Michael S. May

PURPOSE: Combined mitogen-activated protein kinase kinase (MEK) and autophagy inhibition has shown antitumor efficacy in preclinical pancreatic ductal adenocarcinoma (PDAC) models. We evaluated this therapeutic strategy in the autochthonous K-ras ^LSL.G12D/+ ; Trp53 ^R172H/+ ; Pdx-1-Cre (KPC) mouse model and in the MEKiAUTO phase I trial of patients with metastatic KRAS -mutant PDAC, with or without anti–PD-L1 antibody atezolizumab. Methods: Short-term intervention studies in KPC mice and a phase I clinical trial based on a time-to-event continual reassessment method design were performed. Tumor response was assessed through multiplex immunofluorescence, reverse-phase protein array, and single-nucleus RNA sequencing of serial tumor specimens. RESULTS: MEK and autophagy inhibition suppressed tumor growth in KPC mice. In the clinical trial, 14 patients were treated and four experienced a dose-limiting toxicity. The median progression-free survival (PFS) and overall survival were 7.7 weeks (95% CI, 6 to 15.6) and 20.7 weeks (95% CI, 15.6 to 46.1), respectively. snRNA-seq on paired tumor biopsies identified substantial malignant cell heterogeneity, including an epithelial subtype enriched for autophagy and mitogen-activated protein kinase (MAPK) signaling that decreased after treatment. Higher baseline abundance of this subtype correlated with longer PFS but was rare in TCGA PDAC tumors. By contrast, KPC tumors and PDAC cell lines exhibited reduced heterogeneity and uniform enrichment of this MAPK/autophagy-high state, consistent with their stronger preclinical responses. CONCLUSION: Combined MEK and autophagy inhibition showed limited tolerability in human PDAC. Divergent efficacy between preclinical and clinical settings likely reflects differences in tumor cell state heterogeneity between models. Integration of diverse, representative preclinical models is critical to guide development of effective therapies in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is a rising cause of morbidity and mortality. An immunosuppressive, hostile tumor microenvironment, and KRAS-driven biology have contributed to poor outcomes in PDAC. Recent breakthroughs in targeting tumors with homologous repair deficiency, KRAS^G12C mutations, rare gene fusions, and other molecular abnormalities have improved outcomes in subsets of patients. KRAS inhibitors, both allele specific and pan(K)RAS, claudin-targeting biologics, and PRMT5 inhibitors have demonstrated single agent activity in pretreated, biomarker selected PDAC. An improved understanding of the tumor immune microenvironment has facilitated the development of promising cancer vaccines and immunomodulating agents. This review summarizes the current state of PDAC therapeutics and describes drug development targets that will transform outcomes in PDAC in the proximate future.

Background: 20% of patients with cancer are estimated to be ineligible for phase III trials because of restrictive eligibility criteria. Ineligibility rates for earlier phase trials are even greater. In response, several groups, including the US Food and Drug Administration, have advocated for more inclusive study designs. We examined Kirsten rat sarcoma virus (KRAS) G12C inhibitor trials to determine if inclusivity has shifted in the development of molecularly targeted therapies. Methods: We evaluated phase I-III studies of KRAS G12C inhibitors in non–small cell lung cancer (NSCLC) by applying criteria from 15 US trials to a multi-institutional real-world cohort of patients with metastatic NSCLC and universal KRAS testing (n = 2383). Eligibility analysis, multivariate logistic regression for ineligibility, and a Cox proportional hazards model were used on patients with KRAS G12C–mutated NSCLC (n = 185) to compare trial enrollment and overall survival under various eligibility modifications. Results: Of patients with metastatic KRAS G12C-mutated NSCLC, 60%-70% were ineligible for any KRAS inhibitor clinical trial, including studies aiming to establish first-line standard of care. Eligibility criteria remained unchanged from phase I to phase III. Performance status, renal function, and active brain metastases were the main causes of trial ineligibility. Liberalizing criteria for renal function and brain metastases increased enrollment by 25% without affecting overall survival (P = .49), whereas allowing worse performance status reduced study effect sizes (P = .001 in second-line and P = .04 in first-line). Conclusions: Most patients with metastatic KRAS G12C-mutated NSCLC are excluded from trials. There is substantial potential to refine trial entry criteria to better balance generalizability, safety, speed, and success.

PURPOSE: To evaluate the preliminary efficacy and safety of the combination of pexidartinib, an inhibitor of colony-stimulating factor-1 receptor (CSF1R), and sirolimus, a mammalian target of rapamycin inhibitor, to target infiltrating M2 macrophages in malignant peripheral nerve sheath tumors (MPNSTs). PATIENTS AND METHODS: This investigator-initiated, phase II, multicenter, single-arm trial enrolled patients with unresectable MPNSTs. Patients were treated with pexidartinib 1000 mg and sirolimus 2 mg orally daily. The primary end point was progression-free survival (PFS). Secondary end points included objective response, safety profile, and overall survival (OS). Pretreatment and on-treatment tumor biopsies were obtained to evaluate changes in the tumor microenvironment (TME) using multiplex immunofluorescence and differential transcriptional profiling. RESULTS: Fifteen patients with MPNSTs were enrolled and 14 initiated therapy. Eight had neurofibromatosis type 1, five were sporadic, and one was undetermined. Although the target sample size was 25, because of the lower-than-expected accrual during the COVID-19 pandemic, enrollment was halted on April 12, 2023. The median PFS and median OS were 6 weeks (95% CI, 6 to 19.1) and 17.9 weeks (95% CI, 13.7 to not applicable), respectively. One patient achieved confirmed stable disease. Three patients experienced PFS ≥12 weeks. Grade 3 treatment-related toxicities (rash and leukopenia) occurred in four (28.6%) patients. Although the study did not meet its primary end point, correlative analysis demonstrated that four of the five long-term survivors had an immune-rich pretreatment TME, three of whom had a reduction in M2-tumor-associated macrophage signal with treatment. CONCLUSION: Further studies of combination of pexidartinib and sirolimus and/or immunotherapy should be performed in the subset of patients with advanced MPNST with an immune-rich TME.

The gut microbiome plays an important role in the carcinogenesis of luminal gastrointestinal malignancies and response to antineoplastic therapy. Preclinical studies have suggested a role of intratumoral gammaproteobacteria in mediating response to gemcitabine-based chemotherapy in pancreatic ductal adenocarcinoma (PDAC). To our knowledge, this is the first study to evaluate the impact of the PDAC microbiome on chemotherapy response using samples from human pancreatic tumor resections. We performed 16S rRNA gene amplification and sequencing on both formalin-fixed paraffin-embedded (FFPE) and fresh frozen human PDAC resection samples. We analyzed frozen samples from 26 patients with resected PDAC and examined tumor and tumor-adjacent normal tissue. These patients represented nine long-term survivors (LTS) and nine short-term survivors (STS) after neoadjuvant gemcitabine therapy and eight control patients who did not receive any neoadjuvant therapy prior to resection. We also included FFPE samples from five patients, including tumor samples (3 samples per patient), tumor-adjacent normal tissue (2 per patient) and tumor-adjacent paraffin (1 per patient). Within frozen tissue, total DNA yields were high, but bacterial DNA was generally low, comparable to those seen in negative controls. In FFPE tissue, DNA yields were low and bacterial abundances were comparable in paraffin, tumor and normal PDAC samples. Gammaproteobacteria concentrations did not correlate with outcomes in patients treated with neoadjuvant gemcitabine-based chemotherapy. Our study found low microbial biomass in pancreatic tumor tissue, with no detectable association between bacterial taxa and chemotherapy outcomes. These results suggest a limited role of the microbiome in gemcitabine-based chemotherapy response in PDAC. Preclinical studies have implicated the pancreatic tumor microbiome in driving response to therapy. Cytidine deaminase, an enzyme produced by gammaproteobacteria, can metabolize gemcitabine and has been hypothesized to inhibit pancreatic tumor response to chemotherapy. Several clinical trials have evaluated the role of the tumor microbiome in pancreatic cancer treatment. We evaluated the impact of the pancreatic tumor microbiome on chemotherapy response using samples from human pancreatic tumor resections. We found a low microbial load that is partially attributable to contaminants and that gammaproteobacteria levels did not correlate with outcomes in patients with pancreatic cancer treated with gemcitabine-based chemotherapy.

Homologous recombination repair (HRR) pathway deficiency opens multiple therapeutic avenues within pancreatic cancer. Patients with HRR deficiency–associated gene mutations such as BRCA1, BRCA2, and PALB2 are more susceptible to platinum-based chemotherapies and in those with somatic BRCA mutations, PARP inhibitor therapy prolongs progression-free survival. The case discussed herein illustrates the therapeutic opportunities offered through the identification of HRR deficiency in pancreatic cancer, as well as the challenges associated with treatment and prevention of central nervous system metastases in long-term survivors of pancreatic cancer.

KRAS G12C mutations are critical in the pathogenesis of multiple cancer types, including non-small cell lung (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal (CRC) cancers. As such, they have increasingly become a target of novel therapies in the management of these malignancies. However, the therapeutic success of KRAS G12C inhibitors to date has been far more limited in CRC and PDAC than NSCLC. In this review, we briefly summarize the biochemistry of KRAS targeting and treatment resistance, highlight differences in the epidemiology of various G12C-mutated cancers, and provide an overview of the published data on KRAS G12C inhibitors for various indications. We conclude with a summary of ongoing clinical trials in G12C-mutant CRC and a discussion of future directions in the management of this disease. KRAS G12C mutation, targeted therapies, colorectal cancer, non-small cell lung cancer, pancreatic cancer, drug development.

Introduction:In 1889, Stephen Paget proposed the ‘seed and soil’ hypothesis, postulating that metastasis depends on cross-talk between cancer cells and specific organ microenvironments[1]. Subseque...

Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality for the general population and diagnosis, evaluation of treatment response, and detection of recurrence relies primarily on the use of imaging. Identification of minimally invasive techniques to help diagnose, prognosticate, predict response or resistance to therapy, and detect recurrence are desperately needed. Liquid biopsies represent an emerging group of technologies which allow for non-invasive serial sampling of tumor material. Although not yet approved for routine use in pancreatic cancer, the increasing sensitivity and specificity of contemporary liquid biopsy platforms will likely change clinical practice in the near future. In this review, we discuss the recent technological advances in liquid biopsy, focusing on circulating tumor DNA, exosomes, microRNAs, and circulating tumor cells.

565 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a minority of patients (pts) eligible for curative resection. Currently, systemic treatment options for down-staging pts with borderline resectable or locally advanced PDAC is extrapolated from the metastatic setting and modified FOLFIRINOX (FFX) +/- radiation (RT) is the most widely used regimen. Herein, we report the outcomes of combination gemcitabine, docetaxel, and capecitabine (GTX) +RT as compared to FFX +RT in the neoadjuvant (NA) setting via a single institution retrospective cohort review. Methods: We retrospectively reviewed the outcomes of pts with PDAC who underwent surgical resection at Columbia University Irving Medical Center (CUIMC) between 2011-2020. We evaluated demographics, treatment, clinical, surgical, and pathological outcomes. Statistical analysis includes Kaplan-Meier analysis and paired t-tests. Results: We reviewed 717 pts who underwent surgical resection at CUIMC of which 227 pts were confirmed to have received NA chemotherapy. Of those 227 patients, 133 pts also received RT. In total, 39 pts received GTX+RT and 42 pts received FFX+RT. Median age at diagnosis of pts who received NA GTX+RT or FFX+RT was 65 and 63 years, respectively. All pts were AJCC stage III at diagnosis and ECOG 0 or 1. There was a significantly greater percentage of pts who achieved R0 resection after GTX+RT as compared to FFX+RT, 35 (89.7%) vs 29 (69.0%), respectively (p=0.022). Significantly more pts achieved N0 lymph node status after GTX+RT as compared to FFX+RT, 29 (74.4%) vs 22 (52.4%), respectively (p=0.041). No statistically significant difference was detected in recurrence-free survival (RFS) or median overall survival (mOS) in pts who received GTX+RT and achieved R0 resection as compared to FFX+RT. See Table for summary. Conclusions: GTX appears to be a viable and active NA regimen in Stage III PDAC. In our small cohort study, more patients who received GTX+RT achieved R0 resection and N0 status as compared to FFX+RT. No difference in survival was detected but this may be due to inadequate power or choice of subsequent therapies. Larger prospective studies evaluating GTX+RT as an alternative treatment in the NA setting are warranted.