MEKiAUTO: A phase I/II open-label study of combination therapy with the MEK inhibitor cobimetinib, Immune-checkpoint blockade with atezolizumab, and the AUTOphagy inhibitor hydroxychloroquine in KRAS-mutated advanced malignancies.

Abstract

TPS450 Background: Pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC) are aggressive diseases which account for the third and second leading causes of cancer-related death, respectively. Limited progress has been made towards effective treatments or cure. K RAS is mutated or amplified in nearly 30% of all cancers, including up to 95% of PDAC and 45% of CRC. Although no successful KRAS directed therapy has been approved to date, data has emerged demonstrating that inhibition of downstream targets of KRAS, namely MEK/ERK, increases autophagic flux in KRAS-mutated tumors. This catabolic process is used by many tumors to maintain viability and recent preclinical studies have shown that combining MEK/ERK and autophagy inhibitors in KRAS-mutated tumors can synergistically suppress cancer cell proliferation. Inhibition of autophagy has demonstrated an increase in antigen presentation which sensitize tumors to immune checkpoint inhibitors. Presented here is a trial-in-progress that will evaluate combination of cobimetinib (MEK inhibitor), atezolizumab (anti-PDL1), and hydroxychloroquine (autophagy inhibitor) in KRAS-mutated advanced malignancies. Methods: This is a phase 1/2 multicenter, open-label study of combination cobimetinib (40-60mg) orally once daily on days 1-21, hydroxychloroquine (600mg) orally twice daily on days 1-28, and atezolizumab 840 mg IV on days 1 and 15 of each 28 day cycle. Patients with histologically confirmed metastatic or unresectable KRAS-mutant adenocarcinoma for which standard curative or meaningful life-prolonging treatment options do not exist or are no longer effective will be enrolled. The primary objective of the phase I portion of this trial, which seeks to enroll 18 patients, is to estimate the maximum tolerated dose (MTD) of these agents using a two-stage time-to-event continual reassessment method (TITE-CRM). The primary objective of the phase II portion of this trial, which seeks to enroll approximately 66-157 patients, is to evaluate the preliminary efficacy of this combination, based on the objective response by 16 weeks. Secondary endpoints include PFS, OS, and safety. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, reverse phase protein array for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the phase I portion of the study. This study is open with 4 patients enrolled at the time of submission. Clinical trial information: NCT04214418 . This trial is being conducted as part of the imCORE collaboration. Clinical trial information: NCT04214418.

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

“…Notably, autophagic signaling and transcription of autophagyassociated genes were increased in cells with suppressed mKRAS but not in PDAC cells with suppressed wildtype(WT)KRAS. This could represent a therapeutic vulnerability for combinatorial targeted therapy, autophagy inhibition, and IO in mKRAS tumors [86]. Based on these preclinical results, a phase I/II(NCT04214418) is underway evaluating combination of cobimetinib (MEK inhibitor), atezolizumab (aPDL-1), and HCQ (autophagy inhibitor) in KRAS-mutated advanced malignancies, including PDAC [87].…”

Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation

“…Various clinical trials are currently active, investigating the clinical effectiveness of these therapeutic strategies ( Table 2 ) ( 33 ). Also, combinatorial approaches utilizing RAF, MEK and/or ERK inhibitors and autophagy inhibitors, which are thought to increase antigen presentation for enhanced immune responses, are being investigated in clinical trials (e.g., NCT04214418, Table 2 ) ( 220 – 222 ). Particularly simultaneous inhibition of two elements of the RAF-MEK-ERK cascade, also known as vertical inhibition, was proven to result in highly synergistic and apoptotic activity in murine tumor cells that could not be replicated with the administration of only one single inhibitor, even at high dosage regimens ( 223 ).…”