braf inhibitor encorafenib and cetuximab real life investigation of next generation crc treatment

Conditions: Metastatic Colorectal Carcinoma

Summary: the presence of a brafv600e mutation is a marker of poor prognosis in patients with mcrc and associated with a median overall survival (mos) of approximately 12 to 14 months compared to 20 to 25 months for patients with braf wild-type tumours. after 1st line therapy, treatment outcomes with standard therapy are poor in patients with braf-mutated mcrc, with response rates (orr) of ≤ 11%, a median progression-free survival (mpfs) between 1.8 and 2.8 months, and a mos between 4.1 and 6.2 months. failure to achieve adequate survival outcomes with standard treatment regimens in patients with braf-mutated mcrc has encouraged efforts to combine multiple targeted therapies: with 665 randomized patients, the beacon crc trial represents the largest trial and is currently the only phase iii study in patients with brafv600e-mutant mcrc. bering crc - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in brafv600e-mutant mcrc patients, who have received prior systemic therapy. data from this study will contribute to a deeper understanding and characterization to the everyday use of encorafenib and cetuximab in a broader patient population in the german, austrian, and swiss routine setting.

the presence of a brafv600e mutation is a marker of poor prognosis in patients with mcrc and associated with a median overall survival (mos) of approximately 12 to 14 months compared to 20 to 25 months for pa-tients with braf wild-type tumors. after 1st line therapy, treatment out-comes with standard therapy are poor in patients with braf-mutated mcrc, with response rates (orr) of ≤ 11%, a median progression-free survival (mpfs) between 1.8 and 2.8 months, and a mos between 4.1 and 6.2 months. failure to achieve adequate survival outcomes with standard treatment regimens in patients with braf-mutated mcrc has encouraged efforts to combine multiple targeted therapies: with 665 randomized patients, the beacon crc trial represents the largest trial and is currently the only phase iii study in patients with brafv600e-mutant mcrc. after a safety lead in for dose confirmation of the triplet regimen, the phase iii part was per-formed with a total of 665 patients, randomized 1:1:1 to either receive encorafenib plus binimetinib and cetuximab (triplet) or encorafenib plus cetuximab (doublet) or folfiri / iri plus cetuximab (control). the beacon crc study met its primary endpoints overall response rate (orr) and overall survival (os) comparing encorafenib + binimetinib + cetuximab vs. chemotherapy + cetuximab (orr: 26 vs. 2%, p\<0.001; os: median 9.0 vs. 5.4 months, hr 0.52, p\<0.001). the beacon crc study was alpha-controlled also for the secondary endpoint comparing encorafenib + cetuximab vs. chemotherapy + cetuximab in terms of orr and os and showed a statistically significant advantage (orr: 20 vs. 2%, p\<0.001; os: median 8.4 vs. 5.4 months, hr 0.60, p\<0.001). in terms of safety, the overall frequency of adverse events grade 3/4 was 58% (en-corafenib + binimetinib + cetuximab) vs. 50% (encorafenib + cetuximab) vs. 61% (chemotherapy + cetuximab). analysis of quality of life data resulted in a longer maintenance of quality of life in the encorafenib + binimetinib + cetuximab arm and the encorafenib + cetuximab arm com-pared to chemotherapy + cetuximab. between encorafenib + binimetinib + cetuximab and encorafenib + cetuximab, no relevant differences were reported. with a longer follow-up (12.8 months) the updated os data showed a median os of 9.3 months in both the encorafenib + binimetinib + cetuximab arm and the encorafenib + cetuximab arm compared to 5.9 months in the control arm. updated orr rates were 27% in the triplet arm (p\<0.0001 vs. control), 20% in the doublet arm (p\<0.0001 vs. control) and 2% in the control arm. the safety and tolerability were adequate, manage-able and consistent with the known profiles of braf-, mek-, and egfr-inhibitors. regarding the triplet combination, the most common adverse events of any grade were diarrhea (triplet: 62%; control: 48%), dermatitis acneiform (triplet: 49%; control: 39%), nausea (triplet: 45%; control: 41%), and vomiting (triplet: 38%; control: 29%). regarding the doublet combina-tion, the most common adverse events of any grade were nausea (34%), diarrhea (33%), fatigue (doublet 30%; triplet 33%; control 27%) and derma-titis acneiform (29%). the most common updated grade ≥3 adverse events regarding the triplet combination were diarrhea (triplet: 11%; control: 10%), abdominal pain (triplet: 6%; control: 5%), nausea (triplet: 5%; control: 2%,vomiting (triplet: 5%; control: 3%) and intestinal obstruction (triplet 5%; control 3%). with the doublet regimen, the most common updated grade ≥3 adverse events were intestinal obstruction (doublet 5%), asthenia (doublet 4%; triplet 4%; control 5%), fatigue (doublet 4%; triplet 2%; control 5%), diarrhea (3%) and abdominal pain (3%). based on these data, it is expected that the european medicines agency (ema) will approve encorafenib plus cetuximab for the treatment of adult patients with metastatic brafv600e-mutant crc, who have received prior systemic therapy. data from pivotal clinical trials are usually based on a selected patient population in order to provide standardized results in the given indication. however, after marketing authorization usage in a broader patient popula-tion is to be expected. therefore, beringcrc - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in brafv600e-mutant mcrc patients, who have received prior systemic therapy.

Eligibility criteria:
inclusion criteria: * written informed consent of the patient with regard to the pseudonymized documentation of his/her data in the frame of this non-interventional study * legally capable patient ≥ 18 years of age (no upper limit) * metastatic colorectal carcinoma with brafv600e-mutation, pretreated with systemic therapy * decision was taken to treat the patient with the doublet therapy (encorafenib and cetuximab) in accordance with the current smpc and by prescription; this decision was taken prior to and independent from the inclusion into the study; * treatment with the doublet therapy (encorafenib plus cetuximab) has been started ≤ 3 months prior to providing written informed consent for this study or is planned to be started in the near future. exclusion criteria: * more than 2 prior systemic regimens in the metastatic setting (adjuvant systemic therapy with relapse ≤ 6 months will be counted as metastatic treatment line; maintenance treatment will not be counted as separate metastatic treatment line) * prior treatment with any raf-inhibitor or mek-inhibitor. * presence of any contraindication with regard to the doublet therapy (encorafenib plus cetuximab) as specified in the corresponding smpcs * current or upcoming participation in an interventional clinical trial * current or upcoming systemic treatment of any other tumor than metastatic colorectal carcinoma * prisoners or persons who are compulsorily detained (involuntarily incarcerated).

Keywords: brafv600e mutation