Are there clinical trials for relapsed or refractory germ cell tumors?

It is fortunate that we cure the vast majority of men with testicular germ cell tumors.  Estimates show that only approximately 10% of men with metastatic Stage III germ cell tumors are not cured.1  The bad news if that for those who aren’t cured with standard dose combination cisplatin-based chemotherapy with or without eventual high dose chemotherapy with autologous stem cell rescue (stem cell transplant), there are few options.  Palliative chemotherapy is often limited in efficacy, and regimens such as gemcitabine with oxaliplatin have been used.2  

If a patient has refractory or relapsed germ cell tumor after initial cisplatin-based combination chemotherapy, our field debates whether a patient should receive a different salvage combination cisplatin chemotherapy regimen or whether we should move towards high dose chemotherapy with autologous stem cell rescue.  Early data showed that there are long term survivors, essentially cures, with stem cell transplant in the 3rd line.3  However, more recent retrospective data from University of Indiana showed rather impressive outcomes with transplant in the 2nd line.4  There was a definitive study evaluating the role of transplant as first line therapy for patients with intermediate- or poor-risk features, resulting in no benefit over standard bleomycin, etoposide and cisplatin (BEP) chemotherapy.5  However, it is unknown whether transplant offers benefit over salvage chemotherapy in the 2nd line.  The Alliance Cooperative Group in the United States is performing a large randomized trial in this setting testing standard dose salvage chemotherapy vs. high dose chemotherapy with stem cell transplant (Trial 1).  Hopefully, this should answer the question as to what we should do to help patients with refractory or relapsed disease.

We must also recognize that even after salvage chemotherapy or stem cell transplant that some patients will not be cured.  For patients in this setting, we have limited options.  Given the small number of patients with this poor outcome, there are very few trials in this setting.  I have highlighted a few below that specifically target some promising mechanisms of action.  Specifically, embryonal carcinoma expresses CD30, the target for Brentuximab vedotin, already regulatory approved for relapsed CD30-positive Hodgkin’s or anaplastic large cell lymphomas.6  Both Trial 2 and Trial 3 below are investigating Brentuximab vedotin, and the latter combines it with Bevacizumab, an active antiangiogenic agent.  As there have been isolated case reports of the activity of checkpoint inhibitors for patients with resistant germ cell tumors,7,8 it is logical to explore the efficacy of these agents in a prospective clinical trial (Trial 4).   Combination mTOR and EGFR inhibition is being tested in a combination trial of Sirolimus and Erlotinib (Trial 5).  Inhibition of cyclin dependent kinases have also had efficacy in breast cancer,9 and a novel agent, PD0332991, is being tested in patients with multiple different advanced tumor histologies, including germ cell tumors (Trial 6).

Even though outcomes are outstanding for most men with germ cell tumors, our field must continue to explore biology and mechanisms of resistance for refractory disease.  This includes advocacy and academic partnerships with industry to design more clinical trials of novel agents.  Although limited in numbers, we should encourage patient enrollment to clinical trials in these situations where we anticipate sub-optimal outcomes.  This should serve as a reminder to our field that outcomes for this disease were not always outstanding until combination cisplatin-based chemotherapy regimens were developed.  Only through clinical trials will we discover the next wave of therapeutics for those patients with a limited prognosis due to relapsed/refractory germ cell tumors.

Written by: Evan Yu, MD

Highlighted Trials

  1. Standard dose salvage chemotherapy vs. high dose chemotherapy with stem cell transplant 
  2. Brentuximab vedotin 
  3. Brentuximab vedotin combined with Bevacizumab  
  4. Durvalumab combined with Tremelimumab 
  5. Sirolimus combined with Erlotinib   
  6. Phase II Trial of the Cyclin-Dependent Kinase Inhibitor PD 0332991 in Patients With Cancer
References:
  1. International Germ Cell Cancer Collaborative Group.  J Clin Oncol 1997; 15:594-603.
  2. Kollmannsberger C et al.  J Clin Oncol 2004; 22:108-14.
  3. Nichols CR et al.  J Clin Oncol 1989; 7:932-9.
  4. Einhorn LH et al.  N Engl J Med 2007; 357:340-8.
  5. Motzer RJ et al.  J Clin Oncol 2007; 25:247-56.
  6. Younes A et al.  N Engl J Med 2010; 363:1812-21.
  7. Zschabitz S et al.  Eur J Cancer 2017; 76:1-7.
  8. Chi EA et al.  Clin Genitourin Cancer 2017; Epub April 12.
  9. Turner NC et al.  N Engl J Med 2015; 373:209-19.
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