Abstract A001: An open label, phase II trial of ERK inhibition alone and in combination with autophagy inhibition in patients with metastatic cancreatic cancer

Abstract Background: Approximately 92% of pancreatic ductal adenocarcinoma (PDAC) harbor activating mutations in the KRAS oncoprotein. Therapeutic targeting of key elements of the MAPK pathway, including RAF, MEK and ERK, have failed to yield clinical benefit in patients with metastatic PDAC. Autophagy is a putative mechanism of resistance to ERK MAPK inhibition. Hydroxychloroquine (HCQ) is an inhibitor of autophagy and functions by inhibiting acidification of lysosomes. LY3214996 is an inhibitor of ERK 1/2 and has shown anti-tumor activity in pre-clinical models of PDAC. In this study, we evaluate the clinical efficacy of LY3214996 alone and in combination with HCQ. Methods: Eligible patients had metastatic PDAC or poorly differentiated carcinoma of the pancreas. Patients had at least one, but no more than two prior lines of systemic therapy. Twelve patients were included in the safety lead-in. One patient experienced grade 3 acute kidney injury and another experienced grade 3 nausea, thus dose level -1 was chosen as the tolerable dose for combination therapy. Patients were randomized in a 1: 1 fashion to receive either LY3214996 200mg PO daily + HCQ 600mg PO BID (Arm 1) or LY3214996 400mg PO daily (Arm 2). The primary endpoint was disease control rate (DCR), defined as the proportion of patients with complete responses (CR), partial responses (PR) or stable disease (SD) that persisted for at least 4 months. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). Point estimates and exact binomial 95% confidence interval (CI) were used for binary endpoints and the Kaplan Meier method was used for survival analysis. With 20 subjects in each treatment arm, there is 79% power using a one-sided alpha of 0. 1 to differentiate between an unacceptable DCR of 5% and a desirable DCR of 20%. Results: A total of 39 patients met criteria for analysis (20 in Arm 1, 19 in Arm 2). The DCR rate in Arm 1 was 5% and 5. 3% in Arm 2. One patient in each arm had SD. No patients achieved a CR or PR. The median PFS was 1. 31 months in Arm 1 (95% CI 0. 79-1. 77) and 1. 87 months in Arm 2 (95% CI 1. 64-2. 36). The median OS was 2. 43 months in Arm 1 (95% CI 1. 34-5. 77) and 4. 56 months in Arm 2 (95% CI 3. 08-5. 67). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase (CPK), anorexia and cytopenias. Exploratory analysis using patient-derived organoids did not show evidence of synergistic anti-tumor activity of LY3214996 in combination with chloroquine. Conclusion: LY3214996 alone or in combination with HCQ did not result in clinically meaningful activity in patients with metastatic pancreatic cancer. Further studies are needed to evaluate optimal strategies for autophagy inhibition, as well as combination strategies with other ERK MAPK targets (i. e. , KRAS inhibitors) to fully elucidate the role of autophagy as a driver of resistance to ERK MAPK inhibition. Citation Format: Rishi Surana, Hui Zheng, Junning Wang, Micaela Morgado, Lauren K Brais, Kirsten L Bryant, Ashwin Somasundaram, Colin D Weekes, Bruno Bockorny, Mary Linton B Peters, Andrea J Bullock, Jessica A Zerillo, Ahmed A Rattani, Hanna K Sanoff, Jeffrey W Clark, Aparna R Parikh, Matthew B Yurgelun, Anuj Patel, Robert J Mayer, James M Cleary, Peter C Enzinger, Douglas A Rubinson, Nadine J McCleary, Andrea C Enzinger, Sarah E Slater, Kimmie Ng, Thomas A Abrams, Leah Biller, Srivatsan Raghavan, Joseph D Mancias, Jonathan O Nowak, Andrew J Aguirre, Channing J Der, Brian M Wolpin, Kimberley Perez. An open label, phase II trial of ERK inhibition alone and in combination with autophagy inhibition in patients with metastatic cancreatic cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr A001.