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Refractory Testicular Germ Cell Tumors – Where Should We Go Next?

Fortunately, most people are cured, however, 15-20% of patients with metastatic testicular germ cell tumors will relapse following initial chemotherapy.  Approximately half will still be cured with salvage treatments, including either conventional cisplatin-based combination chemotherapy or high-dose chemotherapy followed by autologous stem cell rescue.1-3  Over the years, I’ve written a couple of different Urotoday Clinical Trials Portal articles summarizing the very few clinical trials, at the time, for those who have refractory/resistant germ cell tumors.4, 5  Unfortunately, to date, none of those previously highlighted clinical trials have changed the standard of care for this unmet need population.  In these situations, palliative chemotherapy, with regimens containing oxaliplatin, is commonly used, yet it has limited efficacy.6


One previous article was focused on the use of immune checkpoint inhibitors for men with treatment-refractory testicular germ cell tumors.5  The early data with pembrolizumab and nivolumab provided some early hints of efficacy in case reports/series.7-9  However, 3 clinical trials using pembrolizumab,10 avelumab,11 and durvalumab,12 have been published, showing limited efficacy for monotherapy PD-1/PD-L1 antibody therapy.  There were some anecdotal signs of efficacy using the combination of durvalumab with tremelimumab, with one patient having a partial response and another patient with radiographically stable disease and serum tumor marker decline.12   The majority of ongoing clinical trials I emphasized in that last article, over 1.5 years ago, highlighted trials using combination immune-oncology approaches.  Most of those trials have been completed or closed early to accrual, and we have yet to see results.  For example, we await results from other studies with the combination inhibition of PD-L1 and CTLA4 approach.  That said, nivolumab and ipilimumab are still being studied (NCT03333616) in patients with advanced rare genitourinary tumors, including those with treatment refractory germ cell tumors.

Although PD-1/PD-L1 in combination with CTLA4 inhibition has been a winning formula for multiple tumor types, newer checkpoint inhibition combinations require exploration.  TIGIT is another checkpoint that is being fully explored in many cancer subtypes, including germ cell tumors.  TIGIT is another immune checkpoint receptor that is expressed on many immune cell types.  This includes cytotoxic T cells, memory cells, regulatory T cells, and even NK cells.13  When TIGIT is bound by the ligands, CD155 and/or CD112, immune activation of cytotoxic T cells and NK cells is inhibited.14 

Antibody drug conjugates are also finding success in many neoplasms, hence, germ cell tumors should be fully explored.  For example, brentuximab vedotin, targeting CD30, which is known to be expressed on many non-seminomatous germ cell tumors, has shown some promise in germ cell tumors.  In the first published trial using brentuximab vedotin, 9 patients were treated and 1 had a complete response, while another had a partial response.15  Another trial that included 5 patients who had CD30 expression of their relapsed/refractory metastatic germ cell tumors, resulted in 1 durable complete response and 1 partial response to brentuximab vedotin.16  Another trial enrolled 18 patients with relapsed/refractory non-seminomatous germ cell tumors, however, only 7 patients had positive CD30 staining.17  Unfortunately, none of those patients responded to single agent brentuximab vedotin.  Other targets for antibody drug conjugates warrant exploration for patients with refractory/resistant germ cell tumors. 

Adaptive cellular immunotherapy approaches have also shown promise in various tumor types, with a significant toxicity profile, but warrants exploration in a disease where patients tend to be young and options are limited.  Finally, traditional chemotherapy options are still worth exploring, as overall treatment options and trials are very limited.

Fortunately, few individuals suffer from cisplatin-refractory/resistant germ cell tumors.  Unfortunately, clinical trials are few and far between for these patients.  Additionally, few trials are designed just for patients with testicular germ cell tumors, and many take a tumor agnostic approach, relying on a target or mechanism of action that hopefully has widespread activity across malignancy types.  Below, I highlight some ongoing clinical trials that include patients with treatment-refractory testicular germ cell tumors.

Highlighted Trials:

  • Nivolumab + Ipilumumab for advanced rare genitourinary tumors (NCT03333616)
  • Nivolumab + Etigilimab (TIGIT inhibitor) for locally advanced and metastatic tumors (NCT04761198)
  • SGN-ALPV antibody drug conjugate in advanced solid tumors (NCT05229900)
  • Claudin6-CAR-NK cell therapy for advanced solid tumors (NCT05410717)
  • Testis CAB: Cabazitaxel for cisplatin-resistant germ cell cancers (NCT02478502)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References:

  1. Rajpert-De Meyts E, et al. "Testicular germ cell tumours." Lancet 2016; 387:1762-74.
  2. De Giorgi U, et al. "Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features." Urol Oncol 2011; 29:284-90.
  3. Einhorn LH, et al. "High-Dose Chemotherapy and Stem-Cell Rescue for Metastatic Germ-Cell Tumors." N Engl J Med 2007; 357:340-8.
  4. Yu EY. "Are there clinical trials for relapsed or refractory germ cell tumors?" Urotoday Clinical Trials Portal. September 8, 2017.
  5. Yu EY. "Will Immunotherapy Work as Salvage Therapy for Patients with Testicular Germ Cell Tumors?" Urotoday Clinical Trials Portal. March 1, 2021.
  6. Kollmannsberger C, et al. "Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group." J Clin Oncol 2004; 22:108-14.
  7. Shah S, et al. "Clinical Response of a Patient to Anti-PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors." Cancer Immunol Res 2016; 4:903-9.
  8. Chi EA and Schweizer MT. "Durable response to immune checkpoint blockade in a platinum-refractory patient with nonseminomatous germ cell tumor." Clin Genitourin Cancer 2017; 15:e855-e7.
  9. Zschabitz S, et al. "Response to anti-programmed cell death protein-1 antibodies in men treated for platinum refractory germ cell cancer relapsed after high-dose chemotherapy and stem cell transplantation." Eur J Cancer 2017; 76:1-7.
  10. Adra N, et al. "Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206." Ann Oncol 2018; 29:209-14.
  11. Mego M, et al. "Phase II study of avelumab in multiple relapsed/refractory germ cell cancer." Invest New Drugs 2019; 37:748-54.
  12. Necchi A, et al. "An Open-label Randomized Phase 2 study of Durvalumab Alone or in Combination with Tremelimumab in Patients with Advanced Germ Cell Tumors (APACHE): Results from the First Planned Interim Analysis." Eur Urol 2019; 75:201-3.
  13. Yu X, et al. "The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells." Nature Immunol 2009; 10:48-57.
  14. Stanietsky N, et al. "The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity." Proc Natl Acad Sci U S A 2009; 106:17858-63.
  15. Necchi A, et al. "Brentuximab Vedotin in CD30-Expressing Germ Cell Tumors After Chemotherapy Failure." Clin Genitourin Cancer 2016; 14:261-4.e4.
  16. Albany C, et al. "Treatment of CD30‐Expressing Germ Cell Tumors and Sex Cord Stromal Tumors with Brentuximab Vedotin: Identification and Report of Seven Cases."Oncologist 2018; 23:316-23.
  17. Ashkar R, et al. "Phase II trial of brentuximab vedotin in relapsed/refractory germ cell tumors." Invest New Drugs 2021; 39:1656-63.