The Big Picture for 2017: 6 Experts Weigh In

Howard A. “Skip” Burris, MD

Two of the most noteworthy developments in the oncology field during 2016 were the continued expansion of checkpoint blockade immunotherapy agents into more cancer types and the federal government’s plans for funding and remaking the research paradigm.

In the clinical arena, antibodies that target the PD-1/PD-L1 pathway maintained the rapid pace of approvals that has marked their trajectory since the first agent in this category was approved 2 years ago.

The PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) gained the FDA’s approval in head and neck cancer; nivolumab also was approved in Hodgkin lymphoma while pembrolizumab landed an expanded indication in non—small cell lung cancer (NSCLC). Meanwhile, atezolizumab (Tecentriq) became the first PD-L1 antibody to clear regulatory hurdles and is now approved in bladder cancer and NSCLC.

In the political arena, a campaign that has helped focus national attention on cancer research culminated with President Obama signing the 21st Century Cures Act in mid-December. The legislation endorses spending $6.3 billion over 7 years for opioid addiction, precision medicine, the BRAIN initiative, and mental illness, including $1.8 billion for cancer research and care.

Key provisions expected to advance cancer research include a requirement that data from studies funded by the National Institutes of Health (NIH) be shared among scientists, a condition that is intended to speed up the pace of discovery.¹

Howard A. "Skip" Burris III, MDSarah Cannon Research Institute

Looking forward to 2017, how can we expect these developments to unfold? To find out what might be on the horizon, OncLive spoke with prominent leaders in the field in recent weeks. Here, we present their thoughts.As chief medical officer at Sarah Cannon Research Institute, Howard A. "Skip" Burris III directs the initiation and progress of more than 200 early-phase oncology drug trials annually in communities throughout the United States.

Burris believes the federal Cancer Moonshot initiative, which has now been incorporated into the 21st Century Cures Act, has helped generate important conversations about oncology research and care within the field while focusing renewed public attention on cancer.

“It’s been a long time since President Nixon declared the war on cancer back in the early ‘70s and, with a number of new therapies, to regenerate that level of enthusiasm is so needed,” said Burris, a 2014 Giants of Cancer Care winner. Sarah Cannon is playing a key role in the Moonshot initiative in several ways. The institute is helping to lead a $12 million research project that is aimed at studying and standardizing the role of oncology nurse navigators in patient care.

“We’ve invested widely in nurse navigation, which is the idea that when a patient is first given the diagnosis of cancer, we have a nurse navigator help streamline and accelerate their access to the experts—not to step in front of the physicians but simply to coordinate so that patients get their questions answered, that they’re seeing the various subspecialists that might need to be involved in their case,” said Burris.

“The idea is that this will accelerate the accrual for patients into trials through education and awareness,” he added. “Patients would receive greater combined modality and multidisciplinary approaches to their cancer as part of that goal.”

To implement the program, Sarah Cannon has invested in a software platform that captures data on patients as they move through the system. Burris said data on more than 30,000 patients have been entered into the navigation program.

Similarly, the institute is developing systems to put genomic data on patients into usable formats and in natural language programs to incorporate reports into electronic records starting with radiology and pathology.

Burris feels the data-sharing culture that federal officials are seeking can be promoted thorough systems that give patients access to their own information. “Sarah Cannon is trying to advocate the idea that it’s the patient’s data, “ he said.

“Getting the various collaborators to coordinate and to participate in sharing will be a bit of a challenge,” said Burris. “I do think that with where we’re moving in the direction of having molecular profiling information, where we’re seeing clinical trials that are looking at matching patients, lends itself to the idea that we’re going to have to work together. We’re treating patients much more individually.”

On the clinical front, Burris sees developments in 3 major areas during 2017 and into 2018: blood-based molecular profiling, immunotherapy combinations, and antibody—drug conjugates (ADCs). He said the use of circulating tumor DNA is “here and now,” with Sarah Cannon researchers already publishing and presenting findings on leveraging this information to profile patients’ tumors. In the immunotherapy arena, the institute currently has more than 50 open clinical trials testing combinations.

Suzanne L. Topalian, MDJohns Hopkins University School of Medicine

Burris said advances in creating ADCs are “equally exciting;” scientists are discovering safer linkers to use in coupling drugs and are identifying additional antibodies to incorporate into compounds. “Some cancers are still best treated with chemotherapy, and I think the idea that we can do that more safely and effectively is going to be a great advantage,” he said.One of the pioneers of antibodies targeting the PD-1/PD-L1 pathway, Suzanne L. Topalian, MD, continues to explore what is currently the most dominant form of anticancer immunotherapy with a particular focus on biomarkers that may help identify which patients are more likely to respond to the agents. Topalian is a professor of surgery and oncology at the Johns Hopkins University School of Medicine and director of the Melanoma Program at the Sidney Kimmel Comprehensive Cancer Center.

The prospects for moving these therapies forward in the treatment timeline are attracting much interest in the field, Topalian said. “One major trend I see is applying immune checkpoint—blocking drugs at earlier stages of cancer,” she said.

As an example, Topalian noted recent research in which she and colleagues administered nivolumab as neoadjuvant therapy in patients with resectable NSCLC. Results for the first 16 patients presented at the ESMO 2016 Congress indicated a 40% rate of major pathological response (<10% residual viable tumor) after 4 weeks of therapy.²

“I see this [area] as a new wave of clinical trials: applying these drugs in neoadjuvant and adjuvant treatment settings,” she said. “I think there’s intense interest in that now. Can we prevent cancer from progressing to very advanced stage III and stage IV settings? That is an important goal.” She also mentioned ongoing clinical trials evaluating immunotherapy combinations that appear to be more effective than monotherapy. “As those trials mature, there’s great interest in seeing if that will hold up and if it will hold up in randomized comparison trials."

Topalian also commented upon the explosion of clinical trials exploring agents that target the PD-1/PD-L1 pathway, which has been estimated at more than 600. “I think we need to hit the sweet spot there,” she said. “We need to have enough trials that we’re covering the bases and, certainly, even though there are multiple drugs that hit a single target, they are not identical drugs. So there are some subtleties in the different properties of these drugs. But how many do we need? Do we need 10 drugs hitting the same target? Do we need 20 drugs? That part’s not clear. At some point, it is overkill.

“The same goes for the combination therapies,” added Topalian, noting that one estimate placed the number of such ongoing trials at 800. “Many of them are redundant combinations but they’re using different drugs. I think the hope is that pharma and biotech companies will find ways to work together so that companies with different drugs can pair those drugs in combination therapies rather than having to own their own version of each drug.”

For practicing oncologists, Topalian sees a need for continuing education to become conversant with the adverse events and response patterns that develop with immunotherapies. “There is a learning curve,” she said.

Siddhartha Mukherjee, MD, DPhilColumbia University Medical Center

“There are unique side effects associated with these drugs that can be managed effectively in most cases, if they’re recognized early, and if then treatment is aggressive,” she said. “Also, some of the response patterns that we see are not conventional response patterns. Sometimes the tumors don’t regress right away. Sometimes they appear to enlarge on CT scans before they eventually regress. And so, community oncologists need to be aware of these unique characteristics of immunotherapy.”As the author of the Pulitzer Prize-winning book, The Emperor of All Maladies: A Biography of Cancer, Siddhartha Mukherjee, MD, DPhil, continues to help shape the conversation regarding oncology research and development. He recently published The Gene: An Intimate History. A hematologist, Mukherjee is an assistant professor of Medicine at Columbia University Medical Center and a physician at NewYork- Presbyterian/Herbert Irving Comprehensive Cancer Center.

Mukherjee believes the data-sharing and transparency imperatives of the Cancer Moonshot initiative will enhance cancer research but cautions that leveraging so-called Big Data is only one ingredient of discovery.

“Interacting together in a more transparent way clearly has a huge advantage and hopefully will be actualized in the next decade or so through the Moonshot project, and through other projects,” he said. “There’s no doubt that will be helpful but it’s important to know that almost always these pieces lie atop very basic investigations into cell biology, cancer biology, genetics, etc. It’s important not to forget that.”

Mukherjee cited as an example the evolution of imatinib (Gleevec), one of the first targeted therapies to gain the FDA’s approval. The drug was approved in 2001 for the treatment of patients with Philadelphia chromosome—positive chronic myeloid leukemia (CML) after a series of discoveries dating to the 1960s.

“It really grew out of very simple experiments, understanding what the particular lesion was in CML, particularly a genetic lesion in CML, understanding how that was potentially druggable,” said Mukherjee. “These laboratory experiments demonstrated that that drug particularly would target the cells that carried the BCR-ABL fusion and spare other cells.

Hagop M. Kantarjian, MDThe University of Texas MD Anderson Cancer Center

“At that stage, it wasn’t driven by Big Data,” he said. “Now we have much more data about it and it has helped us to understand things like who becomes resistant to imatinib, but it was built atop a series of extremely small, boutique experiments. It’s important to combine those two things.”As the architect of the largest leukemia practice in the United States, Hagop M. Kantarjian, MD, has helped developed new drugs and regimens that have transformed CML. A 2014 Giants of Cancer Care award winner, Kantarjian chairs the Department of Leukemia at The University of Texas MD Anderson Cancer Center, where he also is a leader of global academic programs.

Kantarjian, who has been a fierce critic of spiraling oncology drug prices in recent years, believes there are many aspects of the research establishment in need of reform. “There is a lot of redundancy, bureaucracy, and levels of risk averse conditions and decisions that are slowing cancer research tremendously,” he said. “Those regulatory processes are also increasing the cost of research and increasing the cost of drugs. Most importantly, they are slowing progress and slowing discoveries in cancer research.

John L. Marshall, MDGeorgetown University Hospital

“I’m very much in favor of any initiative that could reduce the level of bureaucracy and eliminate regulatory steps which have not improved either the quality of care or reduced the risk of those treatments to those patients. The Moonshot initiatives are one such program that will help with that,” Kantarjian said.As a leader in the international colon and gastrointestinal (GI) cancer fields, John L. Marshall, MD, is seeking to develop mechanisms for incorporating precision medicine into routine clinical care. He is chief of the Division of Hematology/Oncology at Georgetown University Hospital.

“We spend billions of dollars on cancer research and, yes, we’ve moved the bar. We’ve cured some cancers, kept people alive longer,” said Marshall. “I worry that we’ve been misguided by what I call basic science. The animal is not the right model, the petri dish is not the right model. They give us clues but they don’t tell us what is going on in the patient. It’s taken us years to see that.

“All this targeted therapy that we’ve developed, we’ve really learned about the molecular profiling from the patients,” he continued. “Not from the mouse, not from the petri dish. We need to shift some of our investment, some of our research dollars into more clinically enriched research protocols.”

Marshall believes the Cancer Moonshot program, if properly funded, could sharpen the focus on patients with its emphasis on data building and on patient outcomes. When it comes to improving collaboration among scientists, Marshall noted that the GI field already has a “culture of sharing” and that other specialties also have encouraged cooperation.

Debu Tripathy, MDThe University of Texas MD Anderson Cancer Center

However, he thinks there is room for improvement throughout the cancer research arena. “Our common cause, our common goal is not promotion, is not papers, although that matters. Our common goal is fixing people,” he said.Breast cancer specialist Debu Tripathy, MD, sees a distinct role for the federal government in streamlining and improving oncology research. Tripathy, chair of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, was among a small group of scientists whose work helped pave the way for trastuzumab (Herceptin) and more recently has served as the lead investigator for the inaugural I-SPY clinical trial that simultaneously tests multiple molecularly targeted therapies.

Tripathy said the Cancer Moonshot will not replace what scientists accomplish through individual research projects. “It’s more a matter of bringing people together and having the ideas cross-pollinate each other, and having a Big Data approach,” he said.

Although greater collaboration has been identified as an important goal, challenges to reaching that objective include the proprietary interests of pharmaceutical companies that intend to patent a drug and scientists’ desire to achieve breakthroughs, Tripathy said.

“You have to overcome a lot of natural barriers that exist for people to communicate,” he said. “The government can serve as sort of an honest broker, as someone who helps provide an infrastructure for data sharing—that is, a data commons where everybody can come to. They are aspects of the Moonshot that we hope can really accelerate discovery.”

References

1. Hudson KL, Collins FS. The 21st Century Cures Act—a view from the NIH [published online December 13, 2016]. N Engl J Med. doi:10.1056/NEJMp1615745.
2. Forde PM, Smith KN, Chaft JE, et al. Neoadjuvant anti-PD1, nivolumab, in early stage resectable non-small-cell lung cancer. Presented at: ESMO 2016 Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA41_PR.