Encorafenib Plus Cetuximab With Nivolumab Under Investigation in BRAF V600E–Mutant mCRC

Van K. Morris, MD

Investigators in the phase 2 SWOG S2107 trial (NCT05308446) are evaluating encorafenib (Braftovi) plus cetuximab (Erbitux) and nivolumab (Opdivo) for patients with previously treated, microsatellite stable (MSS), unresectable, or metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation, according to a presentation at the 2023 Gastrointestinal Cancers Symposium.

In September 2021, the FDA granted approval of a new indication for the combination of cetuximab plus encorafenib for the treatment of adult patients with BRAF V600E–mutated mCRC, as detected by a FDA-approved test, after prior therapy.²

Data from the phase 3 BEACON CRC trial (NCT02928224) demonstrated that patients treated with cetuximab plus encorafenib (n = 220) experienced a median overall survival (OS) of 8.4 months (95% CI, 7.5-11.0) vs 5.4 months (95% CI, 4.8-6.6) for patients treated with irinotecan plus cetuximab or FOLFIRI with cetuximab (n = 221; HR, 0.60; 95% CI, 0.45-0.79; P = .0003).

Additionally, cetuximab plus encorafenib elicited an objective response rate (ORR) of 20% (95% CI, 13%-29%) per blinded independent central review (BICR) vs 2% (95% CI, 0%-7%) with the control (P < .0001). The median progression-free survival (PFS) per BICR in the investigative arm was 4.2 months (95% CI, 3.7-5.4) vs 1.5 months (95% CI, 1.4-1.7) in the control arm (HR, 0.40; 95% CI, 0.31-0.52; P < .0001).

Investigators hypothesized that the addition of nivolumab to encorafenib and cetuximab could increase the median PFS of patients in this population.

“The phase 3 BEACON CRC trial demonstrated an improvement in survival outcomes with encorafenib and cetuximab,” Van K. Morris, MD, lead study author of the SWOG S2107 trial, said in an interview with OncLive®. “However, while the BEACON trial was a step forward, it was a small step forward. [Therefore], we conducted a [phase 1/2] trial [NCT04017650] at The University of Texas MD Anderson Cancer Center, where we [evaluated encorafenib plus cetuximab and nivolumab in] this population.”

Preceding the phase 2 SWOG S2107 trial, Morris and colleagues led the single-institution phase 1/2 study, which examined encorafenib plus cetuximab and nivolumab in patients with BRAF V600E–mutant mCRC, and the triplet produced an ORR of 45% (95% CI, 23%-68%), a median PFS of 7.3 months (95% CI, 5.5–not applicable [NA]), and median OS of 11.4 months (95% CI, 7.6-NA).3 Among responders, the median duration of response (DOR) was 8.1 months (95% CI, 7.3-NA).

“When thinking about this very poor prognostic subpopulation of patients with MSS, BRAF-mutated CRC, staying on a well-tolerated treatment for almost a year is something that's unprecedented and hasn’t been seen before. [Despite this], we saw quite striking clinical outcomes on that [single-institution] trial,” Morris explained.

The SWOG S2107 trial is enrolling patients with confirmed unresectable or metastatic adenocarcinoma of the colon or rectum with the presence of a BRAF V600E mutation and MSS/mismatch repair–proficient status. Patients must have received 1 to 2 prior lines of treatment for mCRC and are required to have an ECOG performance status of 0 or 1.

Key exclusion criteria include prior treatment with a BRAF, EGFR, or MEK inhibitor, as well as immunotherapy. Patients cannot have any coexisting condition that requires corticosteroids or immunosuppressants.

Investigators aim to enroll 75 patients who will be randomly assigned in a 2:1 fashion to receive encorafenib plus cetuximab and nivolumab (arm 1) or encorafenib plus cetuximab alone (arm 2). PFS will serve as the primary end point of the trial, and secondary end points will include ORR, OS, DOR, estimated immune-related response criteria PFS in arm 1, and safety and tolerability.

There will be an interim futility analysis for PFS after 50% of expected events have occurred (33 in pooled arms). Moreover, a final analysis of the primary end point is planned for all eligible patients after 66 PFS events. The statistical plan assumes that the addition of nivolumab to cetuximab plus encorafenib will improve median PFS from 4.2 months to 7.3 months, using 80% power and a 1-sided α of .10.

“If this trial is positive, this can [potentially] move forward to a larger registrational study. It could mean that there is a well-tolerated triplet therapy that is expanding survival outcomes for this group of patients who, as it stands, don’t have many effective options for their treatment,” Morris concluded.

The SWOG S2107 trial is ongoing. Eight of 75 patients have enrolled as of January 2023.

References

1. Morris VK, Guthrie KA, Kopetz S, et al. Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer: SWOG S2107. J Clin Oncol. 2023;41(suppl 4):TPS265. 10.1200/JCO.2023.41.3_suppl.TPS265
2. FDA expands Lilly’s Erbitux (cetuximab) label with combination of Braftovi (encorafenib) for the treatment of BRAF V600E mutation-positive metastatic colorectal cancer (CRC) after prior therapy. News release. Eli Lilly and Company. September 29, 2021. Accessed February 7, 2023. https://investor.lilly.com/news-releases
3. Morris VK, Parseghian CM, Escano M, et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAF V600E metastatic colorectal cancer. J Clin Oncol. 2022;40(suppl 4):12. doi:10.1200/JCO.2022.40.4_suppl.012