The clinical efficacy and safety of single-agent pembrolizumab in patients with recurrent granulosa cell tumors of the ovary: a case series from a phase II basket trial

Abstract

Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibitors in GCT patients. Here, we present a case series of GCT patients treated with pembrolizumab who were enrolled in a phase II basket trial in advanced, rare solid tumors (ClinicalTrials.gov: NCT02721732). Cases We identified 5 patients with recurrent GCT (4 adult and 1 juvenile type); they had an extensive history of systemic therapy at study enrollment (range, 3-10), with most regimens resulting in less than 12 months of disease control. Pembrolizumab was administered in these patients, as per trial protocol. Although there were no objective responses according to the irRECIST guidelines, 2 patients with adult-type GCT experienced disease control for ≥ 12 months (565 and 453 days). In one, pembrolizumab represented the longest duration of disease control compared to prior lines of systemic therapy (565 days vs. 13 months). In the other, pembrolizumab was the second longest systemic therapy associated with disease control (453 days vs. 22 months) compared to prior lines of therapy. In this patient, pembrolizumab was discontinued following withdrawal of consent. PD-L1 expression was not observed in any baseline tumor samples. Pembrolizumab was well tolerated, with no grade 3 or 4 treatment-related adverse events. Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population.

Keywords: Case report; Granulosa cell tumor of the ovary; Immunotherapy; Pembrolizumab.

Conflict of interest statement

Competing interests:

Jeffrey How reports grants from the NIH (T32 CA101642) and the Cedars Cancer Foundation during the conduct of the study.

Amir Jazaeri reports personal fees from Gerson and Lehrman Group, Guidepoint, Iovance Advisory Board Meeting, Nuprobe, Simcere, and Pact Pharma; grants from AstraZeneca, BMS, Iovance, Aravive, Pfizer, Immatics USA, and Eli Lilly; and other funding from AstraZeneca outside of the submitted work.

Shannon N. Westin reports grants from the NIH and the GOG Foundation during the conduct of the study; grants and personal fees from AstraZeneca, Clovis Oncology, GSK/Tesaro, Roche/Genentech, and Novartis; personal fees from Merck, Pfizer, Eisai, CIrculogene, and Zentalis; and grants from Cotinga Pharmaceuticals, Bayer, and ArQule outside of the submitted work.

Anil K. Sood reports grants from the NIH (CA109298 and CA209904) during the conduct of the study and other funding from Merck, Biopath, Kiyatec, and M-Trap outside of the submitted work.

Vivek Subbiah reports grants and other funding from LOXO Oncology/Eli Lilly, Novartis, Pharmamar, and Medimmune; grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, the National Comprehensive Cancer Network, NCI-CTEP, The University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals; and other funding from Helsinn, R-Pharma US, Incyte, QED Pharma, ASCO, ESMO, and Medscape during the conduct of the study.

Jordi A. Rodon reports personal fees from Eli Lilly, Orion Pharmaceuticals, Peptomyc, Roche Pharmaceuticals, Ellipses Pharma, Certera, and Ionctura SA; personal fees and other funding from Kelun Pharmaceuticals/Klus Pharma, Novartis, Spectrum Pharmaceuticals, Inc., Pfizer, and Bayer; and other funding from European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline, ESMO, Department of Defense, Merck Sharp & Dohme, Louisiana State University, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, WIN Consortium, Janssen, Tocagen, Symphogen, BioAlta, GenMab, CytomX, Kelun-Biotech, Takea-Millenium, and Ipsen outside of the submitted work.

Aung Naing reports grants from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and Immune Deficiency Foundation (spouse) and other funding from CytomX Therapeutics, Novartis, Kymab, Genome, and ARMO BioSciences outside of the submitted work.

Lois M. Ramondetta, Mingxuan Xu, Abdulrahman Abonofal, Daniel D. Karp, Bettzy Stephen, and Fei Yang have no conflicts of interest to disclose.

Figures

Fig 1:

Radiologic response to pembrolizumab in patients with granulosa cell tumor of the ovary. Waterfall plot illustrating the best objective response to pembrolizumab in the 5 patients (P1—5) using irRECIST criteria. Each bar represents a patient and shows the maximum percentage change from the baseline in the sum of the longest diameters of all target lesions and any new lesions while on pembrolizumab. The area above the upper red dotted line represents progressive disease (≥ 20% increase in the sum of the diameters of the target lesions compared with the baseline). The area between the upper and lower red dotted lines represents stable disease.

Fig 2:

Tumor response according to irRECIST criteria over time. This spider plot demonstrates the tumor measurements from the baseline using irRECIST criteria during the course of treatment with pembrolizumab in the 5 patients. Patients 1, 3, and 4 experienced disease progression as their best objective response, while patients 2 and 5 had stable disease. All patients experienced disease progression prior to stopping treatment except for patient 5, who withdrew consent.