Pembrolizumab in Patients with Advanced Metastatic Germ Cell Tumors

Abstract

Lessons learned: 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.

Background: Advanced germ cell tumors are associated with poor prognosis. We investigated the role of pembrolizumab in patients with advanced germ cell tumors.

Methods: We analyzed a prespecified 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.

Results: 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%).

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT02721732.

Keywords: Germ cell tumor; Non-progression rate; Pembrolizumab; Phase II.

© AlphaMed Press; the data published online to support this summary are the property of the authors.

Figures

Figure 1

Tumor growth or shrinkage from baseline in 12 patients who underwent treatment with pembrolizumab. Spider plot illustrates changes in lesion tumor burden and presence of new lesions over time. Competed tomography (CT) scan data at the most recent time prior to cycle 1, day 1 was chosen as baseline (time 0). The horizontal (x) axis shows time at restaging CT scans as weeks from baseline. The vertical (y) axis shows percentage of change in tumor measurement from baseline. Each line represents data from an individual patient and is labeled with the patient identifier at the end. Each dot represents a data point collected at each restaging CT scan. The green lines represent stable disease. The red lines represent progressive disease (≥20% increase in tumor measurements from baseline) based on RECIST and/or immune‐related RECIST. Square dot represents presence of new lesions, which were reported in one patient.

Figure 2

Clinical events in 12 patients who underwent treatment with pembrolizumab. Swimmer plot illustrates clinical responses in relationship to duration of treatment and time of study cessation (end of study). Cycle 1, day 1 was chosen as baseline (time 0). Bar length indicates duration of stability or response. Symbols along and at the end of each bar represent relevant clinical events, which include stable disease (circle), progressive disease (triangle), last dose of treatment (cross), and end of study (square). Patient 3 continued treatment beyond disease progression for one additional cycle.

Figure 3

Levels of AFP and β‐HCG in two patients (7 and 9) who had stable disease by time. Cycle 1, day 1 (baseline) is shown as time 0. The horizontal (x) axis shows time as weeks from baseline. The vertical (y) axis shows measurements of AFP levels in ng/mL (normal levels, ≤8.3 ng/mL) or β‐HCG levels in mIU/mL (normal levels, ≤4.9 mIU/mL). (A): Levels of AFP in patient 7. (B): Levels of β‐HCG in patient 7. (C): Levels of AFP in patient 9. (D): Levels of β‐HCG in patient 9.Abbreviations: AFP, alpha fetoprotein; β‐HCG, beta human chorionic gonadotropin; ULN, upper limit of normal.