment arms: ABBV-368 with tilsotolimod, ABBV-368 with tilsotolimod and nab-paclitaxel, or ABBV-368 with tilsotolimod, nab-paclitaxel, and budigalimab. Patients were treated in 28-day cycles. ABBV-368, nab-paclitaxel, and budigalimab were administered intravenously and tilsotolimod via intratumoral injection. Study objectives included safety, tolerability, pharmacokinetics, and preliminary antitumor activity. In addition, biomarker analyses were performed. RESULTS: Overall, 30 patients were enrolled; 16 received ABBV-368 plus tilsotolimod, 7 ABBV-368 plus tilsotolimod and nab-paclitaxel, and 7 ABBV-368 plus tilsotolimod, nab-paclitaxel, and budigalimab. In total, 80% of patients experienced any-grade adverse events related to ABBV-368. ABBV-368 and tilsotolimod induced peripheral interferon-gamma pathway upregulation, Th1 cytokine production, and T-cell activation that was not negatively impacted by nab-paclitaxel. There were no responses in the ABBV-368 plus tilsotolimod arm; one partial response was demonstrated in both the ABBV-368 plus tilsotolimod and nab-paclitaxel, and ABBV-368 plus tilsotolimod, nab-paclitaxel, and budigalimab arms, corresponding to an overall response rate of 14.3%. CONCLUSIONS: The quadruple combination of ABBV-368, tilsotolimod, nab-paclitaxel, and budigalimab was well tolerated and demonstrated pharmacodynamic activity. Several patients had disease stabilization, but clinical responses were limited. Initial priming and T-cell immune activation were inadequate to overcome prior therapy resistance mechanisms including a hypothesized unfavorable tumor microenvironment. Future work investigating strategies to target this inhibitory tumor microenvironment with optimally scheduled immunotherapy combinations in selected patients and indications is urgently needed to improve patient outcomes. TRIAL REGISTRATION NUMBER: NCT04196283.