July 2016 VOL 7, NO 6

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Interview with the Innovators

NCI-MATCH: A Paradigm Shift in the Evolution of Personalized Medicine Trials

An Interview with Douglas R. Lowy, MD, of the National Cancer Institute

Douglas98pxPrecision medicine has become a high-profile term with equally as high expectations. With the president’s announcement last year of a Precision Medicine Initiative (PMI) and his more recent calling for a “moonshot” to cure cancer headed by Vice President Biden, the march toward personalizing care continues to gain momentum. In the PMI budget, $70 million will go to the National Cancer Institute (NCI) to scale up efforts in identifying genomic drivers in cancer and then applying that knowledge to the development of more effective approaches to cancer treatment. The NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) clinical trial supports the objectives of PMI as it accelerates the design and testing of tailored treatments for cancer by expanding genetically based clinical cancer trials, explores fundamental aspects of cancer biology, and establishes a national “cancer knowledge network” that will generate and share new knowledge to fuel scientific discovery and guide treatment decisions.

NCI-MATCH analyzes patients’ tumors to determine whether they contain actionable genetic mutations for which a targeted drug exists. The primary end point for NCI-MATCH is the objective response rate, defined as the percentage of patients whose tumors have a complete or partial response to treatment. The trial opened for enrollment in August 2015 with 10 arms, with an additional arm scheduled to open this year. It is anticipated that more than 20 treatments will ultimately be tested, each in a different arm of the trial. NCI-MATCH is flexible in that it can add or eliminate treatments over time.

In an effort to learn more about NCI-MATCH, we asked the Acting Director, Douglas R. Lowy, MD, to speak with us. What follows is our exchange.

JONS Thank you for speaking with us, Dr Lowy. To begin, can you please provide your definition of precision medicine.

Dr Lowy I believe most people think of precision medicine as being focused primarily or exclusively on cancer treatment. Further, there is the belief that precision medicine takes advantage of the deep molecular understanding that we have of cancer and how this understanding helps us to distinguish one cancer from another. If we can deliver tailored treatment under the best of circumstances based on the particular molecular abnormalities that are in the cancer, we might be able to achieve the goals of precision medicine.

My view of precision medicine is broader, because I feel that it should also be thought of as equally applicable to cancer prevention and screening. I like to define precision medicine as a molecular characterization and understanding of the pathology of cancer and then using that information for intervention. Intervention can occur with prevention, screening, or treatment.

Let me give you an example. In primary prevention, HPV [human papillomavirus] vaccination is something that you would administer to try to take care of HPV-associated cancers. This is a population-wide approach. Conversely, colorectal cancer screening based on molecular abnormalities or cervical cancer screening based on detecting HPV is just as much precision medicine as the treatment aspect.

I believe precision medicine should be understood in a much broader context than just in the important area of cancer treatment.

JONS We are curious about the goals of the PMI and the funding the NCI will receive from that initiative.

Dr Lowy First, we just received funding for the oncology portion of the PMI with this year’s budget. Although we already have a certain amount up and running, it is not as fully developed as it will be now that we actually have the funding.

The president’s PMI in oncology really has several components. It’s focused on cancer treatment, and the long-term goals are to improve the outcome for patients based on a clearer and more detailed understanding of the molecular abnormalities in cancer and to improve our ability to treat those cancers with either single-agent or combination treatment.

The key part from a clinical trials perspective is the NCI-MATCH trial. NCI-MATCH is a major paradigm shift as it is really the first trial where entry is based on your molecular abnormality rather than the site of origin of your tumor.

We currently have the adult NCI-MATCH trial that started back in August, and we are looking forward to initiating a pediatric version of the NCI-MATCH trial by the end of this year.

There are suggested forms of new preclinical models in the proposal, such as patient-derived xenographs, and for using more recent technology for developing cultured tumor material, such as organoids. We are developing these types of models and will support their development by other groups.

The goal is to have these panels of new models available to the research community for designing studies that focus on 2 major areas. The first is for understanding primary and secondary resistance; that is, resistance to drugs and how to overcome that resistance. The second is to try to gain some understanding of how to optimize combination treatment with targeted agents as well as incorporating immunotherapy.

This will be a long-term goal to try to get closer to predictive oncology—that based on the molecular abnormalities in a tumor, we will be able to be more efficient and more effective in giving the right treatment to the right patient.

JONS NCI-MATCH considers genetic mutations as opposed to tissue of origin. Can you give us an example?

Dr Lowy Let’s take mutant EGFR [epidermal growth factor receptor] as an example. A mutant EGFR can occur in a range of tumors. There is an FDA-approved product to treat lung adenocarcinoma. So, we have a patient who has a mutant EGFR, but this patient has, say, liver cancer. If you have a mutant EGFR in liver cancer, EGFR inhibitors are not approved for liver cancer, but you would then be eligible for an EGFR inhibitor given the molecular abnormality.

JONS What about mutations that aren’t necessarily included in the NCI-MATCH trial? KRAS, for example.

Dr Lowy Unfortunately, we don’t have effective interventions for patients who have mutant KRAS in their tumors. The NCI actually has a separate initiative whose goal it is to develop effective interventions against cancers that have mutant KRAS. This is part of a research initiative at the Frederick National Laboratory for Cancer Research. And there are a number of extramural laboratories that are also doing cooperative research in this area.

JONS Can you talk about your research goals regarding drug resistance?

Dr Lowy A fair number of drugs have been approved as single-agent treatment for targeted intervention against a fairly wide range of cancers. But not infrequently with single-agent treatment, patients develop resistance, and the resistance has many different mechanisms depending on the cancer, depending on the drug that is being used as the inhibitor, etc. This is really a major stumbling block or barrier to long-term benefits for patients when we are using targeted treatment.

There are at least 2 problems; the first is that you have an abnormality that suggests this particular intervention should work, but it doesn’t. That’s considered primary resistance. Secondary resistance occurs when the patient makes an initial response to the treatment but then develops resistance, and the tumor recurs. We need to understand both of these areas in greater detail; we need to figure out how to prevent secondary resistance from occurring and how to deal with primary resistance so that we can provide better treatment for our patients.

My own view is that we will eventually get to the point in cancer treatments where we currently are with HIV treatments—where multidrug treatment is given, virtually everyone responds to the treatment, and the risk of resistance is much less than with single-agent treatment.

Although this is a good goal, the major difference is that cancer is far more complicated. When you’re talking about HIV, there are just a few genes in the virus, whereas when you’re talking about cancer, you’re talking about a very wide spectrum of all the different genes in the body.

JONS There is research to suggest that stem cells could very possibly be responsible for resistance, mutation, and metastasis. Is this component considered in your work?

Dr Lowy Cancer stem cells or cancer-initiating cells are a component when you are thinking about resistance and the issue of tumor heterogeneity. The term “cancer stem cells” implies that there are master cells and responder cells. What you really need to go after are those master cells, also called tumor-initiating cells or cancer stem cells. This becomes a very important issue when you are trying to get long-term benefits from a treatment because it takes into consideration that there is heterogeneity, and if your treatment is very effective at basically treating the cells that are more differentiated than the tumor-initiating cells, your treatment is not going to be that successful.

JONS How does immunotherapy fit into the precision medicine story?

Dr Lowy Precision medicine is based on molecular abnormalities in the tumor, and immunotherapy is based on a new understanding of the regulation of the immune system. These approaches have quite distinct origins. But, it turns out that the immune checkpoint inhibitors seem to be more effective in tumors that have more mutations, and, therefore, the mutations that people have are almost certainly going to play a role in the response to immunotherapy.

There are other approaches that take advantage of immunology, for example, CAR [chimeric antigen receptor] therapy. It’s highly targeted, because you’re basically targeting a cell surface receptor on the tumor but taking advantage of activating the immune system.

Also within immunotherapies are therapeutic vaccines. We look forward to vaccines that will directly target the molecular abnormality in a tumor.

Targeted therapies and immunotherapies certainly have distinct origins, but they really are coming together in very complementary ways.

JONS The president is calling for a “moonshot” to cure cancer. Vice President Biden has said he’d like to double our rate of progress. In your opinion, what would be needed to make that goal attainable?

Dr Lowy First of all, it is difficult to have a metric that demonstrates that you have doubled the rate of progress. What he is talking about is an aspirational goal, which is that whatever we’re doing now, to do it faster, better, and more efficiently. I think that is something that is very achievable. But it will require more cooperation, more public-private partnerships, and more data sharing. The vice president is very interested in all these ideas.

In addition, the president’s budget is proposing a 13% increase for the NCI, and such an increase would make it possible for us to accelerate the momentum that we already have.

We are planning to have a blue-ribbon panel that will look at the proposal of the vice president, evaluate its various scientific aspects, and make a recommendation to the National Cancer Advisory Board. That board will provide advice to the NCI on the highest priority areas, areas of the greatest opportunity for cancer research in the near future, and how we should invest that money, whether it is in basic research or in the most applied research.

The vice president’s initiative really runs the gamut. It has support for basic research, support for understanding cancer pathogenesis, and support for prevention, screening, and, of course, treatment. It also talks about trying to increase implementation of standard of care—doing more of what we already know works—to reduce the healthcare gaps that exist within cancer, whether it is talking about prevention, screening, or treatment.

JONS Any thoughts about the challenges of cancer being a heterogenic disease?

Dr LowyThis is both a blessing and a curse. It gives us more to do because when you deal with 1 kind of cancer, your research may not have direct implications for other types of cancer. But on the other hand, there are a lot of common themes between cancers. And what we’ve seen with the NCI-MATCH trial, for example, is that people who have similar molecular abnormalities in different kinds of cancers may respond to similar kinds of interventions. And when they don’t, we need to conduct further research to understand that.

Cancer heterogeneity is certainly a problem, but it is a tractable one. It really underscores how important ongoing and future research is so that we can improve our understanding of the disease in hope of leading to better efforts at prevention and screening as well as better outcomes for patients who develop cancer.

JONS Thank you, Dr Lowy, and best of luck to you in your endeavors with the NCI-MATCH trial.

Dr LowyThank you.

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