The National Institute for Health and Care Excellence (NICE) has issued a Final Appraisal Determination (FAD) recommending BRAFTOVI®▼(encorafenib) plus cetuximab, within its marketing authorisation, as an option for treating BRAFV600E mutation-positive metastatic colorectal cancer (mCRC), in adults who have had previous systemic treatment.1 This positive recommendation addresses the urgent need for effective and well-tolerated treatment options, since the current standard of care for these patients is chemotherapy-based regimens which have shown minimal response rates.[i],[ii],[iii],[iv],[v] Encorafenib plus cetuximab represents the first and only targeted combination regimen licensed in Europe specifically for BRAFV600E mCRC,[vi] and is now funded for these patients on the NHS in England, Wales and Northern Ireland.1
The decision from NICE is based on data from the pivotal, Phase 3 BEACON CRC trial, which met its primary endpoint. Results showed encorafenib plus cetuximab significantly improved median overall survival (OS) in patients with BRAFV600E-mutant mCRC,7 and reduced the risk of death by 39%,7 compared to cetuximab plus irinotecan-containing regimens (control arm) (9.3 months vs 5.9 months; hazard ratio: 0.61; 95% confidence interval: 0.48–0.77; p<0.0001) [secondary endpoint].7 Furthermore, the combination reported an improved objective response rate (ORR) (20% vs 2%; p<0.0001, per assessment by blinded independent central review [BICR]), compared to the control arm [secondary endpoint].7
The encorafenib plus cetuximab combination demonstrated a generally well-tolerated side effect profile.[vii] The most common adverse drug reactions (>25%) observed in the BEACON CRC trial for encorafenib plus cetuximab were fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal pain, decreased appetite, rash and vomiting.8 A smaller percentage of patients receiving encorafenib plus cetuximab discontinued therapy primarily due to adverse events (AEs) compared to the control arm (rate of discontinuation primarily due to AEs [any grade] was 12% with encorafenib plus cetuximab vs 17% in the control arm).8
Dr Harpreet Wasan, Consultant Medical Oncologist, London and BEACON Chief Investigator in the UK said: “This NICE recommendation represents a major milestone for metastatic (stage IV) colorectal cancer patients, with a BRAFV600E mutation. We are now able to combine two targeted therapies, without the need for any conventional, cytotoxic chemotherapy.
“Conventional cytotoxic chemotherapy is associated with suppression of the immune system in many ways, and so this chemotherapy-free option is particularly pertinent in the current COVID-19 climate; potentially also avoiding the use of permanent indwelling venous catheters and reducing the number of patient visits to hospitals. This is now the first and only licensed treatment specifically targeting BRAFV600E metastatic colorectal cancer. Historically, these patients generally have worse outcomes and a poor prognosis, when treated with standard, cytotoxic chemotherapy. Today’s recommendation offers a significantly better option in their disease management.”
Genevieve Edwards, Chief Executive of Bowel Cancer UK, said: “Approximately one in ten people diagnosed with advanced bowel cancer have a BRAFV600E mutation, and their treatment options are currently extremely limited. We worked closely with clinicians to submit evidence to the NICE consultation on the benefits of the combined therapy, and are really pleased that today’s announcement offers new hope to patients.”
“We are delighted that NICE has recognised the value of encorafenib plus cetuximab for this high medical-need population,” said Laura McMullin, General Manager UK & Ireland, Pierre Fabre. “Securing NHS reimbursement is the culmination of collaborative discussions that we have been having with NICE and NHS England since the end of last year. In particular, we would like to recognise the efforts of NHS England who have consistently supported appropriate access for this treatment. The result underscores our commitment to the colorectal cancer community and we hope that as many people as possible will benefit from this innovative treatment.”
[i] Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med. 2019;381(17):1632-1643.
[ii] Loupakis F, Ruzzo A, Cemolini C et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009;101:715-721.
[iii] De Roock W, Claes Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753-762.
[iv] Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J clin Oncol. 2017;35:520.
[v] Loupakis F, Cremonlini C, Masi G, et al. Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer. Eur J Cancer. 2014;50:57-63.
[vi] European Medicines Agency. BRAFTOVI® (encorafenib) Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/braftovi-epar-product-information_en.pdf Last accessed: November 2020
[vii] European Medicines Agency. BRAFTOVI® (encorafenib) Assessment Report. EMA/CHMP/175534/2020/. 30 April 2020.