Maximizing Cancer Cure: How Do We Get There?
Is cancer really “curable,” and if so, how? For a “Cancer Dialogue” held during the 2016 American Association of Cancer Research (AACR) Annual Meeting, half a dozen stellar participants from the research, industry, regulatory, and advocacy communities convened to debate the topic. The ASCO Post was there to capture this provocative conversation.
Jose Baselga, MD, PhD, moderated the session, which included Richard Pazdur, MD, Sandra J. Horning, MD, William G. Kaelin, MD, Douglas R. Lowy, MD, Jane Perlmutter, PhD, MBA, and Richard M. Marais, PhD. Interestingly, in addition to their professional accomplishments, most of the participants had a personal experience with cancer, either as a patient or the spouse of one.
We all share a sense of excitement that cancer research is moving forward, but at the same time, we are not going forward as fast as we would like and as our patients need. So, the topic today is, where are we now, and what can we do better?— Jose Baselga, MD, PhD
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Dr. Baselga, 2015–2016 President of the AACR and Chief Medical Officer at Memorial Sloan Kettering Cancer Center, described the theme of the session. “We all share a sense of excitement that cancer research is moving forward, but at the same time, we are not going forward as fast as we would like and as our patients need. So, the topic today is, where are we now, and what can we do better?”
The Hit Parade
Panelists were quick to rattle off the successes of the past few years—immunotherapies, gene-sequencing techniques, new diagnostics—and to predict rapid and continued advances. “What’s coming in the pipeline of basic research will make current technology such as the gene-editing system CRISPR (clustered regularly interspaced short palindromic repeats) old-fashioned in no time,” said Dr. Marais, Director of Cancer Research at UK Manchester Institute in the United Kingdom. “The next breakthroughs will be driven by technologies, equipment, and biologic techniques we haven’t started to imagine yet.”
Dr. Horning, Chief Medical Officer and Global Head of Product Development at Genentech, said that progress has “never been more real than it is now. Witnessing durable responses and overall survival benefits in diseases for which we had not made progress in decades is energizing the community,” she observed.
But Dr. Perlmutter, President of Gemini Group (a management consulting company) and a cancer survivor herself, injected a sobering note. “I’ve been schizophrenic throughout my advocacy. I keep getting confused,” she said. “Are we really at an inflection point? Are we near or far away? Is the glass half empty or half full?”
As pointed out by Dr. Lowy, Acting Director of the National Cancer Institute (NCI), many cancers are already being cured. “There are 1.5 million cancer cases per year and about 600,000 deaths, meaning that the majority of people who get cancer don’t die from it,” he said. “Of course, the 600,000 who do want treatments yesterday.”
Moonshot: The Right Concept?
Dr. Baselga offered a provocative question to the panelists. Since “words matter,” he said, what do the panelists think of the “Moonshot” approach to cancer research? He was referring to the National Cancer Moonshot, an initiative spearheaded by Vice President Joe Biden that aims to accomplish a decade’s worth of progress in cancer research within the next 5 years.
Sharing his own point of view, Dr. Baselga said that he understands “the magic of the term” but questioned whether it realistically reflects how cancer research is conducted. “‘Moonshot’ suggests that we know where we are going and what we are going to do to get there,” he said. Although some tumors are “planets we can conquer” through such processes as better clinical trial design, others are “more distant planets” that require deeper exploration by “curiosity-driven” science, explained Dr. Baselga. The quest, he suggested, looks more like an entire “space program” than a “Moonshot.”
The consensus of the panelists was that the Moonshot initiative will garner attention and much-needed resources, but it may reflect an oversimplification of the mission. “Cancer is fundamentally still a scientific problem, with some aspects of engineering mixed in,” said Dr. Kaelin, Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School. “The reason President Kennedy could say that we can put a man on the moon within a decade was because all the science that was needed was already known. It was an engineering challenge, not a scientific one.”
“Talk about timelines, deliverables, and Moonshots is the language of engineering, not science. To have truly transformative science, we don’t want our most creative scientists to be held to these… to have blinders to other opportunities and unexpected results that might be the basis for truly out-of-the-box discoveries,” he said. In addition, Dr. Kaelin added, using language more relevant to engineering “can create wildly unrealistic expectations, especially among patients and their families.”
Dr. Lowy agreed that the cancer research community is receiving “an infusion of resources and terrific ideas from many people, but on the flip side, we must not overpromise.”
Basic Science vs Clinical Research
What’s coming in the pipeline of basic research will make current technology such as the gene-editing system CRISPR old-fashioned in no time. The next breakthroughs will be driven by technologies, equipment, and biologic techniques we haven’t started to imagine yet.— Richard M. Marais, PhD
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As pointed out by Dr. Marais, whose research focus is melanoma, virtually every effective cancer treatment began as a laboratory experiment. Both basic science and applied science are critical to curing cancer, he said, but fundamental, basic research “underpins everything we do.” Dr. Lowy agreed: “Ultimately, basic science is where we are going to get the breakthroughs.”
Dr. Kaelin encouraged young basic researchers to concentrate on “finding the truth” rather than “racing to get to the clinical application of their work.” A “robust” result, in his mind, is “reproducible and is not restricted to a very narrow set of experimental conditions.” Dr. Kaelin added: “That’s where we fail. We get excited about the result, but we don’t pressure-test it to know it will withstand real-world conditions.”
Collaboration between the lab and the clinic is often the most productive course, Dr. Marais continued. “Clinicians will allow you to ask questions that are relevant,” he told the research audience, “and when you show your tumor growth curve with a P value that is the inverse of the mass of the universe—that clearly, you got a response—they may respond that, actually, it indicates progressive disease, because the tumor is still growing.”
Dr. Marais agreed: “We need to be honest in how we interpret our data, and the way to do that is to ask people who understand the question.”
Team Up or Foster Independence?
We need the lone hunter scientist and the communal harvester scientist. Both are important in the ecosystem.— William G. Kaelin, MD
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Is research more productive when scientists team up to explore one promising idea, as in the “dream team” approach, or pursue their individual hypotheses? Both approaches are necessary within an “R&D ecosystem,” Dr. Horning said.
Part of the beauty of the Vice President’s initiative, he said, is that “it is not top-down research.” Instead, it involves the research community joining forces to evaluate proposals and coming forward with priorities that will “rise to the top.”
Dr. Kaelin expressed appreciation for the “symbiotic relationship” between academic research and industry. “It’s not either/or. It’s both,” he said. But he reminded the panel that great ideas often stem from a single brilliant mind.
“Sometimes you want people going in different directions, because if you don’t, you run the risk of creating herd mentality and stifling heretical thinking, when that thinking may turn out to be the basis of a whole new way of solving a cancer problem,” he shared. “We need the lone hunter scientist and the communal harvester scientist,” Dr. Kaelin added. “Both are important in the ecosystem.”
Dr. Horning, of Genentech, stressed the importance of all stakeholders joining hands in curing cancer. “The importance of having something like the Moonshot is to galvanize the community toward a greater cause,” she said. “We need to strengthen the spirit of cooperation across the entire value chain and a joint vision of what success looks like—which is squarely on patients and their outcomes,” she continued.
Dr. Marais, the only panelist from outside the United States, reminded the others that curing cancer will be a global, not American-only, effort.
From Whence Comes Funding?
Lack of adequate funding for cancer research continues to impede progress, but there are reasons to be encouraged, according to Dr. Lowy. The NCI, for the first time in years, received a 5% increase in appropriations for fiscal year 2016. Dr. Lowy predicted that with the Moonshot initiative, this funding will grow and will largely be directed to the most promising investigator-initiated projects. “We have the opportunity to put our money where our mouth is,” he said.
Dr. Lowy reminded the panel that although the NCI represents “the key aspect” of the federal investment in cancer research, it is not the sole source. The pharmaceutical and biotechnology industries along with private philanthropy may actually supply more investment dollars, he revealed.
Improving the Clinical Trial System
Speaking for patients, Dr. Perlmutter emphasized the need for innovation in clinical trial design. Dr. Pazdur, Director of the Office of Hematology/Oncology Products at the US Food and Drug Administration (FDA), addressed this issue, noting the shortcomings of the current system and emphasizing the FDA’s commitment to getting drugs to the clinic sooner. “Obviously, we have to be more flexible in the approval of oncology drugs,” he said. “My goal is to develop the next generation of drug regulators who can do so.”
Obviously, we have to be more flexible in the approval of oncology drugs. My goal is to develop the next generation of drug regulators who can do so.— Richard Pazdur, MD
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The disease became “a reality” to Dr. Pazdur, he said, when he lost his wife to advanced ovarian cancer this past year. “I truly understand the urgency of developing drugs in an expeditious manner,” he told the audience.
To this end, the route to drug approval is changing. “We are moving away from traditional phase I, II, and III trials to a more fluid approach to drug development,” Dr. Pazdur said. Dr. Baselga added a note about the value of new “basket trials” of novel combinations tested in smaller populations. This is, he said, a “very fluid strategy that will become more sophisticated, driven by scientific advances.”
Dr. Pazdur added that his additional priorities are to expand trial eligibility criteria, involve patient “voices” in drug development and toxicity labeling, and create a system to help physicians navigate access to unapproved drugs.
The Patient’s Voice Is Louder Now
The public is encouraged by the emergence of novel treatments, especially the immunotherapies, which offer durable responses and less toxicity, but the patient community remains frustrated, according to Dr. Perlmutter. “Remember when we talked about personalized medicine—Everyone would be sequenced, the drug would be matched to the patient, and the patient might even be cured?” she said. “We have had some breakthroughs, but they have been few and not very robust.”
Patients are impatient with the pace of drug development. They hear about exciting new drugs and want access—now. “If we have a drug that might actually keep patients alive for years and make them feel good, that’s something worth getting to them sooner rather than later. Patients don’t have the luxury of patience,” Dr. Perlmutter said.
“This means making sure that all patients get standard of care, and more patients get access to the best of care and clinical trials,” she added. She also called for leveraging what we already know. This might include optimizing dosing, scheduling and sequencing of existing therapies, and putting more focus on lifestyle factors that we know influence cancer risk. These are “smaller problems” than those tackled in laboratories and should be prioritized, she said.
Dr. Horning pointed out that the public often does not understand the heterogeneity of cancer, and to this end, there have been “communication problems.” But she acknowledged the responsibility of industry here: “We have to serve the patients we have today as well as those of tomorrow.”
Cancer Dialogue: Moderator Jose Baselga, MD, PhD (left) seated with panel members to discuss whether cancer is “curable.” From left to right: Dr. Baselga, William G. Kaelin, MD, Richard M. Marais, PhD, Sandra J. Horning, MD, Richard Pazdur, MD, Jane Perlmutter, PhD, MBA, and Douglas R. Lowy, MD.
There are many other “cancer riddles yet to be solved,” noted Dr. Kaelin. According to the panelists, some of them follow:
Non–cross-resistant drugs that have nonoverlapping toxicities must be identified so we can build effective combinations.
Appropriate endpoints for drug approval must be defined for novel therapeutics.
Cost is an issue; there must be conversations that will result in making the cure cost less, balancing affordability with investment in innovation.
“Big data” has arrived and needs to be leveraged as “real-world” evidence of drug efficacy.
Funding for all promising avenues of cancer research must increase.
Organizational differences must be overcome to optimize collaboration.
Academic investigators must be fairly compensated to avoid losing them to other career fields. ■
Disclosure: Dr. Baselga is a paid consultant for Grail Inc. Dr. Horning is employed by Genentech. Dr. Kaelin reported financial relationships with Agios, Arqule, FibroGen, Infinity, Lilly, Medivation, Nextech, Peloton, Sunesis, and Tracon. Dr. Lowy has financial relationships with Merck, GlaxoSmithKline, and Indian Immunologicals. Drs. Perlmutter, Marais, and Pazdur reported no potential conflicts of interest.