The Moonshot’s Metric for Success: Avoiding a Single, Tangible Endpoint

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The Moonshot’s Metric for Success: Avoiding a Single, Tangible Endpoint

How will the success of the moonshot be measured? NCI Acting Director Doug Lowy touched on the subject during the joint meeting of the institute’s Board of Scientific Advisors and the National Cancer Advisory Board June 21.

The moonshots of the 1960s were essentially engineering problems that had tangible goals. Cancer is an evolutionary problem, and the stated goal of the moonshot in cancer research, led by Vice President Joe Biden, is perhaps deliberately vague: to achieve a decade’s worth of progress in just five years.

“Has there been any discussion of an endpoint that you can point to—like planting the flag on the moon, or sequencing the three-billionth base pair of the genome project?” asked BSA member Lincoln Stein, director of the Informatics and BioComputing Platform at the Ontario Institute for Cancer Research, during the meeting. “Something that looks like an achievable endpoint?”

Not a single achievable endpoint, no,” responded Lowy.

I think, perhaps in part because we’ve been trying to advance the important notion that there are enormous gaps still in our understanding of cancer, our knowledge about it, and our ability to deal with it,” Lowy said. “If there were a single target point, it might imply that, well, once we do that, then we’re done.”

I had even heard the vice president talk about the difference between the original moonshot and this moonshot,” added NCAB Chair Tyler Jacks, director of the Koch Institute for Integrative Cancer Research at MIT. “That was one defined, achievable endpoint—and he talks about the fact that cancer is at least 200 diseases, and it is complex. So I think in his mind as well there’s not a single planting of the flag.”

So he gets it,” said Stein.

The question came up over how to best illustrate advancements made with moonshot funding to members of Congress, who will have to continue to vote for it in the future.

“I’ve heard Dr. Lowy talk to Senate members, House members, staffers—and the things that I see really resonating with them are ideas explaining circulating tumor cells, blood tests, biomarkers, early detection; things that are tangible to them,” said M.K. Holohan Quattrocchi, director of NCI’s Office of Government and Congressional Relations. “Other things take a little more understanding and work and seem more abstract and amorphous, but that’s one area that really gets traction.”

“When Dr. Lowy talks about implementing things that we know work now—implementing them on a wider scale—other people can do the kind of presentations that show what kind of cost savings, and what kind of decreased incidence and mortality that those interventions would bring. Those are very meaningful,” she said.

“So there are sort of different groups. There are people much more concerned about health disparities within their communities. There are people who are much more concerned about specific diseases where there is very little ability for early detection and intervention. So I think it’s sort of finding the examples that are very concrete.”

In his opening remarks to the joint meeting, Lowy listed the ways NCI is using recent appropriations for several projects, including $70 million for the Precision Medicine Initiative.

He specified administrative supplements providing funds to improve preclinical models for evaluating targeted therapeutics; to support collaborative efforts to enhance preclinical drug development and preclinical trials utilizing patient-derived xenograph models; and to support biomarker development and correlative studies associated with clinical trials of immunotherapy.

“I just want to make it clear that not everything that’s important is going to be supported by the moonshot, and that NCI will continue to support a great deal of other meritorious research, as well as new initiatives,” said Lowy.

A transcript of Lowy’s remarks, as well as updates from Jim Doroshow, director of the NCI Division of Cancer Treatment and Diagnosis, and Warren Kibbe, director of the NCI Center for Biomedical Informatics and Information Technology, appears below. Doroshow discussed an expansion of the NCI MATCH trial, increasing the number of patients screened from 3,000 to 5,000, while Kibbe detailed the recent launch of the Genomic Data Commons.

The transcript follows:

LOWY: I would like to welcome everyone and tell you that this is a busy day, an active day. Many of us and many of you have been really extraordinarily engaged in the vice president’s initiative, and we’re going to be devoting a certain amount of time to that, but I also want to point out that we are going to be discussing the president’s Precision Medicine Initiative in oncology, as well as some other aspects.

I first want to discuss PMI in several ways, because this year we received the $70 million appropriation for it, and I wanted to tell you some aspects of how we are making use of those funds. Jim is going to be talking about the MATCH trial, which is pivotal to that, and Warren is going to be discussing the Genome Data Commons. I am going to really just try to tell you about some of the activities.

As many of you will remember, it’s a presidential initiative to improve cancer treatments through genomics, and there are preclinical models to advance predictive oncology to get the right drug to the right patient at the right time, in addition to developing the databases. So as I mentioned, Jim will discuss MATCH; and Warren, the databases. But let me tell you about some of the funding announcements that have come out just in the last two months or so.

One is to improve preclinical models for evaluating targeted therapeutics and immunotherapy, and there’s an administrative supplement for the cancer center grants for canine immunotherapy in collaboration with the centers and the veterinary schools, of which there are more than 20 that are involved in this network. Also, there are administrative supplements to support collaborative efforts to enhance preclinical drug development and preclinical trials utilizing patient-derived xenograph models.

In addition, administrative supplements to support biomarker development and correlative studies associated with clinical trials of immunotherapy. Let me just give you an example of one of those trials, and this is the Merkel cell carcinoma trials which were recently published in the New England Journal of Medicine, supported by the immunotherapy group—Paul Nghiem is the first author.

In those Merkel cell carcinoma trials, there were patients who were virus-positive—they contained the polyomavirus—as well as patients who were virus-negative, whose tumors did not. And both groups of patients had long-term responses to a PD1 checkpoint inhibitor. What was particularly interesting about those responses were, first, that there really isn’t—with conventional therapy—long-term responders, whereas more than half of the patients treated with the inhibitor gave a response. And second, there are enormous differences in the number of mutations that are present in the patients who responded.

The patients who are virus-negative are very analogous to patients who have melanoma, and they have, on average, about 1,100 mutations per tumor genome. By contrast, the patients who are virus-positive have fewer than 15 mutations per tumor genome, but both groups responded.

So one obvious hypothesis is that one or more of the tumor virus-encoded epitopes is actually immunogenic in this particular setting—and I’m not trying to say if somebody from this group submits an application that that’s the kind of application that would be supported. But I just think that these hypothesis generating—by being able then to go forward and look at mechanisms, is something that we’re particularly interested in and excited about.

There also are studies on how the microenvironment in pancreatic adenocarcinoma will affect immunotherapy. And, you know, we have been giving emphasis to pancreatic carcinoma as an important recalcitrant cancer. And then there are other administrative supplements to improve optimization for T cell therapies and for GMP manufacturing processes for the production of autologous T cell therapy products.

Finally, administrative supplements to U10 cooperative agreements and SPOREs to study mechanisms of cancer sensitivity and resistance to therapy, utilizing samples and information from clinical human trials, and to create a repository of molecularly analyzed samples of resistant disease—and expand the use of tumor-profiling methods, such as circulating tumor cells and fragments of tumor DNA in the blood, to understand and monitor disease progression.

I would like to turn now to talk about the vice president’s initiative, or the moonshot…I just wanted to give you really a little bit of context. This was initially announced at the State of the Union, where President Obama said I’m putting Joe in charge of mission control. It’s really an opportunity for focused research to accelerate progress and to take advantage of current advances in the understanding of cancer and recent technological innovation, and to apply the knowledge and innovation to focus on specific projects that can have a substantial impact on understanding or improving the outcome for patients.

But I just want to make it clear that not everything that’s important is going to be supported by the moonshot, and that NCI will continue to support a great deal of other meritorious research, as well as new initiatives.

In addition to the vice president’s initiative being heavily dependent on new understanding and new innovative technology, there is also the other end of the spectrum where he wants to try to increase the implementation and dissemination of standard of care of what we already know works and one of the working groups on the Blue Ribbon Panel is devoted to implementation and implementation research.

I now am going to turn the microphone over to Jim, who is going to talk with you about two different important areas: one is the MATCH trial, and the other is our proposal to develop a formulary that is, if you will, qualitatively based on what has happened with the MATCH trial, but really expanding it, so we can think in very serious ways about combination chemotherapy or immunotherapy and targeted treatment from drugs from multiple companies.

DOROSHOW: Thanks, Doug. Let me just say that the impetus for doing this really came in two ways:

Number one, from discussions with many of you and many others, especially cancer center directors and others, who have made clear how difficult it has been over the years to get access for investigator-initiated trials using investigational agents—and in particular the negotiations required to get two drugs from two different companies. It may take a year or better, it may never happen. And that has been a major roadblock to the initiation of precision medicine initiatives at many cancer centers, which is easy to understand because of these kinds of administrative difficulties.

So that, together with what we learned about putting together the drugs for the MATCH trial, which we spent the better part of two years negotiating with twenty-plus companies to get 24 compounds, that I’ll talk about in a minute, that are now part of that trial. I have an office, I apologize if I said this to you before, next to our tech transfer lawyer in our office suite, and he’s a very aggressive person, and I know he’s on the phone with a company when I can hear him through the wall.

And it really is a major achievement to have negotiated one trial with basically a whole series of clinical trials agreements that relate to that single trial that produced, if you will, a formulary of drugs that produce to this umbrella approach to precision medicine. So I never thought that was possible until he actually accomplished that, and his name is Jason Cristofaro, and I want to call him out because he spent a great deal of time doing this.

About a year ago when it was clear that MATCH was going to open and this approach actually had legs, we started thinking about how we could do something not exactly the same, but actually some way to produce a formulary that addressed the needs of the community, to create a system in which NCI could be an honest broker to get compounds from companies to cancer center investigators or other investigators who need agents, in particular for combination trials. So we’ve been talking and trying to put together a program that would actually be initiated with investigator-initiated INDs, INDs that the NCI would not hold, but NCI would act as a broker to get and distribute drugs from a common list of compounds.

And there are, as you might guess, many, many details about how that would work. But two weeks ago we had a meeting with 20 companies at ASCO that went very well. And, in fact, we have sent out to them, if you will, a pledge as well as a form and basically an initial, kind of novel CRADA, that would allow us to work with them and to work with other companies. And we’re hoping actually to get responses before the moonshot summit at the end of the month. I don’t know if that will happen, but we’ve certainly had positive reviews from several companies, and I’m hopeful that, by the end of the year, we’ll at least have our initial batch of drugs and initial group of companies that have agreed to this process so we can make them available to all of you.

So let me just then segue to the MATCH trial very briefly. Many of you know that it reopened on the 31st of May, and it reopened in a variety of different ways. I think it’s improved. We now have 24 arms in this phase II umbrella trial, and there will be combinations.

We put in, using the PMI money, additional resources at both the processing center and the sequencing center, so that they can do their work more expeditiously and keep up with the kind of demand that we observed in the last few months of last year—where we basically had this interest in this enormous amount of accrual.

We have also provided resources to increase the number of patients screened from 3,000 to 5,000, which based on the initial 800 patients who have been studied, should give us a match rate based on what the statisticians tell us of about 20 percent. And given that approximately 1,000 patients will actually get treated on one of these phase II trials, we’ve also put in the resources to do a full—in addition to the MATCH screening panel—to do a full molecular characterization of the tumors of all of the patients who actually get treated.

So we really take maximum advantage of this trial, and we’re very grateful for the money that came in as part of the Precision Medicine Imitative, because that really allowed us to do all of those things.

LOWY: Thanks. Now Warren is going to tell us about the Genomic Data Commons…

KIBBE: It’s great to be here, and I would like to talk very briefly about the Genomic Data Commons.

So for those of you who haven’t heard a lot about it, the Genomic Data Commons has really been the project that Lou Staudt, here at NCI, and his colleagues have been pushing very hard to make sure it happens. Folks at the University of Chicago have been instrumental in it; Bob Grossman is the PI for the Genomic Data Commons and we have great partners at the Ontario Institute for Cancer Research and also at Leidos Biomedical, making all this happen.

So what’s been really exciting, and the reason I’m showing slides, is that Vice President Biden came and spoke at ASCO, and also visited the University of Chicago. So I’ve got a few slides of that event. As you can see, the vice president on the left exhorting to all of us that we make sure we make our data available, and that’s Bob Grossman right behind him Lou Staudt to his left, or to your right. There was a tremendous amount of publicity, and it was all beautiful…

And you can see that it wasn’t just a couple of pictures. He really walked around and got to know the whole crew that was involved in making the Genomic Data Commons possible, and he was genuinely really, really enthusiastic. And that was wonderful to see.

He also then went, immediately afterward, to ASCO where he gave, I believe, a 35-minute talk, and he mentioned the Genomic Data Commons for eight of those minutes. So there’s again tremendous interest and tremendous support by the vice president for this. So I think that’s been just wonderful.

Again, part of the reason the Genomic Data Commons is such a focus for us, is it’s really an opportunity for us to support FAIR—so making data findable, accessible, interoperable and reusable. Those are terms that Force 11 has been really responsible for defining, and also the GDC as part of the NIH Commons, and thinking about then how we participate with lots of other kinds of research that’s happening all across NIH. And there are lots of pieces to this.

I don’t want to belabor it, but the Genomic Data Commons is real, it’s available, and we’re looking forward to people putting their data in it.

When it went live, it went live with about 4.1 petabytes of data, and roughly 1.5 petabytes of harmonized data—actually that number came out to be closer to 2 petabytes of harmonized data. And what’s really exciting is not just TCGA, but it’s also TARGET and the cancer genome characterization initiative data. So that’s all available now through the Genomic Data Commons.

I’m just going to show you a pretty picture because I can’t resist pretty pictures—that is when you go to the data portal, what you’ll see. And if you go to upload data, you actually get a similar kind of graphical view relative to how many specimens and samples you’re going to upload where you currently are. So it’s a nice dashboard, helping people with their submission process. And we’ll see how all of your folks at your organizations like to use it, and please feel free to tell me when things don’t work. I know who to talk to.

I want to mention the GDC itself is really part of a foundation. It’s not the only piece. In particular, the cloud pilots are really important as we think about how do we make these data more accessible—and in particular how do we give people credit for all the data that they’ve submitted.

The algorithms that they’ve developed and attach next to data—and then all the users that come in and want to see and analyze data—how do we make sure that there’s appropriate credit to everyone for the work that they’re doing? And we think that the GDC, plus the cloud pilots, give us the first view into that new kind of data ecosystem.

But I want to highlight that it’s not just the GDC and the cloud pilots. On the left, that’s how will we’re thinking about the well-characterized research data that’s being generated in all of our organizations. It’s just as important to realize that there are lots of cohort studies, clinical trials, and observational studies that are generating data that may not include genomic information today, but there’s an opportunity to really engage patients and make patients part of this process.

The other side, on the right-hand side, is really learning from every single patient. And that’s an incredibly important part of this, and we’re not sure exactly how to make that happen yet, but we recognize that the GDC alone isn’t the whole picture.

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