Maintenance Avelumab Plus Lurbinectedin Under Investigation in Metastatic Urothelial Carcinoma

Investigators are assessing the combination of avelumab (Bavencio) and lurbinectedin (Zepzelca) as maintenance therapy for patients with metastatic urothelial carcinoma who achieve a response or stable disease following first-line, platinum-based chemotherapy in a single-arm phase 2 trial (NCT05574504), according to a poster presentation at the 2023 Genitourinary Cancers Symposium.¹

The primary end point of the trial is progression-free survival (PFS). Secondary end points include objective response rate (ORR) per RECIST v1.1 criteria, duration of response (DOR), overall survival (OS), safety, and tolerability. Exploratory end points include association of tumor PD-L1 expression with PFS, association of tumor genomics and transcriptomics with PFS, and association of circulating tumor DNA and immune response with PFS.

“The current standard of care in patients with metastatic urothelial carcinoma in the first-line setting is platinum-based chemotherapy followed by avelumab maintenance in patients who have responding disease or stable disease,” lead study author, Guru P. Sonpavde, MD, said in an interview with OncLive®. “We wanted to combine lurbinectedin with avelumab in this maintenance first-line space.”

Sonpavde is the medical director of Genitourinary (GU) Oncology, assistant director of the Clinical Research Unit and Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute in Orlando, Florida.

In June 2020, the FDA approved lurbinectedin for the treatment of adult patients with small cell lung cancer (SCLC) with disease progression on or following platinum-based chemotherapy.² The inhibitor induces immunogenic cell death and could have potentially synergy with PD-1/PD-L1 inhibition.

Previously reported data from the phase 1/2 LUPER trial (NCT04358237) showed that the combination of lurbinectedin plus pembrolizumab (Keytruda) elicited an overall response rate (ORR) of 30.8% among the 13 patients with SCLC who relapsed on platinum-based chemotherapy.³

“There are data out there that show lurbinectedin can be combined with an immune checkpoint inhibitor,” Sonpavde noted.

In the phase 2 trial for patients with urothelial carcinoma, investigators are testing the hypothesis that avelumab and lurbinectedin could be used as switch maintenance therapy for those who have a response or stable disease following first-line, platinum-based chemotherapy.¹

The trial is enrolling patients with histologically confirmed, unresectable locally advanced or metastatic predominant urothelial carcinoma diagnosis with an ECOG performance status of 0 to 2. First-line chemotherapy needs to consist of 4 to 6 cycles of platinum-based chemotherapy, and patients must not have progressive disease per RECIST v1.1 criteria. Patients must have completed first-line chemotherapy within 4 to 10 weeks of enrollment on trial. Adequate organ function and provision of archival formalin-fixed, paraffin-embedded tumor tissue are also required.

“The inclusion criteria mirrored that of the [phase 3] JAVELIN Bladder 100 trial [NCT02603432], where patients received avelumab if they had stable disease or responding disease after 4 to 6 cycles of platinum-based chemotherapy,” Sonpavde explained

All enrolled patients will receive 800 mg of intravenous (IV) avelumab every 2 weeks with premedication including an H1 blocker, an H2 blocker, and Tylenol, plus 3.2 mg/m2 of IV lurbinectedin every 4 weeks. Premedication for lurbinectedin includes corticosteroids with 8 mg of IV dexamethasone or equivalent treatment, plus serotonin antagonists with 8 mg of IV ondansetron or equivalent.

Granulocyte-colony stimulating factor will be mandated for cycle 1 and all subsequent cycles. Therapy will continue until progression of disease, unacceptable toxicity, or patient withdrawal. Radiographic imaging will be performed every 8 weeks for 6 months and then every 12 weeks thereafter.

The nonrandomized, single-stage trial has a 6-month median PFS of interest. Up to 36 patients will be enrolled in the trial to account for unevaluable patients.

“With PFS as the primary end point, we are aiming to improve on the historical PFS of avelumab alone, which is around 3.7 months and is a short PFS in the switch maintenance space. The bar is not high for PFS, and therefore we try to improve upon that with this combination,” Sonpavde concluded.

References

1. Sonpavde GP, Alemany CA, Mchayleh W, et al. Phase II trial of lurbinectedin combined with avelumab as maintenance therapy for metastatic urothelial carcinoma with stable or responding disease following platinum-based chemotherapy. J Clin Oncol. 2023;41(suppl 6): TPS590. 10.1200/JCO.2023.41.6_suppl.TPS590
2. PharmaMar announces the US FDA approval of lurbinectedin (Zepzelca) for the treatment of metastatic small cell lung cancer. News release. PharmaMar. June 15, 2020. Accessed March 17, 2023. https://www.prnewswire.com/de/pressemitteilungen/
3. Calles A, Navarro A, Doger B, et al. A phase 1/2 trial of lurbinectedin (L) in combination with pembrolizumab (P) in relapsed small cell lung cancer (SCLC): The LUPER study. J Clin Oncol. 2022; 40 (suppl 16):8581. doi:10.1200/JCO.2022.40.16_suppl.8581