Dual Inhibition Improves Outcomes for Patients with BRAF-Mutated Colorectal Tumors
SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and MSI-High tumors tend to have better outcomes. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to Epidermal Growth Factor Receptor (EGFR) targeted therapy. Approximately 5-10% of all metastatic CRC tumors present with BRAF V600 mutations and BRAF V600 is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 25% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.
The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules.BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600 mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR.
ZELBORAF® (Vemurafenib), is a selective oral inhibitor of mutated BRAF whereas ERBITUX® (Cetuximab) is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR). Preclinical studies have shown that adding CAMPTOSAR® (Irinotecan) to ZELBORAF® and ERBITUX®, in patients with refractory BRAF V600E metastatic CRC, led to a durable responses and this combination was safe and tolerable. However, both single agent ZELBORAF® and ERBITUX® were shown to have limited activity in this patient group.
Based on this scientific rationale, a phase II trial was conducted (SWOG 1406), in which 106 metastatic ColoRectal Cancer patients, with mutations in BRAF V600 and extended RAS wild-type, were enrolled. Patients were randomized to receive CAMPTOSAR® 180 mg/m2 IV every 14 days and ERBITUX® 500 mg/m2 IV every 14 days, with or without ZELBORAF® 960 mg orally twice daily. The median age was 62 years and about 50% of patients had received 1 prior regimen for metastatic or locally advanced unresectable metastatic CRC, and 39% had received prior treatment with CAMPTOSAR® . Prior therapy with anti-EGFR agent or RAF or MEK inhibitors was not allowed. Crossover from the control arm to the experimental group was allowed, after documented disease progression. The primary endpoint was Progression Free Survival.
The median Progression Free Survival was 4.4 months with the triplet, versus 2.0 months with CAMPTOSAR® plus ERBITUX® (HR=0.42; P =0.0002). The response rate was 16% versus 4%, and the Disease Control Rate was 67% versus 22% (P =0.001), with a higher Duration of Response with the addition of ZELBORAF® to CAMPTOSAR® and ERBITUX® (Triplet). Approximately 50% of the patients in the control group crossed over to the experimental group at the time of disease progression. Overall Survival data and efficacy at cross-over, data, remain immature. Patients in the experimental group (Triplet group) experienced more grade 3/4 toxicities such as neutropenia, anemia and nausea, and this increase was attributed to increased duration of exposure to therapy.
The authors concluded that the addition of ZELBORAF® to the combination of CAMPTOSAR® and ERBITUX® resulted in a 58% reduction in the risk of disease progression and a higher Disease Control Rate, suggesting that simultaneous EGFR and BRAF inhibition (Dual Inhibition) is effective in BRAF V600 mutated ColoRectal Cancer. Subgroup analysis will examine the role of CAMPTOSAR® pre-treatment and the outcomes of patients based on tumor MicroSatellite Instability. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). Kopetz S, McDonough SL, Morris VK, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 520)
Use of Molecular Biomarkers to Inform Adjuvant Therapy for Colon Cancer
SUMMARY: The role of adjuvant chemotherapy in patients with stage III ColoRectalCancer (CRC) has been well established, with improvement in Disease Free Survival (DFS) and Overall Survival (OS). The same however, cannot be stated for patients with Stage II CRC. Several Prognostic (outcome regardless of specific treatment) and Predictive (benefit from a specific therapy) molecular biomarkers have been developed to help make treatment decisions which include MSI (MicroSatellite Instability), LOH 18q (Loss of heterozygosity on the long arm of chromosome 18), P53, TS (Thymidylate Synthase), KRAS, BRAF, ERCC1 (Excision Repair Cross-Complementation group 1), Oncotype DX and Coloprint. Even though LOH 18q, P53, TS, KRAS, BRAF and ERCC1 are of prognostic value, they presently do not provide clinical utility in the management of early stage CRC. The biomarkers of interest are MSI, Oncotype DX Colon Cancer Assay and ColoPrint. MMR and MSI: MSI is the hallmark of defective/deficient DNA MisMatchRepair (MMR) system and develops following a germline mutation in one of the MMR genes. The MMR gene system consists of several proteins which are responsible for surveillance and correction of DNA errors. These genes include MLH1, MSH2, MSH6, PMS2 and EPCAM. MSI-high (MSI-H, MMR deficient) is actually a good prognostic marker in early stage CRC, with less likelihood of lymph node involvement, systemic metastases and with improved survival. These patients do not benefit from DNA inhibiting anti-metabolites such as 5-FluoroUracil (5-FU). In fact, treatment with 5-FU could be detrimental, whereas they may be more responsive to Irinotecan. This is in contrast to early stage CRC patients with tumors that are MicroSatelliteStable (MSS) or MSI-low (MSI-L) and MMR proficient, who benefit from 5-FU based adjuvant chemotherapy with significantly improved DFS. It should be noted that the prognosis for patients with early stage CRC, whose tumors harbor V600E BRAF mutation and are MSI-H, is similar to CRC patients with MSS tumors. MSI is a genetic marker of Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC) and approximately 15% of sporadic CRC share the genetics of Lynch Syndrome and are MSI-H and MMR-deficient. By evaluating the MMR/MSI status of a CRC patient, a clinician may be able to assess a patient’s prognosis, predict response to therapy and detect Lynch’s Syndrome, which constitutes about 3-5% of CRC cases. MSI is a functional assay and can be detected by PCR whereas ImmunoHistoChemistry (IHC) can confirm the presence or absence of MMR proteins.
ONCOTYPE DX COLON CANCER ASSAY: Oncotype DX Colon Cancer assay is a multigene expression assay and evaluates genes in the patient’s tumor, using paraffin slides. It consists of 7 potential recurrence genes and 5 internal reference genes and has been clinically validated from three prospective trials, to assess risk of recurrence, in patients with Stage II and III CRC. The Oncotype DX colon cancer assay is able to prognosticate the risk of recurrence of a particular CRC tumor but unlike the Oncotype DX assay for Breast Cancer, is unable to predict clinical benefit from adjuvant chemotherapy.
COLOPRINT: This assay uses an18 gene expression profile and requires fresh tissue. This assay is also able to assess the risk of recurrence in Stage II CRC but is unable to predict the benefit from adjuvant chemotherapy.
In summary, testing for MSI should be performed in all patients with Stage II CRC. Genetic signatures derived from Oncotype Dx Colon Cancer assay and ColoPrint may have limited clinical value for patients with early stage CRC. NCCN guidelines recommend adjuvant chemotherapy for high risk Stage II CRC. High risk for recurrence is defined as tumors that are poorly differentiated (except those tumors that are MSI-H), lymphovascular invasion, perineural invasion, bowel obstruction, localized perforation, close, indeterminate or positive margins and examination of less than 12 lymph nodes. Mettu NB, Hurwitz H and Hsu DS. Oncology 2013;27:746-754