Good morning and thank you for the invitation to present this this morning. Here is the clinical trial, it’s the BRIM-8 which is a randomised double-blind placebo-controlled study of adjuvant vemurafenib monotherapy in patients with completely resected BRAF melanoma at high risk of recurrence. Briefly the background, this has been talked about in the other presentations, but effective adjuvant treatment which is following surgical resection of high risk melanoma is really an area of continued high unmet need and the currently approved adjuvant options are associated with the potential for significant toxicities and/or limited efficacy. The standard of care for patients with stage 2c melanoma to stage 3c melanoma is resection of the primary and/or removal of the effective lymph nodes but, despite this, the risk of recurrence and mortality remains high.

Vemurafenib is a BRAF inhibitor and has demonstrated clinical activity against BRAF mutated melanoma in the metastatic setting. This trial assessed the efficacy and safety of vemurafenib in two cohorts of high risk patients. Cohort 1 was patients with stage 2c to stage 3b melanoma and cohort 2 was patients strictly with stage 3c melanoma.

The overview of the study findings is one year of adjuvant vemurafenib therapy resulted in a substantial clinical benefit in cohort 1. There was a 46% reduction in recurrence risk, that is, in other words, disease free survival, compared to placebo and that magnitude of disease free survival previously hadn’t been demonstrated in this clinical setting. However, and importantly, due to the pre-specified statistical design of the study the results of cohort 1 could not be considered statistically significant.

The study did not meet the primary endpoint for cohort 2 where adjuvant vemurafenib did demonstrate a 20% reduction in disease free survival compared to placebo but this was not statistically significant. Potentially the biology of these higher risk stage 3c patients played a role in this outcome. But adjuvant vemurafenib was tolerable, had a manageable safety profile which was consistent with the known toxicities in the metastatic studies. The results found in cohort 1 suggest that vemurafenib may be a viable option for that group of patients.

Here’s the overall study design, again it was a two cohort study which is different than the other trials presented. Cohort 1 consisted of stage 2c patients to stage 3b patients; this is the only trial that enrolled patients with stage 2 which is a deep, high risk primary melanoma without lymph node involvement. Cohort 2 consisted solely of stage 3c patients. Patients were randomised 1:1 to either receive placebo or vemurafenib 960mg twice daily for one year and the primary endpoint was disease free survival. In the statistical design there was a hierarchical testing where cohort 2 would be analysed before cohort 1 and only if cohort 2 was statistically significant would that allow for cohort 1 to be considered significant as well.

Here’s the primary disease free survival endpoint curves. This is for cohort 2, there was an increase in median disease free survival with vemurafenib compared to placebo at 20 months versus 15 months with a hazard ratio of 0.8 but the p-value was not significant. If you look at the landmark of 12 and 24 months it’s quite interesting. At 12 months almost 80% of the patients in the vemurafenib group remain disease free compared to about 60% in the placebo group. That is, of course, when the medication was stopped. Over the next 12 months those curves come together and at 24 months there’s really no difference in the two groups.

For cohort 1 here’s the primary disease free survival endpoint. Median disease free survival was not reached for vemurafenib, was about 37 months for the placebo group with a hazard ratio of 0.54. The p-value was less than 0.05 but because of the statistical study design that’s more descriptive than statistically significant. You can see that those curves separate early and remain separated even after stopping drug.

So, in conclusion, vemurafenib monotherapy is an effective and well-tolerated adjuvant option for patients in cohort 1, stage 2c to 3b, and further exploration is needed for cohort 2 patients.