Background & Aims: To evaluate safety and efficacy of FGFR1–3 kinase inhibitor derazantinib, in advanced intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions or rearrangements ( FGFR2 F ), mutations ( FGFR2 M ), or amplifications ( FGFR2 A ), previously treated with chemotherapy. Approach & Results: Open-label, non-controlled Phase 2 trial. Patients with advanced iCCA, ≥1 prior chemotherapy, and FGFR2 F (Substudy 1) or FGFR2 M /FGFR A (Substudy 2), received once-daily oral derazantinib 300 mg until disease progression, unacceptable toxicity, consent withdrawal or investigator decision to stop. Efficacy was assessed by central radiology review using RECIST v1.1. Primary endpoints were objective response rate (ORR; Substudy 1) and 3-month progression-free survival (PFS3; Substudy 2). Other endpoints were PFS, ORR (Substudy 2), disease control rate (DCR), duration of response (DOR), and overall survival (OS). In Substudy 1, ORR and DCR were 22.3% (23/103 partial responses) and 75.7%, respectively; median (95% CI) PFS was 8.1 (5.5,8.3) months, DOR was 6.5 (4.6,9.2) months, and OS was 17.2 (12.5,22.4) months. In Substudy 2, PFS3 was 63% (27/43), ORR was 9.3% (3 partial, 1 complete response), DCR was 69.8%, and OS was 11.9 (8.4,15.9) months. There were no Grade 4 or 5 drug-related events. FGFR inhibitor class-specific toxicities included drug-related hyperphosphataemia (38%, Grade 3: 3%) and dry eye (36%). Nail disorders (10%, any grade or causality), stomatitis (5%), retinal events (5%), and palmar-plantar erythrodysesthesia (1%) were infrequent. Conclusions: In previously chemotherapy treated, FGFR-inhibitor-naïve patients with iCCA harboring FGFR2 fusions, mutations, or amplifications, derazantinib showed clinically meaningful efficacy with durable objective responses, and a manageable safety profile.
Emerging immunotherapy for HCC: A guide for hepatologists
Abstract HCC is one of the most common cancers worldwide, and the third leading cause of cancer‐related death globally. HCC comprises nearly 90% of all cases of primary liver cancer. Approximately half of all patients with HCC receive systemic therapy during their disease course, particularly in the advanced stages of disease. Immuno‐oncology has been paradigm shifting for the treatment of human cancers, with strong and durable antitumor activity in a subset of patients across a variety of malignancies including HCC. Immune checkpoint inhibition with atezolizumab and bevacizumab, an antivascular endothelial growth factor neutralizing antibody, has become first‐line therapy for patients with advanced HCC. Beyond immune checkpoint inhibition, immunotherapeutic strategies such as oncolytic viroimmunotherapy and adoptive T‐cell transfer are currently under investigation. The tumor immune microenvironment of HCC has significant immunosuppressive elements that may affect response to immunotherapy. Major unmet challenges include defining the role of immunotherapy in earlier stages of HCC, evaluating combinatorial strategies that use targeting of the immune microenvironment plus immune checkpoint inhibition, and identifying treatment strategies for patients who do not respond to the currently available immunotherapies. Herein, we review the rationale, mechanistic basis and supporting preclinical evidence, and available clinical evidence for immunotherapies in HCC as well as ongoing clinical trials of immunotherapy.