When we try to turn on the immune system to cancer, the cancer has ways to escape the immune system with something called checkpoints or triggering brakes to the immune system. There’s an early brake that is called CTLA4 that can be unleashed by ipilimumab and that therapy has become the standard of care for patients with advanced melanoma because it has improved survival over other treatments like chemotherapies. When the immune system is activated and goes into the tumour there’s another checkpoint or brake that comes into play, which is the PD1 brake and pembrolizumab takes away this late brake on the effector stage of the immune system. We compared head to head what’s the current standard, releasing the CTLA4 brake with pembrolizumab and with the releasing of this late immune brake, PD1, with pembrolizumab.

And what are the numbers coming out of this?

We entered over 800 patients and we randomised patients to two dosing regimens of pembrolizumab and one dosing regimen of ipilimumab. The primary endpoints were overall survival and progression free survival. All of the study endpoints support the benefit of pembrolizumab over ipilimumab. There’s an improvement of 31-37% in overall survival with pembrolizumab over ipilimumab. The progression free survival improves by 1.8 fold and the response rate improves close to threefold with pembrolizumab compared to ipilimumab.

Are you getting these long term survivors that were beginning, in the case of ipilimumab, to hint at the word cure?

This study has a follow-up of fourteen months and at that time 90% of the responders in all three study arms, the pembrolizumab arms or the ipilimumab, continued to respond. So far it seems like the durability of responses is comparable with ipilimumab and pembrolizumab but we’ll have to wait ten years; we haven’t waited ten years with pembrolizumab. We know with ipilimumab once there’s a response that lasts for two to three years, that tends to be a durable response.

What about toxicity?

The toxicity was grade 1-2 or low grade toxicity in the majority of cases and it was evident in all of the three study arms. Patients on pembrolizumab had higher fatigue and vitiligo depigmentation of the skin while patients with ipilimumab had a higher frequency of diarrhoea. The clinically significant toxicities grade 3-4 were higher with ipilimumab compared to pembrolizumab, with around 20% with ipilimumab and around 10-13% with pembrolizumab. So from the risk-benefit ratio it’s clear that pembrolizumab is superior to ipilimumab.

Could you give me just a quick summary of how much superior pembrolizumab is looking on these different counts?

Pembrolizumab improves the overall survival by 31-37% compared to ipilimumab. The progression free survival was improved close to twofold, or doubling, the progression free survival at six months with pembrolizumab compared to ipilimumab and the response rate close to threefold with pembrolizumab compared to ipilimumab.

Is this a class effect? Could you have other PD1 inhibitors that would do the same?

Yes, I think that the totality of the data suggests that pembrolizumab is behaving clinically similar to another PD1 antibody, nivolumab. We have to have more data in melanoma, which is not ready yet, on the PDL1 antibodies but I would assume that we’ll have several agents with similar activity as single agents.

Would you recommend the community to shift over to use pembrolizumab rather than ipilimumab at this point?

I hope the drug regulatory agencies around the world act on this data and make this agent available to patients. It’s better to treat and treat well and treat up front than to deal with a whole bunch of complications of progressive cancer. So it’s going to be cost-effective for society to offer these agents up-front, the PD1 antibodies up-front, to patients across the world.

What about combinations of different immunotherapies?

There’s the patients who don’t respond to these therapies which in melanoma is around two-thirds of the cases, speaking in general terms. So for those patients we have to devise some other treatment. By understanding the mechanism of how this therapy responds in some patients we’re realising that in some other patients what we need to do is to bring T-cells, or immune system cells, into tumours. Those combinations that can do that are being tested prospectively in the clinic.

Finally, what’s your take home message for clinicians, then?

It’s been an exciting time of applying science to patient care and we’re seeing another advance by rationally designing new drugs that unleash the immune system. Once we unleash the immune system the immune system can attack the cancer and has memory, it can do it durably. So we have a bright future of developing these agents and other agents alone and in combinations for patients.