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The Immuno-oncology Traffic Jam

Bruce Booth has a valuable look at the immuno-oncology field here. Everyone knows that it’s a hot area, but the numbers show that it’s even (better, worse) than you thought. There are at least 16 PD1/PDL1 programs in the clinic right now, and if  you count up all the preclinical programs that have been announced, you get about 70 (which is what has Richard Pazdur worried). There are two dozen CTLA-4 programs going on, and the other approaches seem to be filling up in nearly the same way. The agents that have already been approved in this area are getting a mighty workout, too – Keytruda, just by itself, is involved in over three hundred studies (alone and in combination) on

Naturally, all this activity raises a lot of questions, which Booth’s post goes into. How much room is there for all these approaches? How are all these agents going to differentiate themselves, assuming that’s even possible? Since we’re talking about immunology here, the chances for everything being a bit different are actually pretty high – but the chances of being able to figure this out in clinical trials alone are actually pretty low, a problem that’s going to be exacerbating, in many cases, by sheer lack of patients as everyone tries to find this stuff out at the same time. That makes for some difficult decisions on which agents to develop and what direction to take them.

We are most certainly not going to end up with 70 PD-1 drugs when this is all over, that’s for sure. Some of these announced efforts are more serious than others, for one thing. Some of the agents are going to differentiate themselves by being obviously less efficacious than what’s already out there, and some companies are just going to get out of the area rather than spend the huge amount of time and money that might be needed to show how their program is different. This isn’t all that new a phenomenon in the oncology field, when you think about the number of people who’ve gone after, say, VEGF. You do get the impression, though, that there are going to be a lot of tough calls made with not enough data.

That goes for the physicians, too, once things get approved. Now, there are worse problems to have than figuring out what to do with this avalanche of new cancer therapies – like, for example, having no new therapies at all. But a problem it is. It’s worth emphasizing that the reason that there are so many programs in this area is that it’s (simultaneously) extremely promising and rather a black box when it comes to what’s going to work the best. It’s not like some rational actor could come in, blow a big whistle and sort out what should go where: no one knows. On balance, it’s a good thing that we have so many different approaches being tried, mixed blessing though it is. But the uncertainties are not going to end pre-approval:

. . .what happens if a large number of the 100+ different combination regimens today (e.g., PDx plus every other I/O target and chemo stack) deliver an incremental improvement in response rate in different settings? How do clinicians chose between them for their patients, and how do companies and their investors allocate capital? With the sheer volume of studies underway today, and the likelihood that many “rational combinations” will deliver some incremental improvement over PDx foundational therapy, this signal-to-noise becomes a huge challenge. Certainly highlights the importance of patient selection markers and such, but discerning how to combine for best effect will take years of work and significant investment.

The post goes on to sort out the industry players and how they’re maneuvering. I agree with Bruce when he says that by this point, “If you don’t have a compelling clinical-stage checkpoint program to anchor your franchise, you’ve probably missed the boat“. What that means, though, is being ready to move beyond checkpoint targets – there are a lot of ways to go after immune-based therapies, and if you really want to get into this area, you’re going to have to take some of those roads less traveled. Because there’s a heck of a traffic jam on the other routes. . .

8 comments on “The Immuno-oncology Traffic Jam”

  1. It’s worth noting that in addition to the immune checkpoint blockade therapies being more or less a black box right now, there aren’t any biomarkers that are signifying why anti-PD1 or anti-PDL1 treatments are effective in different cancers with different histologies/pathologies.

    I’ve attached a recent review that makes the case for discovering new biomarkers. Hopefully the data from these studies will be analyzed together to help identify something useful.

    1. tally ho says:

      Charles – thanks for passing along the interesting and timely review article.

    2. JIA says:

      Readers may also be interested in this review (linked in my handle) that suggests some hypotheses for why some patients and not others respond to PD1/PDL1 therapies.

    3. Actually Bert Vogelstein has shown that the number of mutations a tumor has correlates with efficacy of PD-1 blockade. The idea is that the greater the number of mutations, the more likely a neo-antigen is recognized as non-self and destroyed.

  2. Pharmacology rules says:

    would it not be great if so many of these were approved that pricing competition resulted in an affordable drug?

    1. Pennpenn says:

      But wouldn’t that also make it a nightmare trying to ensure that the correct patients get the proper treatment?

  3. hn says:

    Thanks for the links to the reviews. What a great community we have here!

  4. Onkologiq says:

    I agree with Pharmacology rules – the treatments should be way much affordable than they are now. Many people struggle to live and afford to pay the proper treatment they need.

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