‘Multipronged effort’ needed to increase diversity in CAR-T clinical trials
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Emerging evidence has shown chimeric antigen receptor T-cell therapies are highly effective regardless of a patient’s race or ethnicity.
Despite this encouraging finding, access to the treatment modality — both in the real-world and research settings — remains limited for historically underrepresented populations.
Lack of diversity in clinical trials has been a longstanding challenge in oncology.
Enrollment barriers for trials of CAR-T and other cell therapies are even more formidable than those for conventional cancer treatments because of their highly personalized nature and specialized collection, manufacturing and post-infusion protocols, according to Rayne H. Rouce, MD, pediatric oncologist at Texas Children’s Hospital, associate professor and associate director of community engagement in the Office of Institutional Diversity, Equity and Inclusion at Baylor College of Medicine.
Despite a “lofty list of demands” placed on CAR-T recipients, clinicians must resist the temptation to doubt a patient’s ability to participate in a CAR-T trial — or receive the therapy commercially — because of perceived socioeconomic challenges or put limited effort into educating historically underserved populations who may be skeptical about the therapy.
“That is not acceptable,” Rouce, a member of the Healio | Cell Therapy Next peer perspective board, said in an interview. “We have to identify the barriers and address them so we can offer this therapy to patients regardless of race or ethnicity.”
Healio spoke with CAR-T researchers and other key opinion leaders in oncology about underrepresentation of historically underserved populations in clinical trials, the explanations for these disparities and the strategies that can be implemented to overcome them.
‘Limited information’
Ancestral traits are known to affect disease biology, as well as how patients respond to some therapies.
The impact race or ethnicity have on the efficacy and safety of CAR T-cell therapy is a nascent area of research.
“At this time, there is limited information from the registrational trials [of approved CAR-T therapies] on the safety and efficacy based specifically on race and ethnicity ... such that meaningful conclusions cannot be drawn,” Nicole Gormley, MD, director of Office of Oncologic Diseases, division of hematologic malignancies II at the FDA, told Healio. “The initial approvals for these products were often based on relatively smaller clinical trials, and we are still gaining additional experience with some of these products.”
In cases when registrational trials lacked diverse populations reflective of real-world disease epidemiology, the FDA is requiring manufacturers to conduct additional post-marketing studies to assess outcomes based on race and ethnicity, Gormley added.
One such study examined real-world outcomes among patients with large B-cell lymphoma treated with axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences), a CD19-directed CAR T-cell therapy.
The analysis — based on data from Center for International Blood & Marrow Transplant Research (CIBMTR) Cellular Immunotherapy Data Resource — included 1,389 patients (81% white, 11% Hispanic/Latino, 6% Asian and 5% Black) who received axicabtagene ciloleucel for diffuse large B-cell lymphoma between October 2017 and August 2020.
The results — presented at this year’s ASCO Annual Meeting — revealed comparable efficacy and safety regardless of patients’ race or ethnicity.
The findings revealed some disparities in objective response rates (white, 74%; Hispanic/Latino, 73%; Asian, 67%; Black, 57%) and complete response rates (white, 57%; Hispanic/Latino, 55%; Asian, 53%; Black, 45%).
Researchers acknowledged the lower response rates among Black patients warrant further investigation into disease biology and immune state of patients with DLBCL based on race and ethnicity. However, they reported no statistically significant differences in measures of treatment durability.
A single-center, retrospective study examined outcomes of 46 patients with non-Hodgkin lymphoma who received CAR T-cell therapy at Montefiore Medical Center between 2015 and 2021.
Investigators divided patients into two groups. The first comprised 26 Black (n = 9) or Hispanic (n = 17) patients. The second included 20 white (n = 15) or Asian (n = 5) patients.
Researchers reported no statistically significant difference between groups with regard to complete response rate (58% for Black/Hispanic vs. 70% for white/Asian), rate of disease progression after CAR-T (23% for Black/Hispanic vs. 10% for white/Asian), median PFS (not reached for Black/Hispanic vs. 11.9 months for white/Asian) or median OS (46.3 months for Black/Hispanic vs. not reached for white/Asian).
The safety analysis yielded similar rates of grade 1 or grade 2 cytokine release syndrome between the two groups (96% for Black/Hispanic vs. 95% for white/Asian). One patient in each group experienced grade 3 CRS. Investigators also found similar rates of immune effector cell associated neurotoxicity syndrome between groups.
Results from a retrospective study presented at the 2021 TCT Meetings Digital Experience suggested younger Black patients who received tisagenlecleucel (Kymriah, Novartis) — a CD19-directed CAR T-cell therapy — for acute lymphoblastic leukemia achieved significantly poorer outcomes than those of other races or ethnicities.
The cohort included 200 patients (46.5% non-Hispanic white, 37.5% Hispanic, 5.5% Black, 4.5% Asian, 2.5% multiracial, 3.5% unknown).
The efficacy analysis showed a complete response rate of 57% among Black patients compared with 86% for all other patients who received tisagenlecleucel (P = .007). Black patients appeared significantly less likely than other study participants to be alive at 6 months (43% vs. 86%) or 1 year (43% vs. 73%; P for both = 0.26).
Fifteen patients did not undergo infusion of tisagenlecleucel after apheresis, including four (36.4%) of 11 Black patients and 11 (5.8%) of the 189 patients of other races or ethnicities (P = .005). Two Black patients did not undergo infusion because of manufacturing failure after apheresis.
Rouce — not involved with the study but familiar with the findings — said the disparities in outcomes are less likely to be attributable to differences in biologic factors. She noted patients from historically underserved communities are more likely to be receive later referrals to CAR-T, when their disease is more advanced and aggressive.
Treatment histories of patients enrolled in the study bear this out, as Black study participants had undergone more prior lines of therapy (median, 5 vs. 2; P < .0001), more relapses before CAR-T (median, 2 vs. 1; P = .0105) and a higher rate of prior stem cell transplantation (71% vs. 24%; P = .0122).
Across-the-board disparities
Despite evidence supporting the effectiveness and safety of cell therapies regardless of race or ethnicity, historically underrepresented populations continue to enroll in CAR-T clinical trials.
Black individuals are particularly underrepresented, according to Heather Stefanski, MD, PhD, vice president of medical services for National Marrow Donor Program/Be The Match.
“We need to be much better about enrolling these patients in clinical trials and finding novel ways to ensure this happens,” Stefanski — a former pediatric bone marrow transplant/cell therapy specialist — told Healio.
Studies published in the past year demonstrate the need to address racial and ethnic disparities in clinical trial enrollment, she added.
Researchers from University of Arkansas for Medical Sciences observed consistent underrepresentation of Black individuals in pivotal clinical trials that led to FDA approval of several CAR T-cell therapies. This trend persisted regardless of the product studied or disease being treated.
The investigators — whose findings appeared in JAMA Network Open — noted the most pronounced enrollment disparity in a pivotal phase 2 clinical trial designed to evaluate idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) for multiple myeloma, a disease that affects Black individuals at a rate of about 2:1 compared with white individuals.
The trial included 140 patients with relapsed or refractory disease, only 8 (5.7%) of whom were Black.
The study authors also highlighted a pivotal phase 2 study of tisagenlecleucel for patients aged 25 years or younger with B-cell acute lymphoblastic leukemia. The study enrolled 88 patients, none of whom were Black.
A separate study by the same group of researchers — also published in JAMA Network Open — showed unequal distribution of trial sites nationwide has led to inequitable access to cutting-edge CAR-T or bispecific antibody immunotherapy trials among Black patients with advanced multiple myeloma.
The analysis included 69 trials with more than 140 trial sites. Among the 10 states with the highest proportion of Black residents (range, 18.6% to 41.4%), three did not have an active trial site for CAR-T or bispecific antibody immunotherapies. Three other states had three or fewer sites with active trials for these treatment modalities.
Results from a retrospective study presented at last year’s ASH Annual Meeting and Exposition revealed challenges in trial enrollment when broken down by ethnicity, as well.
Investigators concluded Hispanic/Latinx patients outside urban areas may face barriers that limit timely access to CAR-T clinical trials for relapsed or refractory B-cell acute lymphoblastic leukemia.
In that study, significantly more younger patients from within the catchment area of and referred to one of five urban academic centers for CAR-T clinical trials had public insurance (65% vs. 31%; P < .001) and identified Spanish as their primary language (24% vs. 6%; P < .001) compared with those referred from outside the center’s system.
Additionally, non-local patients typically traveled 40 times farther to their clinical trial sites than locally referred patients.
“Our findings suggest that barriers to access — such as distance and need for travel — may differentially impact Hispanic patients,” Anurekha Hall, MD, MS, acting instructor at Seattle Children’s Hospital, told Healio. “Additionally, Spanish-speaking patients and patients with public insurance also were underrepresented in referrals from outside institutions, suggesting that language and insurance may also be key barriers to access.”
Identifying the causes
Multiple factors impede participation in CAR-T clinical trials among patients from historically underserved comminutes, Gormley said.
These include:
- clinical trial sites not easily accessible to diverse patient populations;
- investigator cultural competency;
- enrollment and retention practices;
- restrictive eligibility criteria;
- financial barriers to participation; and
- patient mistrust or lack of understanding of clinical trials.
“Addressing this issue will require a concerted effort from the entire community: physicians, industry, academia, patient advocacy groups and regulatory agencies,” Gormley told Healio.
Patient skepticism — particularly among groups with negative historical interactions with the health care community — can be a major barrier to CAR-T access in the clinical trial and real-world settings, Rouce said.
Patients from historically underserved comminutes often will not consider CAR-T because they are less “health literate” about the complex CAR-T process, she added.
Structural racism — including institutions and practices that reinforce discriminatory beliefs — likely is a key component behind all of the factors that lead to disparities in CAR-T access, Stefanski said.
She pointed to a study by researchers from The University of Chicago. In their paper, published in Blood, Abraham and colleagues concluded that structural racism is “a stronger mediator of survival disparities” than health care access, molecular features, comorbidities and treatment.
“Studies have found that implicit bias reduces the likelihood that clinicians offer clinical trials to racially and ethnically marginalized patients compared with patients who are white,” Randall A. Oyer, MD, executive medical director of Ann B. Barshinger Cancer Institute and Cancer Services, clinical professor of medicine at University of Pennsylvania's Perelman School of Medicine and past president of Association of Community Cancer Centers (ACCC), told Healio.
More than half of patients — regardless of race or ethnicity — enroll in clinical trials after being told about them by a health care provider, he added.
“If a patient is not offered the trial, then they do not have equitable access to novel, possibly life‐saving treatments,” Oyer said.
Lori J. Pierce, MD, FASTRO, FASCO, past president of ASCO, echoed Oyer’s sentiment.
Although the list of barriers to clinical trial participation among historically underserved populations is long, bias on the part of physicians likely outweighs biases on the part of their patients, Pierce said.
“Studies have shown that persons of color may choose not to enroll in trials because of distrust of the research/medical communities resulting from medical mistreatment, personal beliefs about the value of trials, fear of possible side effects and lack of awareness about the benefits of trials,” she told Healio. “Skepticism does play a role, but it is part of the many other barriers, and clinicians not offering trials to patients is the larger barrier.”
Commitment to equity
ASCO partnered with ACCC to offer the Just ASK training program, designed to address implicit bias on the part of cancer care professionals. The goal is to increase racial and ethnic diversity in cancer clinical trials.
The organizations also are offering the ASCO-ACCC Equity, Diversity, and Inclusion Research Site Self-Assessment. The online tool helps research teams identify possible opportunities to improve diversity, equity and inclusion in trials, while also allowing for an internal review of procedures, policies and programs.
Oyer recommended that clinicians and all members of clinical trial research teams complete both free online programs.
“To improve access to trials, leaders must commit to and support equity, trials must be designed with specific health equity goals, and programs must partner with diverse stakeholders across their communities,” he said.
The self-assessment requires each team member to review internal processes and procedures, including availability of trials, patient access to the site and how trial participation is offered, Pierce said. The result is formulation of a team-developed action plan.
“The action plan can only be accomplished with buy-in from the entire team,” Pierce said. “It takes a full team effort to make systematic change.”
The Just ASK program and the site self-assessment underwent evaluation as part of a pilot project conducted at 75 research sites across the United States. Results will be published later this year.
Pierce told Healio that “participating sites found the resources useful, in addition to providing feedback on how to functionally improve both resources.”
Improving clinical trial diversity also is “a major focus” of the FDA, Gormley said.
Draft guidance from the agency published in April focused on creating plans to enroll more patients into trials from historically underserved communities. The document recommends trial sponsors develop and submit a “Race and Ethnicity Diversity Plan” to FDA early in the clinical development process to outline how an adequate number of participants from underrepresented racial and ethnic populations will be enrolled in clinical trials of their products.
FDA previously issued recommendations about the collection of race and ethnicity data during trials.
“The trial designs, study assessments and eligibility criteria should be structured where feasible to allow for enrollment of a broader patient population,” Gormley said. “Investigators should incorporate feedback from patient advocates to ensure inclusive elements for all aspects of trial conduct, [and] trial sites should be selected to include geographic locations that will allow participation from a diverse patient population.”
Demystifying CAR-T
Efforts by professional societies and the FDA to improve clinical trial diversity are encouraging, but the field of cell therapy must go beyond generalized guidance and take actions that will help ensure greater access to the treatment modality, Rouce said.
“Trying to be more diverse is nice in an ideal situation, but increased participation must be accompanied by efforts to break down geographic, structural and economic barriers to CAR-T trial participation,” Rouce told Healio.
Rouce’s recommendations start with “reporting the actual data” and taking the necessary time to break it down according to race and ethnicity — particularly results of large phase 2 or phase 3 trials published in peer-reviewed journals or presented at major medical meetings.
“Once it's presented, we need to actually look apples-to-apples and see if there are biologic determinants of outcomes, or whether they truly are more social determinants,” she said.
CAR-T researchers also must budget for a clinical trial navigator, Rouce said.
“[This person] is specifically there to identify some of these barriers upfront and try to address them,” Rouce said.
A scientific educator also may be needed to create simple animations or other communications in multiple languages to promote more diverse trial participation.
“These steps really have to be thought of at conception when trying to translate from bench to bedside, not just a retrospective, ‘Whoops!’” Rouce said.
For patients with lower levels of health care literacy, additional education and communication can help overcome patient skepticism about cell therapy and whether it is the right option for them.
It also is important to be transparent with patients, “thereby demystifying CAR-T and the process of participating in a clinical trial,” Rouce said.
“I participate in health fairs and give different talks to spread the truth about clinical trials for churches and community centers,” Rouce told Healio. “Change is not something that can occur just within the confines of the hospital room — we must be out in the community to make it happen.”
The science behind the CAR-T process is not easy to understand for many patients, Rouce said.
“It's especially hard to wrap your head around when there's a history of experimentation in marginalized populations,” she added. “Communication is key, and multiple focus groups and research studies have shown that patients of all races and ethnicities appreciate transparency, and that transparency can overcome their fears.”
Stefanski agreed that communication is key to diversifying access to CAR-T, both in clinical trials and real-world settings.
She proposed a novel strategy in which former patients serve as ambassadors to historically underserved communities to help explain the process and alleviate potential mistrust.
“Have those patients go talk to their own community and [tell] their story — both the positive and even the negative aspects of what happened to them — so people understand what is possible,” Stefanski said.
She also emphasized the importance of identifying strategies to overcome one of the largest barriers to CAR-T trial participation: the requirement to have a continuous caregiver for a designated period after infusion.
“This can serve as a huge impediment among patients from historically underserved communities,” Stefanski said. “Some people aren't going to have a caregiver, so let's meet them halfway and figure out new novel ways to accommodate patients so they can receive this therapy.”
‘The right thing to do’
Efforts to diversify the clinical trial populations — for CAR-T or otherwise — should be done as a means of social justice, Gormley said.
“Providing greater access to clinical trials advances the health of all patients with cancer and is the right thing to do,” she told Healio. “Addressing clinical trial diversity will require a multipronged effort from multiple stakeholders within the community.”
Promoting greater access — both in clinical trials and real-world settings — will require commitments from commercial sponsors, institutional providers, physicians, advocacy groups and professional societies, Rouce said.
“These barriers don’t just apply to patients of color. They exist for all patients who are of lower socioeconomic status, and those who live in rural areas and are geographically distant,” she told Healio. “We have to address these issues. Until we do, we're not really making these potentially curative therapies available for all.”
The goal should be to ensure every patient with cancer receives the best possible treatment, Stefanski said. Two core principles can help make that objective a reality, she added.
“Everyone should be given an equal chance to survive,” Stefanski told Healio. “Every patient who is a candidate for CAR-T ... should be referred, and then we can find ways to make it happen. First, we need to try and strip away our own biases. Then think outside the box.”
References :
- Abraham IE, et al. Blood. 2022;doi:10.1182/blood.2021012830.
- Alqazaqi R, et al. JAMA Netw Open. 2022;doi:10.1001/jamanetworkopen.2022.28877.
- Al Hadidi S, et al. JAMA Netw Open. 2022;doi:10.1001/jamanetworkopen.2022.8161.
- Baggott C, et al. Abstract LBA7. Presented at: The 2021 TCT Meetings Digital Experience (virtual meeting); Feb. 8-12, 2021.
- Hall AG, et al. Abstract 339. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
- Locke FL, et al. Abstract 7571. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
- Thakkar A, et al. Bone Marrow Transplant. 2022;doi:10.1038/s41409-022-01670-1.
For more information:
Nicole Gormley, MD, can be reached at nicole.gormley@fda.hhs.gov.
Anurekha Hall, MD, MS, can be reached at agollapu@fredhutch.org.
Randall A. Oyer, MD, can be reached at randall.oyer@pennmedicine.upenn.edu.
Lori J. Pierce, MD, FASTRO, FASCO, can be reached at ljpierce@umich.edu.
Rayne H. Rouce, MD, can be reached at rhrouce@texaschildrens.org.
Heather Stefanski, MD, PhD, can be reached at hstefans@nmdp.org.
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