DR McDERMOTT: For many of us this is an exciting area, not just in kidney cancer but for other solid tumors. And I think what makes it particularly important for the people listening to this is this may have impact outside of traditionally responsive tumors, like melanoma and kidney cancer that have responded to varying degrees to a variety of these strategies over the years. These agents may be active in what have been considered immunoresistant tumors, like lung cancer, for example, and maybe in GI tumors. If that proves to be the case, that changes the way, in my opinion — obviously very biased — but it changes the way oncology is practiced because if something can work in lung cancer, then why can’t it work in head and neck? Why can’t it work in ovarian? It needs to be tested.
And what you see based on this early excitement is an explosion of clinical trials across the spectrum of diseases. That said, what we have now — we don’t have a ton of information that’s beyond Phase I. So we need to put this in perspective. What we’ve seen in Phase I trials with a number of different antibodies — so this is not just a nivolumab story, but with a number of different drugs — is major responses in a subset of patients with kidney cancer, melanoma and lung cancer, for the most part. Some anecdotal responses in other areas, responses that have been durable, that have been durable off drug, which is encouraging. So there may be a chance at remission for some of these patients.
We’ve seen reasonable toxicity. Not to say these drugs aren’t toxic. And some of the rare toxicities are very hard to manage because they’re so uncommon, but we’ve seen relatively less toxicity compared to older forms of immune therapy like IL-2, as we’ve talked about, or CTLA-4 blockade. And we’ve seen the potential for selecting patients who might benefit. Early days. We may never be able to get there. It’s a complicated story. But the fact that there’s tolerability suggests you might not only be able to get activity from one of these agents but in combination.
Last year it was all about PD-1 blockade — New England Journal of Medicine paper, Topalian et al, based on a 300-patient Phase I trial, which really wasn’t a Phase I. It was sort of a Phase I/II because there were expansions in a variety of different tumor types that suggested tolerability, activity, maybe selection.
This year what we’ve learned is the story isn’t as clear for the selection piece, meaning it looks like there are going to be patients who have PD-L1-negative tumors that can respond. Last year it was thought if your tumor had PD-L1 on it you were going to respond. If not, you didn’t. That was based on a very small number of patients. Now we have several hundred patients, and that story isn’t as clean. So that in some ways is a setback for development because obviously if you could identify the patients ahead of time who are going to benefit, the chances of your Phase III trial being a positive and these drugs being approved is much easier. That story is going to have to play out over time with much more research.
From a positive direction, though, what we’ve learned over the last year is we have more active drugs. This is not just a 1-drug story. And we’ve seen encouraging survivals. With more follow-up, we have patients who are surviving longer and staying in response off drug.
Probably the other exciting thing about ASCO this year — and the last thing I will say — is, combinations may play a role. Also in New England Journal 2 weeks ago — Jedd Wolchok is the first author — looking at immuno/immuno combinations of PD-1 blockade and CTLA-4 blockade. Small study, 2 institutions, Yale and Sloan-Kettering. So you have to be cautious, but very encouraging response rates, higher than you’d expect with either drug. Now, increased toxicity.
This may not be applicable to the average patient, at least immediately, but not only have we seen more responses, but the depth of response was impressive. We’re seeing patients early on in that study, within 6 or 12 weeks of starting, having 80%, 90% shrinkages of their tumor burden very quickly. And hopefully those dramatic responses will translate into benefit off drug. But at the moment we don’t know if that’s the case. If that proves to be the case, though, we could see more complete remissions, more durable remissions off treatment. And what’s interesting is you’re treating the immune system with these drugs, so that — this was a melanoma study, the Wolchok/Mario Sznol in melanoma — there’s no reason to think this wouldn’t be active in other tumor types. It’s now actively being tested in lung cancer and in kidney cancer.
The bottom line of this is, if these drugs become drugs in lung cancer then we finally have a real seat at the table for immune therapy for our patients.