BRAF V600E-Mutated CRC Offers Poor Prognosis, But Immunotherapy and Targeted Combinations Show New Promise

Dustin Deming, MD

BRAFV600E—mutant metastatic colorectal cancer (mCRC) is a distinct subtype with unique clinical characteristics and particularly poor prognosis, according to Dustin Deming, MD.

“This mutation is a very distinct subset that we really need to think about in a different way than we think about the rest of colorectal cancer,” said Deming, assistant professor of medicine, University of Wisconsin Carbone Cancer Center, during a presentation at the 2018 International Society of Gastrointestinal Oncology Annual Meeting.

Eight percent to 10% of patients with CRC will have aBRAFmutation, and 80% of them are characterized asBRAFV600E mutations. According to Deming, this subtype is more common with woman and the elderly. It also tends to be predominantly associated with right-sided and larger primary tumors.

“These cancers are also associated with mismatch repair deficiency,” he added. “They tend to have a high grade, have a greater rate of peritoneal disease, and also more common extensive lymph node metastasis.”

Patients who present withBRAFV600E mutations have a particularly poor prognosis. In the multicenter, open-label phase III TRIBE study, patients (n = 508) were randomized 1:1 to receive irinotecan, fluorouracil (5-FU), and folinic acid (FOLFIRI) plus bevacizumab (Avastin) or irinotecan, 5-FU, folinic acid, and oxaliplatin (FOLFOXIRI) plus bevacizumab.¹In an updated analysis, the secondary analysis of overall survival (OS) was assessed in the main cohort and treatment efficacy was also assessed in theRASandBRAFmolecular subgroups.

The median OS was 37.1 months (95% CI, 29.7-42.7) in theRASandBRAFwild-type subgroups compared with 25.6 months (95% CI, 1.11-1.99) in theRAS-mutant subgroup and 13.4 months (95% CI, 8.2-24.1;P<.0001) in theBRAF-mutant subgroup.

&ldquo;There is a much worse prognosis for those patients withBRAF-mutant disease,&rdquo; he concluded.

He added that not allBRAFmutations are created equally. In a multicenter, retrospective cohort study, patients with non-V600BRAF-mutant CRC had a significantly longer median OS compared to those withBRAFV600E—mutant andBRAFwild-type CRC (60.7 months, 11.4 months, and 43.0 months, respectively;P<.001).

&ldquo;The majority of patients with non-V600BRAFmutations don&rsquo;t actually activate the kinase,&rdquo; explained Deming. &ldquo;That is a very important point when you are thinking aboutBRAF-mutant cancer. Not allBRAFmutations are bad and some of the more common alterations actually offer a favored prognosis.&rdquo;

In the frontline setting ofBRAFV600E—mutant CRC, chemotherapy options include oxaliplatin, 5-FU, and folinic acid (FOLFOX) or FOLFOXIRI with or without bevacizumab. In the subset of patients with aBRAFV600E mutation in the TRIBE study (n = 32), patients treated with FOLFOXIRI plus bevacizumab achieved a median OS of 19 months compared with 10.7 months for those who were treated with FOLFOX plus bevacizumab.¹However, these data were not statistically significant given the small sample size of patients.

&ldquo;One of the big reasons to give all chemotherapy regimens upfront is because only about a third of these patients will be able to go on and receive second-line therapy. There is a push to give what you can give upfront, because you may not get another chance.&rdquo;

Immunotherapy, however, does show benefit for patients withBRAF&shy;-mutated CRC in the second-line setting, according to Deming. In the multicenter, open-label, nonrandomized, phase II CheckMate 142 study, patients with microsatellite instability (MSI)—high/mismatch repair deficient (dMMR),BRAF-mutant mCRC (n = 12) achieved an overall response rate (ORR) of 25% with nivolumab (Opdivo).³This was significantly higher than historical rates reported with chemotherapy (<10%).

Additionally, an immunotherapy combination of nivolumab plus ipilimumab (Yervoy) demonstrated an ORR of 55% among patients with MSI-high/dMMRBRAF-mutant mCRC (n = 29), and the disease control rate was 79%.⁴

&ldquo;This indicates thatBRAFmutations, although a poor prognostic sign overall, did not predict lack of benefit with immunotherapy in this setting,&rdquo; said Deming. &ldquo;There is plenty of reason to use immunotherapy forBRAF-mutant, dMMR cancers [and] there is an interesting discussion moving forward, specifically for this [subset, about] whether or not first-line immunotherapy is a better strategy.&rdquo;

BRAF-targeted therapies, however, lack response in patients withBRAF-mutated CRC, with response rates from single-agent BRAF-targeted therapies ranging from 5% to 16%. &ldquo;This was quickly found to be related to EGFR signaling,&rdquo; Deming explained. &ldquo;When you inhibit BRAF, it causes reactivation and increased expression of EGFR, and further expression of signaling through CRAF. It bypasses the BRAF inhibitor and activates that pathway, leading to treatment resistance.&rdquo;

This observation has led to combination strategies, including the BRAF inhibitor vemurafenib (Zelboraf) in combination with standard-of-care cetuximab (Erbitux) and irinotecan. In the SWOG 1406 trial, patients (n = 106) withBRAFV600E—mutated and extendedRASwild-type mCRC were randomized to irinotecan and cetuximab with or without vemurafenib.⁵

Although modest, the addition of vemurafenib improved progression-free survival (PFS) with a median PFS of 4.3 months (95% CI, 3.6-5.7) compared with 2.0 months (95% CI, 1.8-2.1) for cetuximab and irinotecan alone (HR, 0.48; 95% CI, 0.31-0.75;P= .001). Additionally, the ORR was 16% versus 4%, respectively.

Other triplet regimens are also being investigated. &ldquo;In many patients, triplet therapies do appear to be better tolerated than even the doublet therapies,&rdquo; said Deming.

In the ongoing, phase III BEACON CRC study, the combination of the BRAF inhibitor encorafenib (Braftovi), MEK inhibitor binimetinib (Mektovi), and the anti-EGFR antibody cetuximab was investigated in patients withBRAFV600E—mutant CRC after 1 or 2 prior lines of treatment. Of the 29 evaluable patients with the mutation, the ORR was 48% with 3 complete responses. Responses were ongoing in 43% of patients at the time of data cutoff. Additionally, the preliminary estimate of PFS was 8.0 months (95% CI, 5.6-8.5).⁶

&ldquo;The BEACON study will surely lend some incredible results related to a potentially new treatment strategy, improving the survival for patients withBRAF-mutant colorectal cancer,&rdquo; Deming concluded. &ldquo;We also fully anticipate that there will be combinations of immune therapies and BRAF inhibitors for this population in the future.&rdquo;

References:

1. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.Lancet Oncol. 2015;16(13):1306-1315. doi: 10.1016/S1470-2045(15)00122-9.
2. Jones JC, Renfro LA, Al-Shamsi HA, et al. Non-V600E BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer.J Clin Oncol. 2017;35(23):2624-2630. doi: 10.1200/JCO.2016.71.4394.
3. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.Lancet Oncol. 2017;18(9):1182-1191. doi: 10.1016/S1470-2045(17)30422-9.
4. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer.J Clin Oncol.2018;36(8):773-779. doi: 10.1200/JCO.2017.76.9901.
5. Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib inBRAF-mutant metastatic colorectal cancer (SWOG 1406).J Clin Oncol. 2017;35(suppl; abstr 520). meetinglibrary.asco.org/record/139642/abstract. 6. Cutsem EV, Culye PJ, Huijberts S, et al. BEACON CRC safety lead-in (SLI) in patients withBRAFV600E metastatic colorectal cancer (mCRC): efficacy and tumor markers.J Clin Oncol. 2018;36(suppl; abstr 627). meetinglibrary.asco.org/record/155628/abstract.