Julia L. Boland, MD candidate
PRETREATMENT CLINICAL findings may predict early treatment discontinuation in patients with ovarian cancer receiving checkpoint blockade immunotherapy agents. Data presented by MD candidate Julia L. Boland at the 2018 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer revealed that patients with ovarian cancer who had bulky disease, liver parenchyma metastases, and bone metastases were more likely to discontinue immunotherapy early due to clinical or radiographic disease progression.1
“Overall, immunotherapy should not be reserved as a last line of treatment for patients with refractory bulky disease; rather, it should be used earlier in the disease course in patients with a lower disease burden,” said Ms. Boland, a researcher at Memorial Sloan Kettering Cancer Center, New York.
Despite the recent progress seen with immunotherapy in the treatment of other solid tumors, response rates reported in ovarian cancer have been fairly low. Currently, there are no U.S. Food and Drug Administration–approved checkpoint blockade immunotherapy drugs for the treatment of ovarian cancer.
Karen A. Cadoo, MD
Dmitriy Zamarin, MD, PhD
Ms. Boland and her co-investigators, Karen A. Cadoo, MD, and Dmitriy Zamarin, MD, PhD, sought to evaluate whether women with ovarian cancer discontinue treatment early on immunotherapy clinical trials and, if so, to delineate the clinical characteristics that lead to early discontinuation for clinical or radiographic disease progression.
Reminder: Delayed Responses With Immunotherapy
IMMUNE CHECKPOINT inhibitors exert their effects indirectly through the immune system rather than by targeting cancer cells directly. As a result, the time to response to immunotherapy agents is often longer than typically seen with cytotoxic agents.
Previous studies have demonstrated that checkpoint inhibitors may take 12 weeks or longer for sufficient evaluation of response. For this reason, the investigators defined early treatment discontinuation as prior to 12 weeks for reasons other than drug toxicity, whereas very early treatment discontinuation was defined as discontinuation prior to 8 weeks on therapy. Another aim of the research was to help guide the selection of appropriate patients who would be more likely to stay on trial beyond 12 weeks, to allow for the potential delayed benefit from immunotherapy drugs.
In this retrospective analysis, the team identified patients with epithelial ovarian, primary peritoneal, and fallopian tube cancers who were treated with programmed cell death protein 1/programmed cell death ligand 1, cytotoxic T-lymphocyte–associated protein 4, and lymphocyte-activation gene 3 inhibitors (alone or in combination therapy) between January 2006 and May 2017 at Memorial Sloan Kettering Cancer Center. Pretreatment clinical properties were recorded from the electronic medical record, and patients with rare ovarian histologic subtypes were excluded; also excluded from the study were patients who received immunotherapy in combination with chemotherapy and those who discontinued treatment prior to 12 weeks due to immune-related drug toxicity.
“Overall, immunotherapy should not be reserved as a last line of treatment for [ovarian cancer] patients with refractory bulky disease; rather, it should be used earlier in the disease course in patients with a lower disease burden.”— Julia L. Boland
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As the majority of the clinical trials included in this current analysis are still ongoing, the findings from this study are not intended to extrapolate the overall response rate, in regard to the survival of patients treated with these agents, noted Ms. Boland.
Predictors of Treatment Discontinuation
OF A COHORT of 103 evaluable patients, 59% discontinued therapy early because of radiographic or symptomatic disease progression, with a median time on therapy of 10 weeks, whereas 41% remained on therapy after 12 weeks. Clinical characteristics were well balanced between the two subgroups; the majority of the patients in the study had high-grade serous carcinoma, and the population was heavily pretreated, with a median number of five prior lines of therapy.
Statistically significant predictors of early treatment discontinuation included pretreatment liver parenchyma metastases (P < .01), bone metastases (P = .05), and bulky disease (defined as the presence of any tumor mass ≥ 5 cm [P = .04)]. After the investigators controlled for confounding effects between the three variables, liver parenchyma metastases was the only independently significant predictor of early treatment discontinuation (P = .02), she reported.
Symptomatic clinical disease progression was the reason for early treatment discontinuation in 43% of patients, mainly due to pain (26.9%), ascites (26.9%), and pleural effusion (19.2%).
“While early disease progression may be of less clinical significance for patients with certain cancer types, ovarian cancer patients may not be able to tolerate disease progression before clinical deterioration,” she said. “Because of this, we thought it important to model which patients were more likely to discontinue therapy very early in treatment, specifically due to clinical progression.”
Bulky disease was the only statistically significant predictor of treatment discontinuation prior to 8 weeks on therapy (P < .01). Patients with bulky disease were about four times as likely to discontinue treatment very early, she reported.
Given the potential for delayed responses to immunotherapy agents, the investigators maintain that patients who are at risk for early treatment discontinuation due to clinical disease progression may not be suitable candidates for immunotherapy clinical trials. “This study is intended to provide guidance for patient selection for immunotherapy clinical trials,” she said. “We aim to prevent potentially irreversible clinical progression that may preclude standard therapies, such as bowel obstructions or fistulas.” ■
DISCLOSURE: Ms. Boland reported no conflicts of interest.
1. Boland JL, Martin M, Zecca N, et al: Predictors of early treatment discontinuation in ovarian cancer patients on checkpoint blockade immunotherapy. 2018 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Abstract 47. Presented March 27, 2018.
Oliver Dorigo, MD, PhD
COMMENTING ON the study, invited discussant Oliver Dorigo, MD, PhD, of Stanford University, said that tumor size and disease site are useful clinical parameters for predicting nonresponse to immunotherapy and should be considered when selecting and “unselecting”...!-->!-->