Pancreatic ductal adenocarcinoma (PDAC) continues to carry a poor prognosis, and only incremental gains in systemic therapy have been made over the past decade. Because activating KRAS mutations are present in more than 90% of PDAC and serve as the inciting oncogenic driver, RAS has long been a coveted but elusive therapeutic target, historically deemed "undruggable." Allele-specific KRASG12C inhibitors provided the first proof of concept, but G12C mutations account for only about 1% of PDAC, in which G12D, G12V, and G12R predominate. Recent advances in the structural and biochemical understanding of RAS have yielded a rapidly expanding therapeutic landscape, broadly comprising non-G12C allele-specific inhibitors, pan-RAS and pan-KRAS inhibitors, and proteolysis-targeting chimeras. This progress is exemplified by the phase III RASolute-302 trial, in which the RAS(ON) multi-selective tri-complex inhibitor daraxonrasib nearly doubled overall survival versus chemotherapy in previously treated metastatic PDAC (13.2 vs 6.7 months), positioning it to become the first broadly applicable RAS-targeted therapy in this disease. Here we review the biology of RAS, the mechanistic rationale and clinical data behind emerging RAS-directed agents, and the central challenges ahead: targeting different KRAS subtypes, managing distinct toxicities, and overcoming the genetic and non-genetic resistance mechanisms that will require rational combination strategies to translate these gains into durable benefit.

Enfortumab vedotin (EV), pembrolizumab, and EV plus pembrolizumab (EV/P) have rapidly reshaped the treatment landscape of advanced urothelial carcinoma, but toxicity increasingly determines treatment delivery, treatment continuity, and real-world benefit. As EV/P moves into broader clinical use, clinicians must distinguish adverse events related to antibody-drug conjugate exposure from immune-mediated toxicities and recognize syndromes in which both mechanisms may contribute. In this practical, mechanism-informed review, we synthesize pivotal trials, mature follow-up reports, and representative real-world cohorts describing the safety of EV monotherapy, pembrolizumab monotherapy, and EV/P in urothelial carcinoma. Because adverse-event reporting and ascertainment are heterogeneous across studies, including differences in preferred terms, composite categories, grading frameworks, and treatment-related versus all-cause reporting, we emphasize clinically interpretable patterns rather than pooled estimates. EV monotherapy is characterized by cutaneous toxicity, peripheral neuropathy, hyperglycemia, dysgeusia, and ocular events, including early epithelial/metabolic events and cumulative neuropathy. Pembrolizumab monotherapy has a lower overall high-grade toxicity burden but is defined by immune-mediated endocrinopathies, pneumonitis, hepatitis, colitis, and nephritis. Combination therapy produces a predictable overlap of these toxicity domains, creating diagnostic and management challenges for syndromes such as skin toxicity, diarrhea, fatigue, and pulmonary symptoms. We provide comparative visual toxicity signatures, regimen-specific summary tables, temporal toxicity mapping, and a pragmatic attribution framework that classifies events as EV-predominant, immune-predominant, overlap/indeterminate, or high-risk requiring initial interruption of both agents. This review aims to support bedside recognition, provisional attribution, early management, and safer implementation of EV/P in contemporary urothelial carcinoma practice.

The integration of ICIs has reshaped therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). ICIs are established in recurrent/metastatic (R/M) HNSCC and have been extensively evaluated in resectable and locoregionally advanced (LA) disease, without success until the recent KEYNOTE-689 and NIVOPOSTOP studies. These pivotal trials demonstrate that perioperative and adjuvant ICIs can improve clinical outcomes and change clinical practice. Their implementation in resectable HNSCC may raise several unanswered questions, including optimal sequencing with surgery and radiotherapy, patient selection, and management of patients who progress to R/M disease after (neo)adjuvant therapy. This review summarizes the most recent evidence on ICIs in LA-HNSCC, highlighting both successes and challenges in clinical development, clinical practice implications, unresolved questions, and emerging strategies. We provide an overview of ongoing studies exploring ICI-based approaches and combinations for neoadjuvant adaptive response, surgical strategies including surgical conversion and organ preservation, and radiotherapy optimization. Additionally, we review ongoing clinical trials evaluating ICIs in combination with chemotherapy, antibody-drug conjugates, targeted therapy, radiotherapy-including stereotactic body radiotherapy (SBRT), novel ICIs, and therapeutic cancer vaccines targeting HPV or tumor neoantigens.