Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA.

Background/objectives: Improvements in esophageal adenocarcinoma (EAC) treatment have reduced mortality. While chemoradiation before surgery was previously a standard of care, updated guidelines recommend peri-operative chemotherapy without chemoradiation. Continued investigation into optimal non-operative treatment paradigms for patients who defer surgery or are not candidates for surgery and certain chemotherapy regimens is needed. The impact of induction chemotherapy prior to chemoradiation on survival and surgical outcomes remains unclear. This study assessed survival and surgical outcomes in a real-world cohort of EAC patients receiving induction chemotherapy before chemoradiation. Methods: This single-institution, IRB-approved, retrospective cohort study included patients with newly diagnosed stage II-IVb (oligometastatic for IVb) EAC who received definitive chemoradiation (radiation ≥ 40 Gy and two cycles of chemotherapy) +/− esophagectomy from 2007 to 2022. Patients receiving induction chemotherapy were compared to those who did not. Endpoints included survival and surgical outcomes. Results: A total of 141 EAC patients received definitive chemoradiation; 83 received induction chemotherapy before chemoradiation. Patients receiving induction chemotherapy were younger (p < 0.01) with slightly lower performance status (p = 0.27) and presented at a more advanced stage (p < 0.001). Median OS was 3.5 years in the induction chemotherapy group compared to 2.2 years (p = 0.10). There was no difference in pathologic complete response (p = 0.81), esophagectomy frequency (p = 0.87), or surgical downstaging between treatment groups (p = 0.84). Conclusions: In this real-world, single-institutional patient cohort investigating induction chemotherapy prior to chemoradiation in EAC, patients receiving induction chemotherapy did well but did not have a statistically significant improvement in survival outcomes or surgical outcomes. This study showed that significant numbers of real-world patients may not receive esophagectomy. Thus, prospective, randomized clinical trials are warranted to better delineate the efficacy and selection of patients for induction chemotherapy when non-operative approaches are favored.

Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, remains one of the most lethal solid malignancies, with most patients presenting with advanced disease and limited therapeutic options. Activating KRAS mutations are present in over 90% of PDACs and drive tumor initiation, progression, metabolic reprogramming, and immune evasion, making KRAS a central therapeutic target. Advances in drug development have transformed RAS from a historically “undruggable” oncogene into a clinically actionable target through the development of mutation-selective inhibitors, pan-RAS inhibitors, targeted degraders, and RNA-based therapies. The 2026 approval of daraxonrasib by the FDA for metastatic pancreatic cancer marked the first regulatory approval of a RAS-targeted inhibitor in pancreatic ductal adenocarcinoma and validated RAS blockade as a clinically actionable therapeutic strategy. This review highlights emerging combination strategies designed to maximize the therapeutic potential of RAS inhibition in PDAC. Early clinical studies combining KRAS-targeted therapies with standard chemotherapy have demonstrated encouraging response rates and have led to multiple ongoing phase III trials. As the field moves toward precision oncology, biomarker-driven patient selection, circulating tumor DNA monitoring, and adaptive clinical trial designs will be essential for translating these advances into meaningful survival benefits. Collectively, rational combination strategies represent the next frontier in KRAS-directed therapy and hold the greatest promise for improving outcomes in PDAC.