publication date: Feb. 24, 2017

Moonshot funds are not a substitute for sustained NCI funding, Lowy warns as prospect of year-long continuing resolution looms

Moonshot appropriations are not a substitute for sustained increases in appropriations, NCI Acting Director Doug Lowy said at the meeting of the National Cancer Advisory Board Feb. 15.

“It’s critically important for us to be able to continue to meet our obligations in terms of inflation, but far more important to meet our obligations to the cancer research community,” Lowy said at the virtual meeting.

“For example, the regular appropriation covers investigator-initiated research and, as I discussed at the joint board meeting back in December, we need to add tens of millions of dollars from that appropriation in order to sustain the out years for the RPG thanks to the substantial increases that we have given to the Type 1 and Type 2 awards over the last few years.

“Also, our important increases for training, which we hope will lead to having better trainees and more successful outcomes in training the best and the brightest of young scientists.

“We have our commitment to the cancer centers to increase the appropriations there and we have ongoing initiatives such as the RAS Initiative and other initiatives that are ripe and ready for expansion and the potential for new initiatives.

“Therefore, if we are in a full year continuing resolution, it will be a substantial challenge to meet all of our goals because the Cancer Moonshot is not a substitute for the regular appropriation.”

A transcript of the director’s report follows:

Doug Lowy: I want to make sure that everyone understands that, currently, for the regular appropriation, we have a continuing resolution that goes through April 28. It is unclear what will happen at that time. There are really two main possibilities. One is that there would end up being a full year continuing resolution and the other is that there will be an appropriation.

If there is a full year continuing resolution, while we would have the benefit of the moonshot appropriation, the moonshot appropriation is not a substitute for the sustained increases in our regular appropriation that we need in order to be able to maximize the progress that we make in cancer research.

And so, from the point of view of NIH and NCI, and I think from the point of view of the cancer research community, having a continuing resolution would be nowhere near as positive as having an appropriation. Part of the reason for that is that last year, the House Appropriations Subcommittee marked an increase of $1.25 billion for the NIH, with the NCI getting around $100 million. And the Senate subcommittee on appropriations marked up a bill to increase NIH appropriations by $2 billion with NCI getting around $200 million.

The advantages of increased sustained funding—I’ve gone over them in the past. But it’s critically important for us to be able to continue to meet our obligations in terms of inflation, but far more important to meet our obligations to the cancer research community.

For example, the regular appropriation covers investigator-initiated research and, as I discussed at the joint board meeting back in December, we need to add tens of millions of dollars from that appropriation in order to sustain the out years for the RPG thanks to the substantial increases that we have given to the Type 1 and Type 2 awards over the last few years.

Also, our important increases for training, which we hope will lead to having better trainees and more successful outcomes in training the best and the brightest of young scientists.

We have our commitment to the cancer centers to increase the appropriations there and we have ongoing initiatives such as the RAS Initiative and other initiatives that are ripe and ready for expansion and the potential for new initiatives.

Therefore, if we are in a full year continuing resolution, it will be a substantial challenge to meet all of our goals because the Cancer Moonshot is not a substitute for the regular appropriation.

I just do want to reiterate what I have said in the past about the broad bipartisan support for NIH in general, including the NCI. Last week, the House Appropriations Subcommittee came to NIH. There were both Republicans as well as Democrats who came and they spent a good part of the afternoon visiting the NIH.

There was one segment where they heard about activities, cancer research activities at NCI. Peter Pinto [an investigator and faculty member in the NCI Urologic Oncology Branch, Peter Choyke [senior investigator and head of the Molecular Imaging Program at the NCI Center for Cancer Research], and Bill Dahut [clinical director and scientific director for clinical research at the NCI Center for Cancer Research] from the Intramural Research Program presented imaging modalities that were pioneered in the Intramural Research Program in the Center for Cancer Research and now have been commercialized.

I will tell you that all of the members of Congress were very engaged—the female members of Congress at least as engaged as the male members of Congress–with issues related to prostate cancer. And there was a presentation of a patient who with random biopsies had not had a definitive diagnosis, but with a directed biopsy was able to get a definitive diagnosis of prostate cancer, get treated appropriately and is doing very well.

Perhaps the highlight from the visit from the House subcommittee, however, was meeting the trainees from the Intramural Research Program, clearly just a subset of them. But I think that the members of the House Subcommittee came away impressed by the passion, the commitment, and the quality of people who want to go into research.  Just before turning the microphone over to Dr. Doroshow, I just want to reiterate, on the one hand there’s tremendous bipartisan support, but on the other hand I do get concerned that if the regular appropriation stays the way it is, that we will have challenges meeting all of our goals.

One aspect that I didn’t mention is that we also need to make compelling arguments, all of us, about the importance of the regular appropriation for cancer research, because there could be some people who might see some of the Cancer Moonshot funds be considered an offset instead of getting a full appropriate increase for the NCI regular appropriation.

Doroshow on Virtual Formulary and NCI-MATCH

Jim Doroshow [director of the Division of Cancer Treatment and Diagnosis and NCI deputy director for clinical and translational research]: You’ve all heard me talk a little bit about the concept of a Virtual Formulary before, and I just wanted to update you very briefly, because that activity launched a couple weeks ago.

This was principally an issue and an idea that many of you and your colleagues at cancer centers came forward with. That is the issue of trying to rapidly obtain investigational agents from multiple different companies for combination trials. And so we began working on this about a year, year and a half ago. Tried to understand whether this might be possible to facilitate these activities.

And what we have now, and I’ll show you the website, is an activity that launched. We have 16 drugs from six companies. We are in active negotiation with several others. I think it’s a near certainty that that number of drugs and number of companies will expand.

For a process, it really involves you as PIs or your colleagues as PIs and whether or not they’re interested in doing a combination or single agent trial at your cancer center or obtaining clinical grade drug for combination or single agent pre-clinical investigations. It involves filling out a relatively modest form.

We serve, the NCI serves, really, only as a middleman. We facilitate this by taking the forms, getting them to our pharmaceutical partners. They have signed agreements that will allow rapid evaluation of those requests. We hope that within six to eight weeks from each of those companies, you or your colleagues would get an up or down reading on whether or not drug will be supplied either for a laboratory set of experiments or for a clinical trial that will be supported at your cancer center.

Microsoft PowerPoint - Feb 15 2017 MATCH-Formulary update NCABFi

NCI-MATCH TESTING AND ENROLLMENT AS OF 1/29/17 – Source: NCI

This is an activity for the time being is focused exclusively on NCI-designated cancer centers, which have the resources to do and support investigator initiated INDs for this process. Let me just, in the interest of time, see if you can, I hope you have a copy of this slide. This is just a screenshot of the website for the formulary. It gives all the details, where you can get additional information, the drugs, the form to request the drugs. I strongly urge you, especially the pre-clinical investigators that need clinical grade drug for in-vivo experiments, where the quantities are much harder to obtain, that are required than for in-vitro or cell culture experiments, to avail yourself of this activity because we will work very hard to get as large a group of drugs from as many companies as possible.

The last thing I would like to say about this is that as you will see if you go to the website, all of the IP issues related to the use of these drugs follow pre-negotiated IP arrangements that we already have with these companies, which essentially all of your cancer centers have signed on to. So that this should be relatively easy in terms of getting the MTAs to allow these drugs to be used for the experiments that are of interest to you.

So I would just ask you please, if your colleagues don’t already know about this, to please make them known and to call us or email us so we can facilitate their access to these compounds.

Let me move on to the MATCH Trial because there are some significant updates for you.

You all know about this study that was opened about a year and a half ago now. We are up to a thousand approved sites. If you see on right of your screens, one of the most heartening things about this issue of this trial is that essentially about 80 percent and 90 percent all of our clinical trial sites have this study open, which is really something of a record and something we’re very thankful. And thankful to all of you and all of your colleagues. We originally estimated that we would have something like 40 or 50 patients screened per week. For now quite steadily for a year and a half we have been at 110, 120 patients per week that have been entered.

Here’s the data of just two weeks ago. So, two-thirds of the accrual has been completed. About 20 percent of the patients who undergo screening are actually eligible and enter a study. This is a dynamic business because it really depends on the nature of the mutations that are found and the nature of the trial arms that are open in any one particular point in time.

So, as I said, we’re averaging about 115 registrations per week. And we have continued again with great thanks to the four laboratories that are doing the screenings to maintain a turn around time of just over two weeks to getting the information back to the investigators and physicians who are enrolling their patients in the study.

This is a question Doug asked me to address, and I think it’s a very important one. This is as of October, but the data are pretty similar now in terms of distribution of patients that have been screened. So one of the concerns when this was started a year and a half ago, is that well all of the patients screened will be in the big four: in breast, colon, lung, and prostate cancer.

You can see that there have been many patients with breast cancer and colorectal cancer screened, but in fact a very few patients with prostate cancer. Probably an underrepresentation, and I can’t tell you why, in the area of lung cancer. But many diseases like uterine cancer, ovarian cancer et cetera and certainly pretty reasonable spread of underrepresented cancers, patients have been entered on this trial. We’re very appreciative because we worried it would be dominated by one set of diseases and that does not seem to be the case.

This is also data as of October, but not substantially different now in terms of distribution based on gender and ethnicity. See that about 80 percent of the patients entered are Caucasian. I think 8 percent are African American, 5 percent are Hispanic. That has held up as the trial has progressed. I hope you can read this if you have copy of the slides because it’s pretty small.

But this is a distribution of accrual by state, which I find very interesting. Because it doesn’t strictly correspond to population. It might be expected that California, and Pennsylvania, Michigan would have high numbers. But it wouldn’t necessarily be expected that Minnesota would be number two. On the flip side, it probably wouldn’t be expected several other states to remain unremarked upon are much lower down on the list of accrual. I think particularly noteworthy is that there’ve been 100 patients from Oklahoma entered on this study. Pretty remarkable event I think.

Here are the first 24 arms that were reopened as of May 31, 2016. And what you can see in red are the patients who accrued their 35 patients. So those trials may accrue a few more patients but by in large they are now undergoing initial evaluation as to efficacy which will take several months. There’s several more in green that are near their 35 patient accrual cut off and so we’re making good progress in completing trials. And these are the additional seven arms that will be opened this month. This is really a large signal seeking trial with something over 30 patient arms that will, we hope, be completed by the time the study is over.

But I’d like to talk to you about how we’re trying to deal with the issue of those diseases, I should say those mutations that are quite rare and for which even with 6,000 patients accrued what is our intention? How do we plan to deal with the fact that it’s unlikely that even after the 6,000th patient screened how do we deal with that? Because we very much want to complete appropriate accrual for all of the arms. And so after a significant amount negotiation over the past many months, an amendment that is winding its way through various regulatory processes has been agreed to.

So that we will be working after the 6,000th patient is biopsied and screed, we will be working with Foundation Medicine and Caris [Life Sciences] as well as with Memorial [Sloan Kettering Cancer Center] and MD Anderson [Cancer Center] to try to make available and specifically focus on these specific patients’ mutations that are hard to find. So that these patients from those companies and from those two institutions can specifically be recommended for accrual. And we hope actually the ability to enhance the accrual and completion of the rare, so called rare mutations process can utilize patients who are being screened in their normal process either of clinical care or as a process that is ongoing at several of our large cancer centers to facilitate the completion of the trial. So I think we are very much working on how to fund this at the present time.

One of the optimal things we will learn if this is completed in an expeditious way is really, the next phase of doing these kinds of experiments. How do we take advantage of all the many institutions that are already screening their patients or in a variety of mutational panels? One thing I will say is that its already been apparent that patients who are screened by these other organizations and who are felt to be eligible and go on study will have their panels and their mutational analysis be confirmed at one of our MATCH assay sites so that data will be homogenous and analyzable across all of the trials that we conduct.

Arm / Target

Drugs(s)

A

EGFR mut

Afatinib

B

HER2 mut

Afatinib

C1

MET amp

Crizotinib

C2

MET ex 14 sk

Crizotinib

E

EGFR T790M

AZD9291

F

ALK transloc

Crizotinib

G

ROS1 transloc

Crizotinib

H

BRAF V600

Dabrafenib+trametinib

I

PIK3CA mut

Taselisib

N

PTEN mut

GSK2636771

P

PTEN loss

GSK2636771

Q

HER 2 amp

Ado-trastuzumab emtansine

R

BRAF nonV600

Trametinib

S1

NF1 mut

Trametinib

S2

GNAQ/GNA11

Trametinib

T

SMO/PTCH1

Vismodegib

U

NF2 loss

Defactinib

V

cKIT mut

Sunitinib

W

FGFR1/2/3

AZD 4547

X

DDR2 mut

Dasatinib

Y

AKT1 mut

AZD 5363

Z1A

NRAS mut

Binimetinib

Z1B

CCND1,2,3 amp

Palbociclib

Z1D

dMMR

Nivolumab

  

Red = accrued 35 patients

Gray = nearing 35 patients

 

Kibbe on GDC

Warren Kibbe [director of the NCI Center for Biomedical Informatics and Information Technology]: I’d like to keep this fairly brief and its just really an opportunity to give you an update on what’s been going on with the Genomic Data Commons, and also talk a bit about the NIH Data Commons, the NCI Data Commons and how that flows into the recommendations from the Blue Ribbon Panel around national data ecosystem for cancer.

The graphic up there is actually describing, if you will, a generic Data Commons framework. It’s, how do we make data discoverable? How do we support open APIs so that different kinds of data and tooling can connect to a Data Commons? How do we support unique IDs? And that’s an incredibly important part of making things searchable and findable and reproducible, so that when we couple a specific dataset, we can find exactly those datasets again. More from a computation standpoint, supporting different kinds of containers and having everything be able to run in either commercial clouds or in high performance computing environments. So that’s kind of, if you will, schematic of how a Data Commons can be constructed.

I’ve shown this graphic before. This is really the Cancer Data Research Ecosystem, and it’s one way depicting part of what came out of the Blue Ribbon Panel. Its focused very much on the NCI view of the ecosystem, not necessarily the national piece. And on the left hand side is really thinking about discovery and discovery data. So where genomics, proteomics, imaging data, clinical trial data, and in data that I would characterize as coming from well characterized research datasets can be combined.

We have one example of a system like that and that the Genomic Data Commons which I’ll come back to in a second. The middle tier, the middle pillar is really around patient engagement. That’s another side of the Blue Ribbon Panel recommendations, thinking about how do we engage patients more effectively in research. And how do we make that a two way conversation? So what is it that would patient most benefit from, from research, as well as, how to get patients engaged in that research? And then in the third pillar is really looking at it from a population standpoint. So what is it that is happening throughout the world, throughout the U.S. in care and incidents? And the SEER Registry in particular is an example of an existing repository that NCI’s been supporting since 1974.

Data_Commons_Framework

So then to transition, just to talk about the GDC a bit. And again, this is a slide that I think you’ve all seen before. There are some principles behind the Genomic Data Commons and it’s really about making data findable, accessible, attributable, interoperable, reusable and provide recognition to the folks that contribute data, contribute tools, contribute annotations to the Genomic Data Commons. And we think that those fair principles are really important for any kind of Data Commons, any kind of repository that has cancer research data in it. And there’s a number of groups that have been really laying out some of those principles very effectively: Global Alliance for Genomics and Health, Force11. And again, it’s keeping in mind and keeping aligned with the activities of those groups as well.

Just to show you the GDC, if you go to gdc.cancer.gov you get this view of the current data in the Genomic Data Commons. And I won’t go through the graph except for to say that data is both live and it’s very graphically pleasing. I’m going to just, again this is a slide that all of you have seen with perhaps the exception of the last two lines. And that’s that Genomic Data Commons went live back in June with rough four petabytes of data and a little bit more than 1.5 petabytes of highly harmonized data for the whole community to use.

Foundation Medicine announced back in June that they would release 18,000 genomic profiles and I’ll give you an update on that submission in a minute. And then also in September, the Multiple Myeloma Research Foundation announced that it would be releasing its CoMMpass Study of more than a thousand cases of multiple myeloma patients back in September. So those have all been very exciting contributions that the community’s been making for the Genomic Data Commons.

I want to highlight GDC’s monthly usage in December. I apologize, I would’ve rather had January, cause as we all know, in December some of us do take break and may not be working quite as hard as in other months. But these are the monthly usage stats from GDC. So folks visiting the front page: there were more than 16,000 visits that month and more than 29 gigabytes of data were delivered to users across the world.

Hitting the APIs, that’s how investigators can access the datasets behind the front end of the GDC—roughly three terabytes, three and a half terabytes were downloaded that way. And then the other websites that are really around how to use it and how to think about getting training on using GDC and those were all very active as well. So multiple thousands of users even in the month of December. And the bottom table is just showing the capacity, the current capacity of the GDC for storing data and it’s in the safe zone, which is good.

The next page is just looking at specific disease areas and seeing where most of the traffic has been. And you can see that breast cancer and glioblastoma in particular, have been a major source of traffic for the GDC as well as kidney clear cell carcinoma.

Last two things I want to talk about are just where we are with the Foundation Medicine dataset. So 18,000 cases were sent to the GDC and they have been working for the last six months or so realigning all the data, moving it to the most recent human genome build and making it all compatible with the existing GDC data. There’s a last QA process that’s in place, cause of the number of things as it was moved to the new build are different than the old genome build and it’s going back to Foundation Medicine and making sure that, in fact, we’ve interpreted all those data appropriately. So, we’re hoping that by April all that data will be available to the community.

And the last thing that I’m going to talk about is the Multiple Myeloma Research Foundation that I mentioned. They agree to submit all their data through the GDC for public release back in September. And that work is ongoing as well. The GDC folks are mapping all the data from the CoMMpass Study into the GDC and the data is being uploaded as we speak. So we’re hoping that by summer those data will also be available through the GDC.

Singer on moonshot implementation

Dinah Singer [director of the NCI Division of Cancer Biology]: As all of you are undoubtedly aware, the Cancer Moonshot identified three major goals, with the acceleration in the progress in cancer including across the entire cancer research continuum, from basic research to clinical to population sciences being a major focus.

While we are actively looking at all three to achieve those goals, our major focus right now is on accelerating the progress in cancer research. To identify those opportunities that were as we called them, poised for acceleration, the NCAB actually established the Blue Ribbon Panel that was charged with identifying major scientific opportunities and developing a set of recommendations of opportunities that we would or should pursue through the Cancer Moonshot through the support and the funding that that provided. The Blue Ribbon Panel worked through the spring and summer looking very broadly at what those opportunities were and by the fall established a set of recommendations that were summarized in the report that you’ve all seen.

I’ve highlighted or summarized all of them here. Again, to remind you of the breadth and scope of those recommendations across the entire cancer continuum. There are 10 of them. In addition to those 10 specific recommendations, we also identified cross cutting themes that emerged in all of the discussions. They include importantly health disparities, prevention, technology development, data sharing [and other aspects] of the moonshot and partnerships, which I’ll come back to.

Even though the Blue Ribbon Panel finished its work by the end of September, or the beginning of September, we didn’t have an allocation until the end of December, and so we couldn’t do much until we got that allocation, which came at the very end of September through the funding in the 21st Century Cures Act.

That act actually provided funding to the Cancer Moonshot, which is now called the Beau Biden Cancer Moonshot Initiative, and it provided $1.8 billion over seven years for cancer research in support of the moonshot recommendations with $300 million already allocated in FY17 with the broad guidance to support cancer research. So with that in hand we’re now in a position to begin to implement the recommendations of the moonshot.

The funds in FY17, as welcome as they were, came in the middle of the year which limited our ability to go out to the broader community to get input on their implementation. But we did have sufficient … so let me backup, that our goal for FY17 really is to establish the foundation to lay the groundwork for implementing the broader initiatives through the Blue Ribbon Panel report.

We were in a position to accelerate the progress on some areas of research, which could be funded in FY18 and those are summarized here. In six recommendation areas, we’re going to be able to support a number of new initiatives that will lay the foundation for the implementation in FY18 and FY19 of the broader initiatives that were recommended. And they’re summarized here and you’ll see all of these are already out on the street and will be funded with FY17 funds. So for FY18 and FY19 we’re now putting into place a much more structured process to allow us to have broader input, both from the NCI community and the broader cancer research community. And I’m going to summarize that process for you, again, very briefly.

Clearly, with so many different and disparate recommendations, with so much to achieve, we need to have a very structured process and that’s what’s outlined here. I’ll take you through it. A number of people have responded to this by saying, “Oh my God, it’s so bureaucratic and cumbersome.” I hope to convince you that that’s not the case, but if it is, we are prepared to revise it.

So let’s start from the bottom. Each of the recommendations has an implementation team assigned to it. Two of the recommendations actually have two teams which is why we have a total of 12 teams. Immunology has both a adult and a pediatric immunotherapy team and prevention has both a cancer screening and prevention team. There are a total of 12 teams. In total, we have representatives from Intramural NCI, Extramural NCI, and representatives from other institutes. And at the last count we had over 250 people participating in these teams, helping to formulate the initiatives that are going to be started to support the goals of each of those Cancer Moonshot recommendations. The teams are specifically charged with discussing and developing initiatives for FY18 and FY19. And they are asked to identify the gaps and opportunities in the current landscape of existing initiatives, even though the recommendations were quite explicit on what is to be achieved. It’s going to be important to understand what we’re already doing that can be leveraged, what gaps are there, and what opportunities there are to build on.

Importantly, we’re going to have the teams seek input from others including the broader cancer community, including the boards like the NCAB, advocates, and the professional associations. An important component of what we want to achieve is to identify partners. I’ve said in the past, and I think it’s worth repeating, that NCI cannot, on its own, achieve all of the goals of the moonshot. Nor would we want to. We really want to do this in partnership with academia, with industry, with pharma, and with other government agencies. And I’ll tell you in a minute about the partnership committee that we’ve organized with the explicit task of identifying the appropriate partners for the different initiatives and the different recommendations.

Once the initiatives have been funded, the teams will continue to work by providing oversight and coordination to those initiatives making sure they’re progressing appropriately, making linkages across the different initiatives as appropriate, organizing meetings, and providing general program management.

In addition to the teams, and because there’s so many of them, it’s very clear that communication across all those teams and throughout the NCI is going to be critical to the success of the implementation. While we want the teams to function independently, we don’t want them to function in isolation. An so the idea of the coordinating team, that big blue box on the slide is really to be a point of communication.

Each team has a coordinator assigned to it who will represent that team on the coordination committee which will meet every other week to share ideas, information, discuss concepts that are being developed. Because we fully expect that there’s going to be a lot of crosstalk, a lot of areas where groups can work together on a common initiative.

For example, the immunotherapy group, the human tumor atlas group, and the prevention group, all had components of their recommendations, the development of a human tumor atlas. So we anticipate that they will at some point work together to collaborate on developing initiatives of common interest.

That coordinating committee really serves as a communication vehicle but also to provide feedback to the teams in ways that their initiatives might be refined, and finally to forward to the steering committee initiatives or concepts that they think have high priority.

In addition, and this is where the partnership committee comes in, this will be the venue it will be clear where we need partners. And the partnership committee will be able to, then go out and identify appropriate partners for the initiatives as they are being developed.

Once the concepts are approved, they go to the implementation steering committee, which Doug chairs. That’s also the place where we’re going to merge the science with the budget and prioritize all of the initiatives that will finally go to the SPL for approval.

The teams were first launched a week ago. Nine of the 12 teams have met at least once. Some of them have met twice. As I said, there are over 250 people involved and there’s a huge amount of enthusiasm within the NCI and the NIH to begin to implement these recommendations.

Copyright (c) 2017 The Cancer Letter Inc.