Advanced germ cell tumors are aggressive and associated with poor prognosis. Pembrolizumab was overall well-tolerated in 12 heavily pretreated patients. Three patients had radiographic stable disease that lasted for 10. 9 months, 5.5 months, and 4.5 months, respectively. Published data of immunotherapeutic agents in patients with advanced germ cell tumors are confirmed. The limited antitumor activity of immunotherapy in germ cell tumors is, at least partially, attributed to tumor biology (low tumor mutational burden; low PD-1 expression) and other poor-risk features. Tumor profiling to understand the mechanisms of resistance to pembrolizumab and innovative clinical trials that may include immunotherapy are warranted.
Advanced germ cell tumors are associated with poor prognosis. We investigated the role of pembrolizumab in patients with advanced germ cell tumors.
We analyzed a pre-specified cohort of an open-label, phase II clinical trial in which patients with advanced germ cell tumors were treated with pembrolizumab (200 mg) intravenously every 21 days. The endpoints of the study were the non-progression rate (NPR) at 27 weeks, safety, and tolerability. An NPR >20% was considered successful and worthy of further pursuit.
From August 2016 to February 2018, 12 patients (10 men, 2 women) were treated (median age, 35 years [range, 22-63 years]; median number of prior systemic therapies, 3.5 [range, 2-7]; median number of metastatic sites, 3 [range, 2-8]). Overall, pembrolizumab was well tolerated. One patient experienced both grade 1 immune-related skin rash and grade 3 immune-related pneumonitis. No patient died from toxicity. Three patients had radiographic stable disease that lasted for 10.9 months, 5.5 months, and 4.5 months, respectively. No objective response was noted. The median progression-free survival was 2.4 months (95% confidence interval [CI], 1.5-4.5 months) and the median overall survival was 10.6 months (95% CI, 4.6-27.1 months). The 27-week NPR was 9.0% (95% CI, 0.23-41.2%).
Overall, pembrolizumab was safe and had limited antitumor activity in these patients. In the advanced, metastatic setting, tumor profiling to understand the mechanisms of resistance to immunotherapy and innovative clinical trials to identify efficacious combination regimens rather than off-label use of pembrolizumab are warranted.
Germ cell tumors are associated with a diverse histopathology and clinical prognosis. Approximately 20%-30% of patients with metastatic germ cell tumors have disease resistant to standard chemotherapy [1], and 15%-20% of these tumors are incurable with the available treatments [2]. The optimal therapeutic approach for advanced germ cell tumors has not been established, and thus, there is a need to identify novel effective therapies. Pembrolizumab is a programmed cell death 1 (PD-1)-blocking antibody that is indicated for the treatment of the following metastatic tumor types: melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell cancer, Hodgkin lymphoma, gastric cancer, gastroesophageal junction adenocarcinoma expressing PD-L1, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, and endometrial carcinoma. It is also indicated for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient solid tumors and unresectable or metastatic tumor mutational burden-high (≥10 mutations/megabase) solid tumors [3]. Our study demonstrated that pembrolizumab was well tolerated overall, with some exceptions, and had limited antitumor activity in patients with advanced and metastatic germ cell tumors. Changes in tumor measurement from baseline over time are illustrated in a spider plot (Fig. 1) and response and relevant clinical events in a swimmer plot (Fig. 2). The median progression-free survival duration was 2.4 months (range, 0.13-10.9 months; 95% CI, 1.5-4.5 months), and the median overall survival duration was 10.6 months (range, 3.1-36.8 months; 95% CI, 4.6-27.1 months). A 24-year-old man with testicular germ cell tumor was alive and progression-free at 27 weeks (27-week NPR = 9.0%; 95% CI, 0.23-41.2%). Eleven of 12 patients were evaluable for response. One patient was nonevaluable for response because he withdrew consent on cycle 1, day 4 to pursue another treatment. The best RECIST response was stable disease, which lasted for 10.9 months, 5.5 months, and 4.5 months, respectively. Eight patients had progressive disease. No objective response was noted. Tumor profiling to understand the mechanisms of carcinogenesis and resistance to pembrolizumab, as well as innovative clinical trials that may include immunotherapy, are warranted to improve the clinical outcomes of patients with germ cell tumors.
The oncologist. 2021 Jan 24 [Epub ahead of print]
Apostolia-Maria Tsimberidou, Henry Hiep Vo, Vivek Subbiah, Filip Janku, Sarina Piha-Paul, Bulent Yilmaz, Jing Gong, Mohammad Faraz Naqvi, Shi-Ming Tu, Matthew Campbell, Funda Meric-Bernstam, Aung Naing
Departments of Investigational Cancer Therapeutics and The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Departments of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.