Durable Remission After Targeted Therapy in BRAF V600E–Mutant Metastatic Colorectal Cancer: Case Report

Mutations involving BRAF proto-oncogene are present in 3% to 4% of cancers, of which BRAF V600E is the most common variant.^[1]BRAF V600E mutations have an estimated prevalence of 8% to 12% in metastatic colorectal cancer (CRC). Of note, nearly 80% of metastatic-deficient mismatch repair (MSI-H/dMMR) CRCs are BRAF mutant due to hypermethylation of the MLH1 promotor.^[2,3] BRAF encodes for a serine/threonine kinase involved in the MAPK signaling pathway that, when mutated, leads to constitutive activation of the kinase, resulting in cellular proliferation. BRAF V600E mutations are generally associated with a poor prognosis, with studies demonstrating limited survival in stage II-IV CRC and limited response to conventional therapeutic agents.^[3,4]

Vemurafenib, a BRAF inhibitor, was first approved in unresectable BRAF V600E-mutated melanoma after demonstrating increased overall and progression-free survival. In contrast, BRAF inhibition as a monotherapy for BRAF V600E–mutant CRC did not demonstrate clinical activity.^[5] Subsequent efforts identified acquired resistance through intratumor heterogeneity of KRAS/NRAS mutations (upstream of BRAF in MAPK pathway) and rapid feedback activation of EGFR as potential mechanisms of resistance.^[5,6] The BEACON trial, which assessed the combination of the BRAF inhibitor encorafenib with the anti–epithelial growth factor receptor (EGFR) antibody cetuximab demonstrated improved overall survival and progression-free survival compared with chemotherapy (8.4 vs. 5.4 median overall survival; 4.2 vs. 1.2 median progression-free survival) and lead to Food and Drug Administration approval in the second line for unresectable BRAF V600E mutant CRC.^[7] Despite meaningful improvements in survival with this regimen, the vast majority of patients nevertheless develop progressive disease. Herein, we report an unusual case of a patient with metastatic BRAF V600E–mutant CRC with a durable complete response (CR) to vemurafenib plus cetuximab and chemotherapy. The patient consented to the publication of their case and photographs.

A 68-year-old man without significant medical comorbidities presented to his primary care physician with abdominal pain and anemia evaluated by colonoscopy and endoscopy, which demonstrated a circumferential mass in the ascending colon. A biopsy of the mass revealed a poorly differentiated carcinoma. Shortly thereafter, the patient was hospitalized after developing fever and abdominal tenderness. He then underwent an emergent right hemicolectomy, revealing perforation of the mass. Pathology again demonstrated a poorly differentiated carcinoma, favoring a primary colon cancer. The mass had invaded the pericolic soft tissues. Lymphovascular invasion was present. None of the 21 dissected lymph nodes were negative for carcinoma. Contemporaneous CT of the abdomen was only notable for a nonspecific liver lesion that was negative for malignancy on biopsy. The clinical stage at diagnosis was pT3N0M0.

After diagnosis, the patient was initiated on systemic chemotherapy with FOLFOX. Interval imaging after six cycles demonstrated pericolic necrotic lymphadenopathy and 5.5 × 5.2 cm local recurrence around the cecum, involving the adjacent small-bowel retroperitoneum, most consistent with carcinomatosis. Next-generation sequencing (NGS) of the tissue revealed BRAF V600E (c.1799T>A p.V600E) and PIK3CA (c.1173A>G p.I391M) mutations in addition to methylation of the MLH1 promotor consistent with an MSI-H phenotype. The patient was initiated on FOLFIRI plus cetuximab for two cycles with radiographic progression before enrolling in a Phase I clinical trial of vemurafenib in combination with cetuximab and irinotecan. Vemurafenib dosing was initially 720 mg taken orally. Approximately 2 months after the initiation of the trial, computed tomography (CT) of the abdomen revealed near-complete resolution of the recurrent disease along with significant radiologic response in lymphadenopathy. After completing five cycles, the patient developed a bowel obstruction complicated by perforation and abscess. Therapy was held. Approximately 2 months later, the patient redeveloped the bowel obstruction and underwent resection of the ileum, mesenteric mass resection, ileocolic anastomosis, and primary ileotransverse colostomy. Pathology from the surgery revealed necrosis and fibrosis of the mesenteric mass, possibly consistent with a necrotic lymph node. The resected small bowel and colon demonstrated multiple adhesions with foreign body giant cell reaction, fibrosis, and associated chronic mucosal injury, but no tumor tissue was identified. Roughly 2 months after surgery, a repeat abdomen CT demonstrated no evidence of disease, and therapy was resumed. The patient developed grade 2-3 diarrhea, requiring dose reduction of vemurafenib to 240 mg twice daily and eventual cessation of irinotecan by 18 months after the start of treatment. Cetuximab infusion was discontinued 60 months after initiation of therapy due to unclear additional benefits and patient preference.

The patient remained on the trial protocol for 89 months, with routine imaging every 3 to 6 months, before transitioning to standard-of-care use of vemurafenib at the same dosing. The patient has maintained a complete radiographic response at the last follow-up, 120 months after initiating vemurafenib (Fig. 1). Carcinoembryonic antigen levels obtained in tandem with imaging ranged between 3.3 and 11.4 ng/mL on treatment. Circulating tumor DNA was unavailable at the time of the initial treatment.

We present a patient with BRAF V600E mutation and MSI-H metastatic (m)CRC, with no evidence of disease 10 years after the initiation of combined BRAF/EGFR inhibitor therapy despite the high disease burden, including peritoneal involvement. Of note, the patient had a robust and rapid response, which resulted in a small bowel obstruction, necessitating surgical intervention. While durable CRs have been observed with immune checkpoint inhibitors, such as in the case of dMMR CRC after exposure to immune checkpoint blockade, it is uncommon to see a sustained CR with targeted therapies given the heterogeneity of driver alterations and activation of feedback pathways, which lead to the eventual development of therapeutic resistance. In the BEACON trial, which assessed the BRAF inhibitor and anti-EGFR combination (without irinotecan), 4.5% (n = 10) of patients achieved a CR. However, the duration of response is unknown, with the longest follow-up at 18 months.^[7] In the SWOG S1406 study, which randomized patients with BRAF V600E–mutant mCRC (n = 106) to receive either irinotecan and cetuximab with vemurafenib (VIC regimen) or irinotecan and cetuximab, no CRs were observed among the 17% of patients who had a response, indicating it is an uncommon occurrence.^[8]

One possible explanation for the durable CR is that inhibiting BRAF heralded a robust anti-tumor immune response. BRAF mutation correlates with increased PD-L1 expression and with the immune-activating molecular subtype of CRC, consensus molecular subtype 1.^[9,10] Moreover, there appear to be higher levels of immune-cell infiltration on BRAF-mutated tumors compared with their wild-type counterparts.^[11] The patient in the case also had an MSI-H tumor, which is a phenotype associated with increased immunogenicity and immune infiltrate, possibly explaining the improved overall survival with BRAF V600E-mutant/MSI-H CRC compared with BRAF V600E–mutant/microsatellite stable (MSS) phenotype.^[12] A single-arm, phase I/II trial studying the combination of encorafenib (BRAF inhibitor), cetuximab, and nivolumab (PD-L1 inhibitor) produced encouraging results, with overall response rate (ORR) of 45% and disease control rate (DCR) of 95% in MSS, BRAF V600E–mutated mCRC suggesting a possible benefit with the addition of immunotherapy in this context.^[13] Furthermore, a Phase II study of combined PD-L1, BRAF, and MEK inhibition in BRAF V600E–mutant mCRCs revealed greater upregulation of T-cell signatures in treated tumor cells of patients with better clinical outcomes, with an ORR of 24.3% and DCR of 70.3%.^[14,15] Results from the ongoing randomized phase III SEAMARK trial (NCT05217446), looking at the combination of encorafenib (BRAF inhibitor), cetuximab, and pembrolizumab (PD-L1 inhibitor) in MSI-H mCRC, are awaited.^[16] An alternative hypothesis is that the combination of irinotecan with EGFR/BRAF-combined may have sufficiently eradicated the tumor cells before developing resistance. A subset of CRCs may rely extensively on a singular pathway, in which case inhibition produces a robust response. For many targeted therapies, it may be a matter of sufficient blockade of the signaling pathway to prevent resistance. Therefore, more potent and selective inhibitors and drug combinations would be of interest.

There are few biomarkers that have been shown to identify patients with tumors responsive to BRAF-targeted therapy. In the SWOG S1406 trial, a decline in circulating tumor DNA BRAF V600E–mutant variant allele frequency corresponded with improved progression-free survival.^[8,17] Other biomarkers that may be of significance include RNF43 and transcriptomic signatures.^[18,19]

Given the patient’s complex clinical course, the contribution of various therapeutics toward his outcome is unclear. For example, it is difficult to exclude the possibility that the patient would have achieved a similar response to irinotecan, vemurafenib, or cetuximab alone or as a part of a doublet regimen. However, a study of BRAF V600E–mutant mCRC tumor xenografts found the most tumor growth inhibition in specimens receiving a combination of FOLFIRI with encorafenib plus cetuximab, compared with FOLFIRI or encorafenib plus cetuximab alone, suggesting an additive benefit.^[20] Additionally, molecular features associated with response beyond NGS were not examined in this case. In summary, this case demonstrates that therapies targeting genomic alterations present in CRC, such as BRAF V600E, can confer sustained CR in the right clinical context. Further work is needed to harness the potential of targeted therapy in more patients.