CLINICAL NEWS 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 . ●
Hematology at the Forefront
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 .”
“Hematologic malignancies were among the first diseases targeted .”
— RICHARD LARSON , MD
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 chemotherapyresistant cancers like malignant melanoma and lung cancer are going to show promise in leukemia , lymphoma , [ and ] multiple myeloma ,” he added .
REFERENCE
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 .
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