SO-26 Clinical efficacy of combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients

Abstract

Background: KRAS p.G12C mutation is an oncogenic driver occurring in 1e3% of gastrointestinal (GI) cancers. AMG 510 is a first-in-class small molecule inhibitor of KRAS G12C. Previously, AMG 510 demonstrated a favorable tolerability profile and preliminary efficacy in the phase 1, first-in-human trial involving patients with advanced solid tumors harboring KRAS p.G12C. In this updated report, we present data in a subset of patients with advanced colorectal cancer (CRC) or other GI cancers.Methods: Key inclusion criteria: KRAS p.G12C mutation identified through molecular testing, measurable disease, and prior systemic anticancer therapy. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), as assessed per RECIST 1.1, and overall survival (OS). Oral daily doses of 180, 360, 720, and 960 mg were evaluated in dose escalation, and 960 mg was selected for dose expansion. Response was assessed every 6 weeks for 24 weeks then every 12 weeks thereafter.Results: As of the data cutoff of Jan 8, 2020, 59 patients (25 [42.4%] female), including 42 with CRC and 17 with other GI cancers (10 pancreatic cancer, 4 appendiceal cancer, 1 bile duct cancer, 1 small bowel cancer, and 1 esophageal cancer), were enrolled and dosed. The median age was 58 years (range: 33e82).Patients received a median of 3 (range: 1e4) prior lines of therapy, with 24 patients (40.7%) receiving > 3 prior lines. Median follow-up time was 7.7 months (range: 1.2e 15.9). Of all 59 patients, 17 patients (28.8%) died, and 16 patients (27.1%) remained on treatment. The most common reason for treatment discontinuation was disease progression. 28 (47.5%) and 10 (16.9%) patients had remained on treatment for more than 3 and 6 months, respectively. Treatment-related adverse events (TRAEs) occurred in 27 patients (45.8%), most of whom had grade 1/2 TRAEs. 3 patients (5.1%) had grade 3 TRAEs, including diarrhea (3.4%) and anemia (1.7%). No doselimiting toxicities, fatal/grade > 3 TRAEs, or TRAEs leading to treatment discontinuation were reported. All 42 patients with CRC had been followed up by at least 7 weeks and were evaluable for response. ORR and DCR were 7.1% (3/42, all confirmed) and 76.2% (32/42), respectively. In patients with CRC receiving the 960 mg dose, ORR and DCR were 12.0% (3/25) and 80.0% (20/25). 15 of 17 patients with other GI cancers were evaluable: 1 had confirmed partial response (appendiceal), 9 had stable disease (6 pancreatic, 2 appendiceal, and 1 bile duct), and 5 had progressive disease (2 progressed before the 1 st postbaseline assessment). 3 patients with pancreatic cancer achieving stable disease had the best tumor burden reduction of 28.0%, 28.9%, and 31.6% from baseline, respectively. PFS/OS will be reported at the congress. Conclusion:In patients with heavily pretreated KRAS p.G12C mutant GI cancers, AMG 510 monotherapy was well tolerated, with the majority of patients achieving disease control. The study is ongoing. (clinical trial informat...

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

“…A significant improvement in ORR was also observed in the triplet-therapy group (26%, 95% CI 18-35% vs. 2%, 95% CI 0-7%; p < 0.001) [5]. Besides, an exploration of up-front use of the triplet therapy, titled ANCHOR CRC, is currently ongoing [158].…”

“…An anti-programed cell death 1 (PD-1) antibody could serve as a partner agent with a BRAF inhibitor and anti EGFR mAb. Recently, Corcoran et al demonstrated the early results of their clinical trials (NCT03668431) using dabrafenib, trametinib and spartalizumab (anti-PD-1 antibody) in BRAF V600E -mutated mCRC patients at the ESMO World Congress on GI Cancers held in July 2020 [158]. They revealed promising data, i.e., ORR of 33%, in the patients with MSS (n = 17) and MSI-H (n = 8), which was superior to the previous result [158] (ORR 12%, dabrafenib and trametinib).…”

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

“…This led to reason that BRAF V600E mutant MSS mCRC patients might benefit from a combination of targeted agents and a CPI. Interestingly, initial results obtained with the combination of dabrafenib, trametinib and spartalizumab (NCT03668431) were recently presented and demonstrated a promising 35% ORR and 75% DCR [ 73 ]. Of note, patients pretreated with CPIs or BRAF inhibitors were allowed to enter the trial but efficacy was reported lower [ 73 ].…”

“…Interestingly, initial results obtained with the combination of dabrafenib, trametinib and spartalizumab (NCT03668431) were recently presented and demonstrated a promising 35% ORR and 75% DCR [ 73 ]. Of note, patients pretreated with CPIs or BRAF inhibitors were allowed to enter the trial but efficacy was reported lower [ 73 ]. Translational analysis of circulating tumor DNA (ctDNA) and patients-derived organoids (PDO) carried out in this trial are expected to clarify mechanisms of resistance and efficacy of this approach [ 73 ].…”

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

“…Preliminary results of this strategy showed that the combination is well tolerated with a favorable response rate (ORR 33%) in BRAF V600E mutated mCRC patients [185].…”