Earlier this year, the Institute of Medicine’s (IOM’s) National Cancer Policy Forum (NCPF), the National Academies of Sciences, Engineering, and Medicine, and the Health and Medicine Division (HMD) sponsored the “Policy Issues in the Clinical Development and Use of Immunotherapy for Cancer Treatment” workshop to discuss challenges in the creation and adoption of novel therapeutics – from designing clinical trials to managing patients’ expectations about treatments.
During the two-day event, oncologists, hematologists, pharmaceutical industry representatives, and regulatory officials shared insights on the state of immunotherapy and presented strategies to improve the development process and facilitate patient access.
“Many people might conclude that we’ve gone as far as we can with cytotoxic chemotherapy, in part because of the collateral damage that’s caused by the drugs that have been used for the last 40 years to treat solid tumors and hematologic malignancies,” said Richard Larson, MD, professor of medicine at the Pritzker School of Medicine in Chicago, and an NCPF member who attended on behalf of ASH. “Immunotherapy offers a more targeted approach and, perhaps, a more user-friendly, patient-friendly approach in terms of overcoming the immunological tolerance for malignancies.” (To see how the field of hematology is embracing immunotherapy, see the Sidebar.)
As the field of immunotherapy advances with great alacrity and enthusiasm for this treatment modality grows, the cancer community must acknowledge that older testing paradigms may not apply, said Amy Abernethy, MD, PhD, chief medical officer and senior vice president of oncology at Flatiron Health in New York City and a member of the IOM workshop’s planning committee.
People have a general understanding of how vaccines work, but there is a disconnect between established “mental models” of how a therapy works and what immunotherapy potentially offers, she explained. “Anti-cancer vaccines don’t really work the same way as vaccines that immobilize the immune system – that’s hard for people [to wrap] their heads around.”
Malcolm Brenner, MD, PhD, professor at the Center for Gene Therapy at Baylor College of Medicine in Houston, Texas, who also served on the IOM workshop’s planning committee and presented on adoptive T-cell transfer said, “There’s always an educational lag when a field develops so quickly, but that’s changing,” with immunotherapies making their way to the mainstream.
With chimeric antigen receptor (CAR)-modified T-cell therapies, people are beginning to realize how valuable T cells are in cancer therapy, Dr. Brenner said. “In particular, with their ability to recognize internal antigens, traffic through multiple tissue planes, self-amplify and recruit lots of other effector mechanisms – [they reduce] the risk of resistance, and evolve with the tumor,” making them very attractive therapeutic candidates, he said.
Although there is excitement about the potential of T cell-based immunotherapies, there remain a host of questions about their application and of immunotherapy in general, he told ASH Clinical News.
“We still don’t know how best to use them: Which tumors should we use them on? What should we use them with? Should they be used with other immunomodulatory agents? Should they be used with chemotherapy and radiation?” he asked. “Designing the studies to look at all that is going to be a major challenge.”
Clinical Trial Challenges
Evaluating immunotherapies in clinical trials presents unique challenges, specifically with vaccines engineered to a patient’s specific immune system.
In one presentation, Lisa Butterfield, PhD, professor of medicine, surgery, and immunology at the University of Pittsburgh Cancer Institute in Pennsylvania, proposed integrating biomarkers into clinical trials for immunotherapies as a possible solution. These biomarkers would help avoid toxicity and aid toxicity treatment, avoid ineffective therapies for specific patients, and help researchers understand immunotherapeutic mechanisms of action.
Given that some people are considered “complete responders” to immunotherapy, Dr. Butterfield wondered why clinicians don’t have more useful biomarkers from this cohort. “We need the right specimens collected under standardized conditions. Many trials bank only non-viable tumor and blood samples and variably banked specimens give noisy data that would block the identification of biomarkers” she said.
There’s also the issue of what assays should be tested. Immune assays can be costly, Dr. Butterfield noted, and testing small numbers won’t give robust, reproducible signals. Though there are remarkable new technologies available to conduct immune profiling, there still is not a robust set of data available that show how effective they are in identifying patients.
Development of immunotherapy biomarkers is limited not by technology, according to Dr. Butterfield, but by diminished funding and protocols. For example, she said, the National Cancer Institute’s (NCI’s) Cancer Therapy Evaluation Program (CTEP) won’t allow exploratory biomarker inclusion in protocols and won’t bank specimens for undefined exploration of biomarkers; they want only integrated or integral biomarkers.
“For immunotherapy biomarkers, there are no integral biomarkers yet, they are all exploratory,” Dr. Butterfield stated. “This is a hurdle in the multi-institutional trial setting.”
Historically, Dr. Abernethy explained, clinicians have been attacking the tumor head on but are now being asked to unlock the immune system to attack the tumor. This means clinicians can no longer work with the same historical approach to biomarkers.
“We’re leaving the rather old-fashioned paradigm and recognizing that there is some interaction between the host immune system and the tumor,” she said. “But we don’t necessarily understand all of the elements of the host milieu in which we are expecting this anti-tumor attack to happen.”
Immunotherapy is different, said Richard Simon, DSc, chief of the computational and systems biology branch of the division of cancer treatment and diagnosis at NCI, in a presentation at the workshop. Because immunotherapy is a novel type of therapy, there is a lack of pre-clinical models, its mechanisms of action are more complex, and the need for combination regimens makes clinical trial design a challenge.
“These are not small details; these are profound differences that influence clinical trial design and the culture of immunotherapy development,” Dr. Simon noted.
“The disease landscape is changing so fast, it makes it tough to plan trials thoughtfully,” observed Dr. Abernethy. “I think we are going to get better at designing our trials because we have more and higher-quality data about what is going on in clinical practice.”
Even in well-characterized populations, understanding mutations at one point in time is not enough. “We have to understand how things will change over time,” she explained. Dr. Abernethy cited an example of a patient with epidermal growth factor receptor (EGFR) mutation, whose EGFR mutation changes over time and acquires resistance. “So, it’s a different mutation now. If we think about how that patient’s story changes over time – including what his mutation looked like, how sick or healthy he was, what drugs he received – it’s a reflection of his new state.”
Immunotherapy offers a place to start untangling all of these issues, Dr. Abernethy noted, but researchers need to improve the ability to characterize evolving populations, and then match drugs to patients based on their status at a particular time.
Regulatory Framework Fluidity
Given that so many elements are at play in developing and optimizing immunotherapies, the U.S. Food and Drug Administration (FDA) is working with researchers to develop clinical trial guidelines that are applicable to their mechanisms of action. Rajeshwari Sridhara, PhD, director of the FDA’s Division of Biometrics V, offered her thoughts on the challenges in a presentation at the workshop.
Exploration of alternate intermediate endpoints (other than objective response rate and progression-free survival, which are used in conventional therapies) are needed. In addition, she noted that critical consideration on duration of treatment and length of follow-up are areas that need to be addressed.
Lastly, she pointed out that innovative trial designs – including master protocols, enrichment, and adaptive designs – could be considered if network infrastructure and resources were available to implement such designs.
“There are a lot of trends aligning right now,” Dr. Abernethy commented. “One of those trends involves getting better at using technology and communication to find patients for a trial, and then match patients to the right trials for them.” The White House and the National Institutes of Health’s Precision Medicine Initiative Cohort Program, for example, plans to recruit more than 1 million volunteers to examine genetics, lifestyle factors, and health in an effort to propel precision medicine and identify cures.
Finding the middle ground between the collaborative culture in academia (where clinical trials are designed) and the confidential culture in the pharmaceutical industry (where different companies develop competing products) is another concern. “We are faced with a situation where different companies may have immunotherapies that might work even better in combination, but because of intellectual property issues, it’s been difficult to develop that collaboration between academics and pharmaceutical companies,” Dr. Abernethy added.
Patient and Clinician Education
With an explosion of interest in immunotherapies (but not necessarily an explosion of data), clinicians are struggling with how to share information about immunotherapies with patients. The information is out there, but getting the right information to the right individual at the right time is a challenge.
“The public has a specific mental model on how accelerating the role of the immune system works, but that’s not how the rapidly developing field of immuno-oncology works,” said Dr. Abernethy. “In clinicians’ conversations with patients, we are going to have to figure out how to overcome that.”
“The clinician community has been taught to take care of patients in a fairly standard way. But immuno-oncology is asking clinicians to think differently,” she added. “That means the adverse effects look different; the way we educate patients looks different; the way we talk to patients looks different.”
Dr. Brenner and Dr. Abernethy concur that immunotherapy is changing the conversation with oncology patients.
“We’re in this ‘magical thinking’ mode,” she said. “Patients are hearing a lot of good things about immunotherapy – that this treatment can work wonders.” But, as more data are acquired and patient selection criteria are narrowed, providers will need to have difficult, honest conversations when there is documented proof that immunotherapy does not work for every patient.
Dr. Brenner said he hopes that, when talking with patients about immunotherapy, the cancer community follows the example of the bone marrow transplant community, where providers have been more upfront with patients about the pros and cons of transplants.
“All you can do is be honest and say, ‘Yes, this treatment offers you the chance to live with your disease rather than dying from it. There is the percentage of people for whom this treatment is curative, but that is not always the case. Our hope is that you will be one of those people who lives with the disease, and we’ll do everything we can to make that happen,’” he offered.
Richard Larson, MD, a member of the workshop planning committee, shared with ASH Clinical News how the field of immunotherapy has affected hematology in particular.
“Hematologic malignancies were among the first diseases targeted with monoclonal antibodies,” he said. “Drugs like rituximab have been a mainstay in the treatment of B-cell malignancies for more than a decade.”
“Some of the newer innovations – such as checkpoint inhibitors or vaccine therapies – are further along in solid tumor oncology than in hematologic malignancies. Nevertheless, a drug like nivolumab – the PD-1 inhibitor – clearly has activity in Hodgkin lymphoma.” (Note: the FDA has recently granted nivolumab priority review in this setting.)
An ongoing clinical trial has demonstrated that nivolumab offered “substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin lymphoma.”1
The U.S. Food and Drug Administration granted priority review to a supplemental biologics license application to expand the use of its nivolumab to patients with previously treated Hodgkin lymphoma.
As the immunotherapy field moves forward, Dr. Larson said his hematology colleagues can certainly track the successes in solid tumors to get a better idea of how these agents may work in hematologic malignancies.
“I think these same agents that seem to be successful in chemotherapy-resistant cancers like malignant melanoma and lung cancer are going to show promise in leukemia, lymphoma, [and] multiple myeloma,” he added.
- Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-9.