LBA-5 ANCHOR CRC: a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer

Abstract

nivolumab showed clinical benefit. Here, we present long-term follow-up results from CheckMate 459.Methods: In CheckMate 459, 743 systemic therapyenaive patients ! 18 years of age with aHCC and Child-Pugh A liver function were randomized 1:1 to nivolumab (240 mg intravenous every 2 weeks; n ¼ 371) or sorafenib (400 mg oral twice daily; n ¼ 372). The primary endpoint was OS. Secondary endpoints were objective response rate and progression-free survival by blinded independent central review per Response Evaluation Criteria in Solid Tumors v1.1; efficacy by programmed death ligand 1 (PD-L1) tumor cell expression; and safety.Results: At a minimum follow-up of 33.6 months, nivolumab demonstrated a clinically meaningful improvement in OS versus sorafenib (median OS, 16.4 months [95% CI, 14.0e18.5] vs 14.8 months [95% CI, 12.1e17.3], respectively; hazard ratio [HR], 0.85 [95% CI, 0.72e1.00]; nominal P value ¼ 0.0522). The 33-month OS rates for nivolumab and sorafenib were 29% (95% CI, 25e34) and 21% (95% CI, 17e25), respectively. A consistent benefit was observed with nivolumab regardless of baseline PD-L1 expression (PD-L1 ! 1% HR, 0.80 [95% CI, 0.54e1.17]; PD-L1 < 1% HR, 0.84 [95% CI, 0.70e1.01]). Median OS (mOS) in patients with PD-L1 ! 1% was longer with nivolumab versus sorafenib (16.1 months [95% CI, 8.4e22.3] vs 8.6 months [95% CI, 5.7e 16.3], respectively). Among patients with hepatitis C virus (HCV) and hepatitis B virus (HBV) etiology, mOS was numerically longer with nivolumab versus sorafenib (17.5 vs 12.7 months; HR, 0.72 [95% CI, 0.51e1.02] for HCV and 16.1 vs 10.4 months; HR 0.79 [95% CI, 0.59e1.07] for HBV, respectively). Nivolumab demonstrated greater liver function preservation over time than sorafenib as evidenced by albumin-bilirubin levels and Child-Pugh scores. Seven patients (2%) in the nivolumab arm and 77 patients (21%) in the sorafenib arm received subsequent immuno-oncology therapy. Nivolumab demonstrated a more favorable safety profile compared with sorafenib, with grade 3e4 treatment-related adverse events occurring in 82 patients (22.3%) and 180 patients (49.6%), respectively. Conclusion:At a minimum follow-up of 33.6 months, 1L nivolumab monotherapy continued to demonstrate clinically meaningful survival benefit in aHCC. Nivolumab had a more favorable and manageable safety profile and greater preservation of liver function over time compared with sorafenib, consistent with previous reports, with no new or unexpected safety signals observed.

The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan

“…Triplet therapy with encorafenib (BRAF inhibitor), binimetinib (MEK inhibitor), and cetuximab was recommended by four sites (Sites C, E, I and K) because the triplet/doublet (encorafenib plus cetuximab) regimens showed a survival benefit in pre-treated metastatic colorectal cancer patients with BRAF V600E mutation in the BEACON global phase 3 trial [ 13 , 14 ]. Although the ANCHOR global phase 2 trial with the triplet regimen was ongoing in Japan at that time, the eligibility was restricted to chemotherapy-naïve patients; thus, the other seven sites did not recommend it [ 15 ]. TP0903, an AXL kinase inhibitor, was recommended by Sites F and I [ 16 ].…”

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

“…Second, the control arm has been questioned since the use of a regimen including an anti-EGFR in the second line setting is of very limited efficacy [ 44 , 45 ]. Based on the BEACON results, the active but not recruiting phase II ANCHOR-CRC trial is going to explore the role of the triplet combination in first-line setting [ 63 ]. Initial results of the triplet combination in the first-line setting were recently presented and demonstrated a 50% ORR and 85% DCR with a mPFS 4.9 months and a safety profile similar to the BEACON study [ 63 ].…”

“…Based on the BEACON results, the active but not recruiting phase II ANCHOR-CRC trial is going to explore the role of the triplet combination in first-line setting [ 63 ]. Initial results of the triplet combination in the first-line setting were recently presented and demonstrated a 50% ORR and 85% DCR with a mPFS 4.9 months and a safety profile similar to the BEACON study [ 63 ]. Based on that, a comparison with standard chemotherapy in the upfront setting is awaited with great interest.…”

“…Among them, the BREAKWATER study (NCT04607421) is the only phase III trial currently ongoing specifically designed for BRAF V600E mutant mCRC patients. Based on promising results from BEACON and ANCHOR-CRC trials [ 25 , 63 ], this trial is evaluating the efficacy of the combination cetuximab plus encorafenib compared to the same combination plus FOLFOX or FOLFIRI compared to physician choice. Interestingly, MSI patients are excluded unless they are ineligible to receive CPIs.…”

Perspectives in the Treatment of RAS or BRAF Mutated Metastatic Colorectal Cancer Patients

“…This strategy has been foreshadowed in the first-line treatment of these patients. However, when examining the use of triplet therapy in the latter context, the first results of the phase II ANCHOR-CRC trial did not live up to expectations, reporting a median PFS of only 5 months ( 25 ).…”