ASCO 2017: Taking Us Out of the Refractory State: Combination Chemotherapy to Immunotherapy for Refractory Germ Cell Tumors

Chicago, IL (UroToday.com) Dr. Gillessen from Switzerland provided a very thorough and excellent discussion of three testicular cancer abstracts presented at the 2017 ASCO annual meeting. The abstracts she discussed were Abstract 4519 (Infusional gemcitabine + docetaxel/melphalan/carboplatin (GemDMC) +/- bevacizumab as an effective high-dose chemotherapy (HDC) regimen for refractory of poor risk relapsed germ-cell tumors [1]), 4520 (Phase II trial of pembrolizumab in patients with incurable platinum refractory germ cell tumors [2]), and 4521 (FDG PET scan positive residual lesions after chemotherapy for metastatic seminoma: Results of an International Global Germ Cell Cancer Group (G3) registry [3]).

Nieto et al. [1] had 70 patients that received HDC included bevacizumab (5 mg/kg) preceding GemDMC (HDC #1) and ifosfamide/CE (ICE) (HDC #2). Following accrual of 42 patients, the trial was amended to omit bevacizumab. Inclusion criteria was intermediate or high risk disease, with creatinine <1.8 mg/dL and adequate organ function. Tumor markers normalized in 90% of patients with active tumors at HDC. After HDC, 19 pts were in complete remission and 28 patients in partial remission over a median follow-up of 39 months (range: 2-105). Dr. Gillessen notes that the strength of this study is the importance of using patients with unsatisfactory initial treatment and that prior to this study the significance of VEGF/VEGFR inhibition in germ cell tumors was unclear. Weaknesses of the study include the non-randomized design, two consecutive cohorts, and no established role for melphalan in germ-cell tumor treatment. The authors concluded that tandem HDC with GemDMC is highly active with superior than expected outcomes, however Dr. Gillessen cautions that in small cohorts these conclusions are preliminary and that the results of phase II studies are usually better than the same therapies in phase III trials. The authors also concluded that the addition of bevacizumab to HDC increased toxicity without improving activity. Taken together these data do not encourage the use of VEGF/VEGFR targeting agents in this patient population and that we require new concepts for treatment.

In the Adra et al [2] study, patients that had germ cell tumor relapse after initial cisplatin-based chemotherapy and second-line chemotherapy were given pembrolizumab 200 mg IV for 3 weeks until disease progression or toxicity. Among 12 patients enrolled, no patient had a complete response, two patients had stable disease but rising AFP, and 10 patients had disease progression – thus, the trial was discontinued. Dr. Gillessen notes that the strength of this study is that this disease setting is an unmet clinical need and that this is the first prospective trial data for immunotherapy for patients with refractory germ cell tumors. The weaknesses of this study is the small sample size and unselected patient population. In Dr. Gillessen’s opinion, potential selection could include patients with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), since pembrolizumab is active in MSI-H or dMMR cancers. The authors concluded that pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractor germ cell tumors, however Dr. Gillessen hopes that this is not necessarily the end of immunotherapy in this setting and that with appropriate identification of patients, further trials may be possible.

The Cathomas et al. [3] study enrolled 90 patients with seminoma and FDG PET scan positive residual lesions after chemotherapy. Among these patients, 4 had primary radiotherapy, 26 had primary resection, 9 had primary biopsy and 51 had repeated imaging. For the patients undergoing repeat imaging, 11 patients had progressed and 33 of 39 still had PET positivity of which 6 underwent resection. For all 90 patients, the PPV for viable tumor was 23%; 7 of 32 patients (22%) had seminoma found at resection. Dr. Gillessen notes that the strength of this study is that the management of PET-positive residual disease in men after chemotherapy for seminoma is an important clinical question and that this is the largest data collection of PET-positive seminoma patients. Weaknesses of the study include the retrospective nature of the analysis, no central review of PET scans, and no definition for PET positivity is provided. In contrast to early data that reported high PPV, this study confirms the rather low PPV of FDG PET scans. The authors concluded that in cases of a positive PET, they suggest repeated PET 8-12 weeks later. According to Dr. Gillessen, it is reasonable to undergo strict follow-up or resection and that we should consider these on an individual patient basis, but that resection has to be performed by an experienced surgeon and team. Finally, Dr. Gillessen notes that we need prospective data in metastatic seminoma, especially for dose de-escalation and highlights that two such trials exploring PET for de-escalation of treatment in metastatic seminoma are ongoing.

Presented By: Silke Gillessen, Kantonsspital, St. Gallen, Switzerland

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @zklaassen_md

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

References:
1. Nieto Y, Tu SM, Campbell MT, et al. Infusional gemcitabine + docetaxel/melphalan/carboplatin (GemDMC) +/- bevacizumab (BEV) as an effective high-dose chemotherapy (HDC) regimen for refractory of poor risk relapsed germ-cell tumors (GCT). J Clin Oncol 2017;35(suppl; abstr 4519).
2. Adra N, Althouse SK, Reddy N, et al. Phase II trial of pembrolizumab in patients (pts) with incurable platinum refractory germ cell tumors (GCT). J Clin Oncol 2017;35(suppl; abstr 4520).
3. Cathomas R, Klingbiel D, Bernard BD, et al. FDG PET scan (PET) positive residual lesions after chemotherapy (chemo) for metastatic seminoma: Results of an International Global Germ Cell Cancer Group (G3) registry. J Clin Oncol 2017;35(suppl; abstr 4521).
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