Yarchoan, Mark

Abstract Purpose: The addition of MEK inhibition (MEKi) to programmed cell death ligand 1 (PD-L1) blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer. Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination. Patients and Methods: We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1–21, off days 22–28)] in unresectable biliary tract cancer following at least one metastatic therapy. Overall response rate (ORR) and PFS were coprimary endpoints. Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm]. A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced. Both regimens were well tolerated without new safety signals. Objective responses were rare [0% (CAV); 3.8% (AV)]. The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.38–1.18]. Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18–1.62). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines. Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.

Cholangiocarcinoma (CCA) represents a biologically and clinically heterogeneous group of biliary tract malignancies. Growing evidence underscores that the 3 major anatomic subtypes—intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA)—are distinct tumor entities rather than a single disease. Each subtype differs in embryologic origin, carcinogenesis mechanisms, molecular landscape, and immunogenic profile, all of which contribute to variability in diagnosis, treatment responsiveness, and prognosis. The importance of understanding these distinctions is reinforced by the rising global incidence of CCA, which highlights the need for precision medicine approaches based on these subtypes. Recent advances have deepened our insight into subtype-specific risk factors, including chronic biliary diseases and metabolic conditions, while artificial intelligence–driven tools are improving diagnostic accuracy and risk stratification. Surgical innovations now allow for more tailored resections and perioperative care, and therapeutic strategies are increasingly guided by molecular and immune profiling. Emerging strategies for early diagnosis and chemoprevention in high-risk populations further emphasize the significance of recognizing the unique biology of each subtype. In this review, we provide a comprehensive overview of the distinct anatomic subsets of CCA, integrating their molecular and biological foundations with clinical management to inform practice and guide future research.

PURPOSE Biliary tract cancers (BTCs) are aggressive cancers that carry a poor prognosis. An enhanced understanding of the immune landscape of anatomically and molecularly defined subsets of BTC may improve patient selection for immunotherapy and inform immune-based combination treatment strategies. METHODS We analyzed deidentified clinical, genomic, and transcriptomic data from the Tempus database to determine the mutational frequency and mutational clustering across the three major BTC subtypes (intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer). We subsequently determined the relationship between specific molecular alterations and anatomical subsets and features of the BTC immune microenvironment. RESULTS We analyzed 454 samples of BTC, of which the most commonly detected alterations were TP53 (42.5%), CDKN2A (23.4%), ARID1A (19.6%), BAP1 (15.5%), KRAS (15%), CDKN2B (14.2%), PBRM1 (11.7%), IDH1 (11.7%), TERT (8.4%), KMT2C (10.4%) and LRP1B (8.4%), and FGFR2 fusions (8.7%). Potentially actionable molecular alterations were identified in 30.5% of BTCs including 39.1% of IHC. Integrative cluster analysis revealed four distinct molecular clusters, with cluster 4 predominately associated with FGFR2 rearrangements and BAP1 mutations in IHC. Immune-related biomarkers indicative of an inflamed tumor-immune microenvironment were elevated in gallbladder cancers and in cluster 1, which was enriched for TP53, KRAS, and ATM mutations. Multiple common driver genes, including TP53, FGFR2, IDH1, TERT, BRAF, and BAP1, were individually associated with unique BTC immune microenvironments. CONCLUSION BTC subtypes exhibit diverse DNA alterations, RNA inflammatory signatures, and immune biomarkers. The association between specific BTC anatomical subsets, molecular alterations, and immunophenotypes highlights new opportunities for therapeutic development.

Abstract Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2–5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

AbstractImmune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi‐AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22‐110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2‐12.9 g/dL) and 6.3 g/dL (IQR, 6.1‐8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi‐AIHA were similar in DAT positive and negative patients. ICPi‐AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi‐AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first‐line treatment in the majority of patients with ICPi‐AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.