(UroToday.com) The 2025 GU ASCO annual meeting featured a session on emerging trends in germ cell tumors and a presentation by Dr. Darren Feldman discussing the landscape of new trials and targets in refractory germ cell tumors. For the definition of this talk, Dr. Feldman notes that relapsed/refractory germ cell tumor is a germ cell tumor that is probably not curable. This includes most patients with:
- Progressive disease after high-dose chemotherapy
- Absolute refractory germ cell tumor (no response to first line chemotherapy)
- Progressive disease after >= CDCT regimens who are not candidates for or refuse high-dose chemotherapy
- Unresectable late relapse germ cell tumor
The following table highlights post high-dose chemotherapy options (single agents and combinations):
There are several reasons why we need novel therapies for germ cell tumors. Despite dramatic improvements in outcomes, when death occurs, it still accounts on average for the largest number of life years lost of any non-childhood malignancy. Secondly, there are no curative systemic therapies for progressors after high-dose chemotherapy. Third, to potentially lower toxicities of the current treatment:
To date, there have been prior targeted therapy approaches in relapsed/refractory germ cell tumors as highlighted in the following table:
Furthermore, there have been phase II trials of PD-1/L1 inhibition in patients with platinum refractory germ cell tumors, however there has been virtually no benefit in best response:
Similarly, results for combinations of immune checkpoint blockade and platinum based chemotherapy for refractory germ cell tumors demonstrate very little clinical efficacy:
Dr. Feldman then discussed several new targets for patients with relapsed/refractory germ cell tumors. The first is Claudin-6, which is a tight gap junction protein expressed during embryonal development but lost in adult tissue. This protein plays a role in cell polarity, adhesion, and permeability, and is highly expressed in germ cell tumors (>90%). Mechanism of targeting Claudin-6 include monoclonal antibodies (previous negative study), bispecific antibodies, antibody drug conjugates, and CAR-T. Both the TORL-1-23 and DS9606a are Claudin-6 antibody drug conjugates.
Additionally, four CLDN6 bispecific and trispecific antibody studies are ongoing:
Finally, Claudin-6 CAR-T +/- CAR-VAG for relapsed/refractory germ cell tumors has shown early promising results:
The second novel target is methylation, which is highest in teratoma > embryonal carcinoma > seminoma. Embryonal carcinoma cell lines, even cisplatin-refractory lines, are hypersensitive to low doses of hypomethylating agents. Sensitivity to hypomethylating agents correlates with tumor DNMT3B protein/RNA expression, and hypomethylating agents can re-sensitize cisplatin-resistant cells to cisplatin. Clinical activity in relapsed/refractory germ cell tumors has been seen in two trials:
- Guadecitabine + cisplatin led to 3 responses in 14 patients with relapsed/refractory germ cell tumors, including two complete responses, one of which was in a patient with PM-NSGCT
- Guadecitabine + cisplatin + gemcitabine led to response in 2/2 patients with relapsed/refractory germ cell tumors, a complete response in a testicular germ cell patient, and partial response in a PM-NSGCT patient
The ASTX727 study is under development at COG, looking at a phase I/II trial design:
The third novel target discussed by Dr. Feldman was glypican 3 (GPC3), which is a cell surface glycoprotein in which heparin sulfate glycosaminoglycan chains are covalently linked to a protein core. GPC3 also plays a role in regulating cell proliferation and is expressed on nearly all yolk sac tumors (>95%) as well as hepatocellular carcinomas (but not normal liver). Ongoing studies assessing GPC3 include:
The final target is VEGFR and cMET. A trial assessing cabozantinib 60 mg daily until progression of disease or toxicity in men with advanced germ cell tumors with progression of disease after >= 1 salvage regimens is currently enrolling:
A second VEGFR and cMET inhibitor, zanzalintinib, is also assessing relapsed/refractory germ cell tumors in combination with etoposide:
Dr. Feldman concluded his presentation by discussing the landscape of new trials and targets in refractory germ cell tumors with the following take-home points:
- Relapsed and refractory germ cell tumor is an unmet need with a poor prognosis
- Standard options include gemcitabine + oxaliplatin or paclitaxel, oral VP-16
- There is limited activity with immunotherapy
- Claudin 6 is an exciting new target with multiple inhibitory strategies demonstrating activity including CAR-T, antibody drug conjugates, and bispecific antibodies
- Other exciting novel approaches include hypomethylating agents, GPC3 targeting, and dual VEGFR and c-MET inhibitors
Presented by: Darren R. Feldman, MD, Memorial Sloan Kettering Cancer Center, New York, NY
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.