Two studies presented at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer underscore the importance of enrolling patients with gynecologic cancer on clinical trials and of assuring trial access to racial minorities. One study found a statistically significant improvement in overall survival for patients with platinum-resistant ovarian cancer enrolled on clinical trials, vs not.1 Another study showed that some common eligibility exclusion criteria disproportionately affected Black women and thus restricted their access to such trials.2
Carol Aghajanian, MD
Offering additional insight on the topic of clinical trial access, Carol Aghajanian, MD, Chief of the Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center, New York, noted that the aims of clinical trials can be at cross purposes.3 “We want a homogeneous patient population, so we can answer the scientific question. And we want to improve clinical trial safety, so we want to exclude patients who may be at greater risk of adverse events. We also want to exclude patients not expected to benefit. However, overly restrictive eligibility criteria result in lower accrual, increased accrual timelines, increased complexity and cost, and decreased generalizability. So, we must strike a balance,” Dr. Aghajanian said.
Improved Overall Survival for Trial Participants
Clinical trial participation was associated with improved overall survival compared with no trial participation among women with platinum-resistant epithelial ovarian cancer, in a retrospective, single-institution cohort study reported by Molly Morton, MD, of the Cleveland Clinic.1 Women with platinum-resistant ovarian cancer treated at the Cleveland Clinic between 2009 and 2017 were divided into two cohorts: those who were participants in clinical trials (n = 46) and those who received standard-of-care treatment outside a trial (n = 259).
Between the two groups, there were no significant differences in age, body mass index, race, medical comorbidities, and Eastern Cooperative Oncology Group performance status. In addition, there were no differences in oncologic demographics, such as stage, histology, germline mutation status, primary cytoreduction vs neoadjuvant chemotherapy, and residual disease, as well as treatments such as bevacizumab, intraperitoneal chemotherapy, or PARP inhibitors. There was also no difference between the groups in terms of time to platinum resistance.
The clinical trial participants, however, were exposed to more treatment lines than the standard-of-care group: five vs four (P < .001), with a median time on trials of 3.9 months. The result was a significant improvement in overall survival, from a median of 10.5 months with standard therapy to 13.8 months after trial participation; the 3-year overall survival was 19.6% vs 8.6% (P = .020), representing a 50% improvement. The magnitude of difference favoring clinical trial participation persisted in the multivariate analysis.
“The standard of care was associated with significantly worse overall survival from the time of platinum resistance, when compared with trial participation,” Dr. Morton reported. “Our data underscore the importance of access to clinical trial for all patients with this condition, to improve patient outcomes.”
Exclusion Criteria Eliminate Black Women Disproportionately
Currently, Black women constitute about 6% of all participants in Gynecologic Oncology Group (GOG) clinical trials. “Such a low participation rate is discordant with the increasing proportion of Black women suffering some kind of gynecologic cancer,” said Ann Oluloro, MD, of the University of Washington, Seattle.2
Ann Oluloro, MD
The reasons are multifactorial, but one of the main reasons is exclusion because of the presence of comorbidities. “It’s well known that across multiple comorbid conditions, disparities in comorbid conditions may translate into underrepresentation of Black individuals in clinical trials,” she said.
Data from National Cancer Institute (NCI)-designated cancer centers have shown that several comorbidities are associated with lower trial eligibility rates for Black compared with White patients who have cancer. In addition, clinicians are known to discuss trials less often with individuals who have comorbidities.
The study’s objective was to evaluate NCI-sponsored gynecologic cancer trial protocols for the frequency and trends in comorbidity exclusion criteria. Researchers identified 279 studies conducted between 1994 and 2021, approximately half of which were phase II therapeutic intervention trials of patients with ovarian cancer.
Some Interesting Exclusions
There was an obvious trend toward more exclusions in recent years (2015–2021), including growing exclusions for cardiovascular disease, hepatitis, human immunodeficiency virus (HIV), and mental health or social situation. Also, over time, fewer patients with a poor performance status and renal dysfunction were enrolled.
“For HIV, which we know disproportionately impacts racial minority groups, one-quarter of clinical trials over time [and 66% currently] had this as an exclusion criterion. Over time, there was a 7.3-fold, or 3.3%, increase in the proportion of clinical trials with HIV exclusions. Among trials with HIV exclusion criteria, just 18% had enrollment exceptions for inclusion, whereas 82% did not, such as adequate CD4 levels, undetectable viral load, or use of antiviral medications,” Dr. Oluloro said.
“Similar to HIV, mental health (social situations) was another factor we were surprised to find in increasing proportions of trials [51% currently]. Exclusions related to mental health increased by 2.7% per year. Although the awareness of mental health and social situations is important, the language of these criteria is often fraught,” she added. For example, one protocol described this factor as “no psychological, familial, sociologic, geographic condition that would preclude compliance,” reflecting “broad and subjective criteria that are highly subject to racial bias.”
Modernizing Eligibility Criteria
The good news is that efforts have been made to eliminate much of the restrictive criteria in study protocols, Dr. Aghajanian said. In fact, “modernized” eligibility criteria put forth by ASCO and Friends of Cancer Research Joint Research Statement (ASCO/Friends) in 20174 and 20215 were adopted by the NCI in 2021. Some of the new recommendations for immediate implementation follow:
- Conditions that should not be excluded: Prior or concurrent malignancy whose natural history or treatment does not interfere with the investigational regimen; HIV-infected patients on antiretroviral therapy with an undetectable viral load within 6 months; concomitant medications that are not known to interfere with the investigational drug
- Protocols should not have exclusion criteria for patients with psychiatric illness and social situations or life expectancy criteria.
In addition, there are recommendations for modernizing laboratory testing protocols to reduce patient and institutional burden.6
The changes should not only improve access and fairness but should spell a change in what has become a perfunctory practice. “Everyone can agree on this—some of the eligibility criteria copied forward, year after year, from one template to the next—they just have to go!” she said.
Dr. Aghajanian encouraged attendees to “challenge assumptions and past practices.” If you receive protocols that do not reflect the modernized eligibility criteria, consider “it’s time to take action…. Send it back and make the sponsor fix it before you participate.”
Clinical Trial Design Implications
The U.S. Food and Drug Administration has also developed proposals that may result in more inclusion of patients with comorbidities and a poor performance status in trials.7 Such a trial would include an intent-to-treat population of all enrolled patients and then with hierarchical testing a primary analysis of the modified intent-to-treat population with restricted eligibility criteria; there could also be a subsequent intent-to-treat population analysis with restricted eligibility criteria plus expanded eligibility criteria. If the sample size were adequate and preplanned, there would be a separate analysis of the expanded population.
Another option is a simultaneous randomized controlled trial (with restricted eligibility criteria) that allows a single-arm cohort of patients with expanded eligibility. The expanded eligibility would include a poorer performance status, more prior therapies, and various subsets such as platinum-resistant vs platinum-sensitive ovarian cancer, Dr. Aghajanian said.
Equitability Starts in the Clinic
Finally, the speakers emphasized that all potential improvements would be futile without clinician involvement. As Dr. Morton pointed out, clinical trial access and equitability start at the provider/patient level. “It’s also important to recognize the role of the provider. About 50% of patients with gynecologic cancer report never having had a discussion with their provider about clinical trial participation. It starts with us!”
DISCLOSURE: Dr. Aghajanian has served as a principal investigator for trials funded by AbbVie, AstraZeneca, Clovis, and Genentech/Roche. Dr. Morton and Dr. Oluloro reported no conflicts of interest.
REFERENCES
1. Morton M, Yao M, Chalif J, et al: Clinical trial participation is associated with improved overall survival in patients with platinum-resistant epithelial ovarian cancer. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Abstract 140. Presented March 25, 2023.
2. Oluloro A, Swisher E, Gray H, et al: Assessment of gynecologic cancer clinical trials by a new measure of equitable access: Restrictive comorbidity criteria. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Abstract 144. Presented March 25, 2023.
3. Aghajanian C: Distillation: Clinical trial participation abstracts. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 25, 2023.
4. Kim ES, Bruinooge SS, Roberts S, et al: Broadening eligibility criteria to make clinical trials more representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. J Clin Oncol 35:3737-3744, 2017.
5. Kim ES, Uldrick TS, Schenkel C, et al: Continuing to broaden eligibility criteria to make clinical trials more representative and inclusive: ASCO–Friends of Cancer Research Joint Research Statement. Clin Cancer Res 27:2394-2399, 2021.
6. Spira AI, Stewart MD, Jones S, et al: Modernizing clinical trial eligibility criteria: Recommendations of the ASCO–Friends of Cancer Research Laboratory Reference Ranges and Testing Intervals Work Group. Clin Cancer Res 27:2416-2423, 2021.
7. Jin S, Pazdur R, Sridhara R: Re-evaluating eligibility criteria for oncology clinical trials: Analysis of investigational new drug applications in 2015. J Clin Oncol 35:3745-3752, 2017.
