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EAU 2021 | Key immunotherapy combinations for urothelial cancer

Matthew Galsky, MD, FASCO, Icahn School of Medicine at Mount Sinai, New York, NY, talks on the use of immunotherapy combinations for the treatment of urothelial cancer. Prof. Galsky comments on the findings of the Phase III DANUBE study (NCT02516241) of durvalumab with or without tremelimumab. This study did not show a survival benefit of durvalumab therapy in comparison to standard of care (SOC) chemotherapy in primary analysis, but demonstrated a survival benefit in patients with high PD-L1 expressing tumors in secondary analysis. Prof. Galsky also talks on the Phase III CheckMate 901 study (NCT03036098) of nivolumab in combination with ipilimumab or SOC chemotherapy versus SOC chemotherapy alone in patients with untreated inoperable or metastatic urothelial cancer. Prof. Galsky comments on the role of antibody-drug conjugates in combination with immune checkpoint inhibitors, highlighting data on pembrolizumab and enfortumab vedotin in the frontline treatment of patients with urothelial carcinoma, and discusses the role of HER2-targeted agents and multi-targeted kinase inhibitors such as sitravatinib, lenvatinib and cabozantinib. This interview took place at the virtual European Association of Urology (EAU) Virtual Meeting 2021.

Transcript (edited for clarity)

There are a number of combination strategies with immune checkpoint blockade in urothelial cancer that are showing promise. Probably the furthest along is the combinations involving PD-1 or PD-L1 blockade, plus CTLA-4 blockade. We know from the DANUBE study that the combination of durvalumab plus tremelimumab did not show a survival benefit compared to standard of care platinum-based chemotherapy for the first-line treatment of patients with metastatic urothelial cancer, as determined in the primary study analysis...

There are a number of combination strategies with immune checkpoint blockade in urothelial cancer that are showing promise. Probably the furthest along is the combinations involving PD-1 or PD-L1 blockade, plus CTLA-4 blockade. We know from the DANUBE study that the combination of durvalumab plus tremelimumab did not show a survival benefit compared to standard of care platinum-based chemotherapy for the first-line treatment of patients with metastatic urothelial cancer, as determined in the primary study analysis. However, in the secondary analysis, limiting the comparison to patients with high PD-L1 expressing tumors, there actually was a benefit suggested. So, that combination certainly is of interest and the combination of CTLA-4 blockade plus PD-1 blockade that is ipilimumab plus nivolumab is being studied in the CheckMate 901 study which we should have results for hopefully in the not too distant future to define whether or not there’s a role for such combinations.

Other combination showing lots of promise in smaller studies include combinations with antibody-drug conjugates, plus immune checkpoint blockade. We know that the combination of pembrolizumab plus enfortumab vedotin results in a very high level of clinical activity in the frontline treatment of patients with metastatic urothelial cancer in a smallish cohort of cisplatin ineligible patients and that regimen has been moved forward to a number of Phase III studies.

More recently we’ve seen combinations with anti-HER2 antibody-drug conjugates with immune checkpoint blockade, also showing lots of promise raising the concept of whether or not there’s something special about antibody-drug conjugates in terms of their immunomodulatory activity. And then finally, combinations with multi-targeted kinase inhibitors. We’re seeing activity with combinations with sitravatinib, lenvatinib, cabozantinib with PD-1 or PD-L1 blockade. The mechanism of action of the multi-targeted kinase inhibitors and how they’re conferring immunomodulatory activity isn’t entirely clear, but potentially acting by inhibiting or repolarizing suppressive myeloid cells. So, promise for those combinations and those are being advanced to larger studies as well.

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Disclosures

Matthew Galsky, MD, FASCO, has a stock or other ownership interest in Rappta Therapeutics; has participated in a consulting or advisory role for BioMotiv, Janssen, Dendreon, Merck, GSK, Lilly, Astellas Pharma, Genentech, Bristol-Myers Squibb, Novartis, Pfizer, EMD Serono, AstraZeneca, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inovio Pharmaceuticals, NuMab, Dragonfly Therapeutics, Basilea, Urogen, Infinity Pharmaceuticals and Gilead; and has received research funding from Janssen Oncology, Dendreon, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca and Genentech/Roche.

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