Promising new data from trials aimed to delay resistance to BRAF inhibitors

BRAF and MEK drug combinations reveal more understanding in acquired resistance to melanoma treatment

Estimated Survival Function

Estimated Survival Function
Credit: Dr Georgina Long
Restrictions for use: ESMO website only

Promising new data on drug combinations of BRAF and MEK inhibitors indicate delayed resistance to treatment with BRAF inhibitors alone in metastatic melanoma. The phase I and II trials focus on combination therapy to slow the development of resistance to drugs that inhibit BRAF, a gene that is mutated in about half of melanomas. The results are presented at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna. 
Earlier trials with drugs that target BRAF generated excitement for their ability to quickly shrink melanoma tumours in suitable patients. But for many patients the benefits proved short-lived, as the cancer cells develop resistance to the drugs.

These studies exemplify an important landmark of some tumours, which has emerged from recent laboratory research: the presence of specific mutations, such as the BRAF mutation in metastatic melanoma which exposes an Achilles' heel, MEK in this case, according to Prof Yossef Yarden from the Weizmann Institute

BRIM7 Efficacy Results

BRIM7 Efficacy Results
Credit: Dr Rene Gonzalez
Restrictions for use: ESMO website only

of Science, Israel, a chair of the ESMO 2012 Basic Science and Translational Research programme track.

Phase II of the BRAF inhibitor dabrafenib alone vs. combination with MEK1/2 inhibitor trametinib 

Dr Georgina Long from Westmead Hospital and the Melanoma Institute Australia and colleagues reported that combining the new drugs dabrafenib and trametinib provided a clinically meaningful improvement in progression-free survival, response rate and duration of response in 162 patients with melanoma that had BRAF V600 mutations.

Patients in the study received either dabrafenib 150 mg twice daily; twice-daily dabrafenib plus once-daily 1 mg trametinib; or twice daily dabrafenib plus once-daily 2 mg trametinib. The combination prolonged progression free survival over single-drug therapy from 5.8 months to 9.4 months, which represents a 60% improvement. Among patients who received both drugs at the higher dose, 41% had not progressed 12 months after treatment began, compared to 9% in the monotherapy arm of the study.

Adverse events of pyrexia and chills were reported by 71% and 58% of patients receiving combination treatment compared to 26% and 17% of patients in the dabrafenib arm, respectively. Dose reductions and interruptions, respectively, were made in 35% and 42% of patients in the combination arm compared to 4% and 6% in the dabrafenib arm.

With dabrafenib/trametinib the most common grade 3+ adverse events were neutropenia and hyponatremia, which were seen in 11% and 7% of patients, respectively. Incidence of hyperproliferative skin lesions was much lower with combination compared to dabrafenib; cutaneous squamous cell carcinoma was 7% versus 19%, skin papilloma 4% versus 15% and hyperkeratosis was 9% versus 30%, respectively.

Phase IB study of vemurafenib in combination with the MEK inhibitor, GDC-0973

A phase I study shows that the combination of the MEK inhibitor GDC-0973 and vemurafenib can be delivered safely, Dr Rene Gonzalez of the University of Colorado Cancer Centre, Denver, and colleagues reported.

BRAF inhibition has resulted in high response rates and improved survival in patients with BRAF mutated melanoma. One of several mechanisms of resistance has been reactivation of the MAPK pathway. Preclinical models show that combined inhibition of BRAF and MEK can delay the acquisition of resistance compared to BRAF inhibitor monotherapy. Inhibition of the pathway downstream from BRAF with the MEK inhibitor GDC-0973 could theoretically overcome or delay this resistance mechanism and improve outcomes, according to Dr Gonzalez.

The study was not designed to evaluate efficacy. While early data in a small number of patients did show tumour reduction, it would be premature to comment on efficacy based on these preliminary results and further research is warranted, according to Dr Gonzalez.

The most commonly reported adverse events by all patients regardless of attribution were diarrhoea (54.5%), rash (50.0%), nausea (38.6%), fatigue/asthenia (34.1%), liver function abnormality (25.0%) and photosensitivity/sunburn (25.0%). Most frequent treatment-related grade ≥3 adverse events were diarrhoea, rash, increased creatine phosphokinase and liver function abnormality which was seen in 6.8%, 6.8%, 6.8% and 4.5% of patients, respectively. Just one patient developed cutaneous squamous cell carcinoma.