We have excellent treatment options for patients who are BRAF mutant; this is a mutation which has been detected in roughly 40% of the melanoma patients. We are analysing, or patients should be analysed, on a regular basis for BRAF mutations, also in stage 3 already because we have treatment options in the adjuvant setting as well as in the metastatic setting. All other patients who are not showing the BRAF mutation in their tumour are called BRAF wildtype. There is a substantial fraction of these BRAF wildtype patients who have mutations in the MAP kinase pathway and the most predominant mutation is the NRAS mutation which is there to be found and to be analysed. There have been clinical activities, drug development activities, over the last years trying also to target NRAS as a specific molecule, as a specific mutation. Particularly MEK inhibitors have been tested in NRAS mutant melanoma. The most favourable studies, the most studied drug, is binimetinib which has been tested in a phase II study and has shown activity in BRAF mutant but also NRAS mutant melanomas which was in the range of around four months PFS which was taken forward into a registrational study which was called NEMO. The NEMO study compared monotherapy of binimetinib, of the MEK inhibitor, in comparison to DTIC, an alkylating chemotherapy, and the primary endpoint was median PFS which turned out to be indeed promising, a hazard ratio of 0.61 in favour of the monotherapy of the MEK inhibitor. But the median time to progression was with the chemotherapy six weeks, 1.5 months, and for the MEK inhibitor below three months so it was statistically significant but clinically meaningful? No way. That actually was confirmed by the overall survival which was completely overlapping and the hazard ratio was 1.0 so there was no difference in overall survival between the chemotherapy and the monotherapy using binimetinib.

So monotherapy, obviously, for NRAS mutant melanoma was not the way out. There had been some studies been conducted using MEK inhibitor plus other targeting agents, LEE011 was one of those trying to target the CTK4/6 molecule. There was an improvement in comparison to monotherapy, an improvement in median PFS to more than six months, but the number of patients which are publically available at the moment is too small. So there was a poster in 2017 at ASCO demonstrating these preliminary phase II data and the larger cohort of this patient cohort, I’m not aware that this has been published. In addition there is also some toxicity issue.

So what do we do in the meantime with BRAF wildtype patients and NRAS mutant patients? What we have learned in the meantime that checkpoint blockade is acting on these patients quite nicely. There is a study comparing nivolumab against chemotherapy, DTIC, in the CHECKMATE-066 study which was designed for BRAF wildtype patients specifically. Here we have seen at ESMO three year survival data and there is a 30% benefit in survival using nivolumab in comparison to the chemotherapy and progression free survival of these patients is still maintained in roughly one-third of the patients after two years and after three years. So that’s actually the best option we have for NRAS and BRAF wildtype patients at the moment.

The latest development, which I think is very promising, is trying to bring together checkpoint blockade and targeted therapy. We have seen initial phase Ib study data using cobimetinib and atezolizumab, which is the Roche combination, with a median PFS of that combination in the range of more than 16 months. Keeping in mind that the median PFS of both agents alone is in the range of 5-6 months, so this is definitely more than additive, the effect which was seen in this small phase I trial. This has now been escalated to a phase III study, IMspire170, which is a registration study testing this combination of the MEK inhibitor, cobimetinib, in combination with atezolizumab in comparison to pembrolizumab as a standard of care in that. This study is recruiting one to one randomisation, more than 600 patients and recruitment was actually closed today, it has reached full recruitment so now we are waiting for the follow-up and the data over the next years. Probably that’s the most promising combination we are going to see for this patient cohort, hopefully emerging as a new standard of care.

What are your thoughts on different staging for adjuvant and neoadjuvant treatments?

Adjuvant treatment, obviously there is no trial at all specifically targeting NRAS or BRAF wildtype patients so BRAF wildtype patients are included in the checkpoint inhibitor studies and the nivolumab study as well as the pembrolizumab studies. What we have seen at the early read-out points for both studies using both drugs that obviously there is a benefit for BRAF wildtype patients as well. So for those patients we have treatment options using checkpoint blockade also in the adjuvant setting; whether they are BRAF mutant or not, whether they are NRAS mutant or not, checkpoint blockade is a viable option for patients in the adjuvant setting.

Do you think there are enough patient numbers to warrant having specific trials for them in the setting?

Keeping in mind that roughly 15-20% of the patients are carrying an NRAS mutation in melanoma, there are probably a lot of patients, yes. On the other hand, you need to show a really specific benefit for this patient cohort. Whether you need a specific treatment option just for NRAS mutant melanoma patients is questionable if you have excellent treatment options for BRAF wildtype patients. So if the combination of cobimetinib and atezolizumab turns out to be having really durable responses, is really prolonging median PFS times, it will be the new standard of care and there is, on the short run at least, no need for an NRAS specific treatment option.