Patients with metastatic colorectal cancer (mCRC) and tumours harbouring BRAF V600E mutation that received triple therapy comprising dabrafenib, trametinib, and panitumumab showed an improved best overall response and prolonged progression-free survival (PFS) compared to panitumumab plus either drabrafenib or trametinib, according to results reported at the ESMO 2016 Congress in Copenhagen, Denmark on 9 October, 2016.
Dabrafenib acts by inhibiting BRAF and trametinib by inhibiting MEK1 and MEK2; both agents block the MAPK pathway. Both drugs have demonstrated activity and have been approved for BRAF-V600E-mutated melanoma, for use either as single agents or in combination. BRAF-V600E mutations have also been reported in 5% to 10% of mCRC cases; however BRAF and MEK inhibiting monotherapies have been shown to have little activitiy in mCRC, where the presence of a BRAF V600E mutation often signals a poorer prognosis.
Lead author Ryan B Corcoran, Translational Research Director for the Gastrointestinal Cancer Center at Massachusetts General Hospital, Boston, USA and a Damon Runyon Clinical Investigator, presented findings on behalf of collegues from a study testing whether combined inhibition of the EGFR pathway with panitumumab, and dual inhibition of the MAPK pathway could provide clinical benefit in BRAF mutated mCRC. This study evaluated the efficacy and safety of panitumumab plus dabrafenib or trametinib, and in triple combination with both. The trial enrolled 134 patients with BRAF mutated mCRC who were randomised to received panitumumab plus dabrafenib (n=20), panitumumab plus trametinib (n=31), or triple combination with panitumumab, dabrafenib and trametinib (n=83). Each agent in the combination could be administered at a dose of up to the full monotherapy dose.
The trial included integrated biomarker analyses. Tumour biopsies were taken prior to and during treatment and evaluated by immunohistochemistry for phosphorylated ERK (pERK). Serial circulating tumour DNA (ctDNA) samples were obtained and profiled for mutations in the BRAF, KRAS, NRAS, and PIK3CA genes.
Improved PFS demonstrated with triple over double therapy
The majority of study participants, 120 patients, had received prior chemotherapy for mCRC and 14 were treatment-naive.
In the dabrafenib/panitumumab treatment arm, the confirmed complete response and partial response (CR/PR) rate was 10%, and 80% of patients achieved stable disease (SD). With trametinib/panitumumab no patients attained CR/PR but 53% showed SD. However, the two agents combined with panitumumab yielded an 18% CR/PR rate and 67% of patients showed SD.
Median PFS for combined dabrafenib/trametinib/panitumumab has not yet been reached compared with median PFS of 3.4 and 2.8 months demonstrated with dabrafenib/panitumumab and trametinib/panitumumab, respectively.
The safety analysis showed that the most commonly reported adverse events overall were dermatitis acneiform, diarrhoea, fatigue, nausea and rash.
Integrated biomarker analysis showed changes detected in different genes with response and upon disease progression
Immunohistochemistry done in on-treatment and pre-treatment biopsies revealed a reduction in pERK in on-treatment versus pre-treatment biopsies. The median pERK reductions were 23% for dabrafenib/panitumumab, 50% for trametinib/panitumumab, and 54% for the triple combination.
Serial ctDNA analysis also showed reductions in the BRAF V600E mutant fraction of more than 70% as early as week 4 of treatment in 12 of 14 (86%) patients in the dabrafenib/trametinib/panitumumab arm. This finding corresponds with the partial response achieved by 6 of these 12 patients by week 6.
Conversely, ctDNA analysis also demonstrated increased BRAF V600E mutant fraction in 10 patients upon progression.
Other mutations that were not present at baseline were detected in ctDNA upon progression. Of the 12 patients showing a best response of CR/PR or SD, 7 (58%) patients had RAS mutations in ctDNA upon progression that were not detectable at baseline; 3 of these patients developed multiple RAS mutations. In addition, BRAF V600E and RAS mutations were co-expressed in 2 patients at baseline.
Volker Heinemann who discussed the study findings asked if the triple combinataion with dabrafenib, trametinib and panitumumab is more active than doublet therapy, considering higher ORR, but similar DCR, PFS, and OS. There is a need for further molecular characterization of BRAF-mutant tumours with regard to MSI, additional RAS, and PIK3CA mutations. Evaluation of post-study therapy would help to understand the clinical benefit. He made an observation on evolution of RAS mutations during triplet treatment. ctDNA monitoring of BRAF and RAS mutations is feasible, but clinical relevance needs to be demonstrated. Overall, in BRAF mutant tumours triplet therapy appear to be effective but do the results change medical practice? Prof. Heinemann answered clearly not at present time, but the results stimulate further research.
Conclusions
Combined dabrafenib/trametinib/panitumumab demonstrated acceptable tolerability and activity in BRAF mutated mCRC, according to the authors, who further concluded that integrated biomarker analysis by immunohistochemistry provided evidence of downstream target inhibition. The ctDNA data suggested that changes in BRAF V600E mutation frequency may serve as a biomarker, and allow for monitoring of both treatment response and disease progression. The investigators explained that pre-existing and emergent RAS mutations may represent potential mechanisms of resistance to combination treatment.
Reference
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Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E–mutated (BRAFm) metastatic colorectal cancer (mCRC)
R.B. Corcoran, T. André, T. Yoshino, J.C. Bendell, C.E. Atreya, J.H.M. Schellens, M.P. Ducreux, A. McRee, S. Siena, G. Middleton, M. Gordon, Y. Humblet, K. Muro, E. Elez, R. Yaeger, R. Sidhu, M. Squires, S. Jaeger, F. Rangwala, E. Van Cutsem
This trial was funded by GlaxoSmithKline. Dabrafenib and trametinib are assets of Novartis AG as of 2 March 2015.