Rachael Ann Safyan

Epigenetic regulators represent a novel strategy to modulate the tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC). In preclinical models, DNA hypomethylating agents enhance cytotoxic T-cell infiltration, synergize with PD-1 blockade, and improve survival when combined with immune checkpoint blockade. This single-institution, phase II study evaluated the safety, efficacy, and biomarkers of azacitidine plus pembrolizumab in patients with previously treated PDAC. Patients with locally advanced or metastatic PDAC after one prior regimen received 50 mg/m² subcutaneous azacitidine on days 1-5 of a 28-day cycle, starting week 1, and pembrolizumab 200 mg intravenously every 3 weeks starting week 3. Baseline and on-treatment blood and tumor was collected for exploratory biomarker analysis. Thirty-six patients enrolled between October 2017 and September 2021 (median age: 62.5 years); 34 were evaluable for safety; 31 for efficacy. Treatment was generally well-tolerated, with Grade 1-2 fatigue and diarrhea most common AEs. Three patients (9.7%) had a partial response, and the disease control rate was 35.5%. Median progression-free and overall survival was 1.51 and 4.83 months, respectively. Exploratory analysis suggested higher baseline CD8⁺ T cells and lower tumor Ki-67 was associated with response, whereas low baseline CD8+ T cell and Granzyme B infiltration correlated with higher exponential tumor growth rate. PD-L1 and CD68 expression were not predictive of benefit. Azacitidine plus pembrolizumab demonstrated limited clinical activity in second line, locally advanced or metastatic PDAC. Biomarker analysis suggests higher baseline CD8⁺ T-cell infiltration and lower proliferative index may identify patients more likely to benefit. (NCT03264404)

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.

PURPOSE: Clonal evolution is a mechanism of treatment resistance against epidermal growth factor receptor inhibitors (EGFRi) in metastatic colorectal cancer (mCRC). When EGFRi is discontinued, EGFRi-resistant tumor subclones decay with time, allowing for EGFRi rechallenge at later time. We conducted a meta-analysis to investigate the efficacy of EGFRi rechallenge in mCRC. METHODS: Clinical trials and observational studies investigating the efficacy of EGFRi rechallenge in mCRC were included from PubMed and Embase from inception to December 8, 2024. Hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were aggregated using Bayesian random-effects models. Objective response rates (ORRs) were aggregated using meta-random-effects models. RESULTS: Twenty-nine studies were included. The pooled median PFS, median OS, and ORR were 3.83 months (95% CI, 3.25 to 4.50), 10.43 months (95% CI, 8.14 to 13.36), and 14.61% (95% CI, 8.70 to 23.51), respectively. EGFRi rechallenge was associated with significantly longer pooled PFS (HR, 0.54 [95% CI, 0.31 to 0.93]) and numerically longer pooled OS (HR, 0.71 [95% CI, 0.46 to 1.09]) than non-EGFRi systemic therapy. Patients without detectable RAS/RAF mutations by circulating tumor DNA (ctDNA) at the time of EGFRi rechallenge had significantly longer OS (HR, 0.43 [95% CI, 0.24 to 0.75]) and PFS (HR, 0.40 [95% CI, 0.26 to 0.62]) than those with ctDNA RAS/RAF mutations. Studies with EGFRi-free intervals ≥4 months before rechallenge (18.77%) had a numerically greater pooled ORR than those with EGFRi-free intervals <4 months (6.60%). No unexpected adverse events were reported, and treatment discontinuation because of adverse events was 2.7%. CONCLUSION: EGFRi rechallenge is associated with significantly longer PFS, numerically longer OS, and clinically meaningful ORR as compared with non-EGFRi systemic therapy in mCRC, particularly for ctDNA RAS/RAF wild-type mCRC.

Background: The epidermal growth factor receptor (EGFR) is overactive in many tumors. This phase I trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma (PDA), biliary tract cancers (BTC), and other solid tumors. Patients and Methods: The phase Ia study had a 3 + 3 design with capecitabine 1000 mg/m² twice daily on days 1–14 and afatinib 20 mg, 30 mg, or 40 mg daily in 21-day cycles. In phase Ib, 15 patients, each with PDA and BTC, were treated at maximum tolerated dose (MTD). Results: A total of 41 patients were enrolled. No dose-limiting toxicities were observed, and the MTD was 40 mg afatinib plus capecitabine. Among 36 response-evaluable patients, one had a partial response (3%), and eight (22%) had stable disease. Median progression-free survival (PFS) was 1.9 months (95% CI 1.0, 2.0) for PDA and 1.9 months (95% CI 1.6, 3.4) for BTC. Median overall survival (OS) was 3.2 months (95% CI 2.0, 5.8) for PDA, and 4.6 months (95% CI 1.9, 6.1) for BTC. Median OS was 5.8 months (95% CI 2.0, 9.6) for KRAS^WT PDA, and 5.0 months (95% CI 1.6, 6.1) for KRAS^WT BTC, vs. 3.9 months (95% CI 1.9, 5.8) for KRAS^MUT PDA and 3.1 months (95% CI 1.0, 22.8) for KRAS^MUT BTC, respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory PDA/BTC. Future studies should test novel anti-EGFR/HER2 therapies in KRAS^WT cancers further selected with a comprehensive molecular profile.

A new dawn in cancer immunotherapy: the promise of mutant KRAS-specific vaccines

Supplementary Table S3. HMGA2 vs GATA6 Differential Genes.

Supplementary Figure S3. Consort Diagram and Mixed Populations. A) Consort diagram of analyzed samples. For survival analyses, all patients with intact cores (n = 491) were assessed. For treatment response analyses, patients were further subdivided by type of chemotherapy received, and neoadjuvant-treated samples were considered separately (n = 51). B) Mixed (HMGA2+ GATA6+) and double negative (HMGA2- GATA6-) populations show intermediate survival between basal and classical tumors.

Supplementary Figure S4. CK5 and CK17 do not predict treatment response or time to recurrence. A) Combining CK5 and GATA6 IHC does not predict overall survival. B) CK17 high, GATA6 low tumors display improved survival compared to CK17 low, GATA6 high tumors. C) Kaplan-Meier survival curves for CK5 positive and negative tumors treated with first-line gemcitabine chemotherapy. D) Kaplan-Meier survival curves for CK17 positive and negative tumors treated with first-line gemcitabine chemotherapy. E) CK5 status does not predict time to recurrence. F) CK17 positive tumors show longer time to recurrence than CK17 negative tumors, the opposite phenotype expected from the basal subtype.