Promising combination treatment gives additional hope to patients with the most aggressive form of skin cancer

New data announced has demonstrated that combinational treatment of cobimetinib with Zelboraf® (vemurafenib), the first personalised medicine to extend life in the first-line setting for over 30 years, (1,2) in patients with advanced melanoma (BRAFV600 mutation-positive) can prevent disease progression (progression-free survival; PFS) by 9.9 months compared to 6.2 months following treatment of vemurafenib alone. (3)

New data announced has demonstrated that combinational treatment of cobimetinib with Zelboraf® (vemurafenib), the first personalised medicine to extend life in the first-line setting for over 30 years, (1,2) in patients with advanced melanoma (BRAFV600 mutation-positive) can prevent disease progression (progression-free survival; PFS) by 9.9 months compared to 6.2 months following treatment of vemurafenib alone. (3)

The results presented at the European Society for Medical Oncology (ESMO) Congress show that patients treated with cobimetinib in combination with vemurafenib reduces the risk of their disease worsening by half (49). (3) In addition, the study found that the objective response rate (tumour response to treatment) was higher in the combination compared to vemurafenib alone (68% vs. 45%). (3) This expands on the wealth of data for vemurafenib, which was launched in 2012 as the first BRAF inhibitor proven to extend overall survival in this patient population by over one year. (1,2)

Dr James Larkin, Consultant Medical Oncologist at The Royal Marsden and Lead Investigator for the trial, said: “We are delighted to have been able to further explore the treatment options for patients with advanced melanoma. This data could represent a significant step forward in the treatment of this disease. The data shows that the combination of vemurafenib with cobimetinib prolongs progression-free survival significantly in comparison with vemurafenib alone. Not only that but it also shows that the side effects are generally manageable, which is incredibly important for our patients. Vemurafenib has been hailed as one of the biggest breakthrough treatments for malignant melanoma in the past 30 years and in just three years we have been able to make major strides in improving on its effectiveness as a treatment for patients. This latest trial is helping to cement The Royal Marsden as a global leader in this field of research.”

“This data announcement for cobimetinib represents positive progress for the thousands of patients in the UK who are suffering from melanoma”, said Charlotte Fionda, from Skcin, the Karen Clifford Skin Cancer Charity. “Melanoma is a devastating disease for patients and their families and there is a real need for additional and efficacious combination treatments, which if approved, have the potential to give additional time to those affected.”

The findings presented at ESMO are the results of CoBRIM, an international randomised, double-blind, placebo-controlled Phase 3 study evaluating the safety and efficacy of cobimetinib in combination with vemurafenib, compared to vemurafenib alone. This study included patients from nine English trial centres out of 11 based in the UK. (3,4) In addition, the latest data follows further evidence stemming from the open-label, Phase 1b study (BRIM7), which initially showed that the combination of cobimetinib and vemurafenib can be safely co-administered and had demonstrated anti-tumour activity. (5)

The safety profile of the CoBRIM study was also consistent with the BRIM7 study. (5) The most common adverse events observed in the combination arm compared to vemurafenib alone included diarrhoea (57% vs. 28%), nausea (39% vs. 24%), photosensitivity (28% vs. 16%), liver lab abnormalities (increased alanine aminotransferase [24% vs. 18%], increased aspartate aminotransferase [22% vs. 13%]), increase in creatine phosphokinase (an enzyme released by muscles, 30% vs. 3%) and vomiting (21% vs. 12%). (3)

There has been a significant rise in melanoma cases in recent years. It is estimated that 13,300 people developed the condition in the UK in 2011, equating to 37 people every day, (6) compared to 1,800 in 1975. (7) Advances in treatment have meant that more than eight in ten people with melanoma survive for five years or longer following their diagnosis. (6) However, latest statistics tell us that approximately 2,000 malignant melanoma patients die every year, (6) making continued research and development in this therapy area essential.

References:

1. McArthur GA et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3 randomised, open-label study. Lancet Oncology. 2014; 15: 323-32
2. Zelboraf (vemurafenib) Summary of Product Characteristics
3. Larkin J et al. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma. N Engl J Med. 2014; [accepted for publication]
4. National Institutes of Health. A phase 3 study comparing GDC-0973, a MEK inhibitor, in combination with vemurafenib vs. vemurafenib alone in patients with metastatic melanoma. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01689519 [Last accessed: September 2014]
5. Ribas A et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. The Lancet Oncology. 2014;15( 9):954-965
6. Cancer Research UK. Skin Cancer Statistics. Available at: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/skin/ [Last accessed: September 2014]
7. Cancer Research UK. Press release: Skin cancer rates five times higher than in 70s. Available at: http://www.cancerresearchuk.org/about-us/cancer-news/press-release/skin-cancer-rates-five-times-higher-than-in-70s [Last accessed: September 2014]
8. Algazi AP, Soon C et al. Treatment of cutaneous melanoma: current approaches and future prospects. Cancer Management and Research. 2010;2:197-211
9. Rigel D. Malignant melanoma: Perspectives on incidence and its effects on awareness, diagnosis, and treatment. CA: A Cancer Journal for Clinicians. 1996:46:195-198
10. Cancer Research UK. Two young adults diagnosed with skin cancer every day. Available at http://www.cancerresearchuk.org/about-us/cancer-news/press-release/two-young-adults-diagnosed-with-skin-cancer-every-day [Last accessed: September 2014]
11. Mistry M, Parkin DM et al, Cancer incidence in the United Kingdom: projections to the year 2030. British Journal of Cancer. 2011;105:1795-1803
12. McArthur G. Phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutation- positive patients with unresectable locally advanced or metastatic melanoma. Oral presentation at ESMO Congress, Madrid, Spain; 29 September 2014
13. Johnston S. XL518, a potent, selective, orally bioavailable MEK1 inhibitor, downregulates the Ras/Raf/MEK/ERK pathway in vivo, resulting in tumor growth inhibition and regression in preclinical models. Poster presented at: AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics; October 22, 2007; San Francisco, CA. Abstract C209