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With doublet therapy the established frontline standard of care for advanced clear cell renal carcinoma (ccRCC), researchers are investigating the possibilities of triplet regimens and other novel treatment approaches, noted authors of a review in the

"As we continue to make strides in our management of advanced ccRCC, the question of whether less is more remains uncertain," said Naomi Haas, MD, of the Abramson Cancer Center, Perelman School of Medicine, at the University of Pennsylvania in Philadelphia, and co-authors. "We have several examples across oncology where additional therapies and associated toxicities were accepted due to improved outcomes for patients."

Preliminary evidence on triplet therapy in advanced ccRCC suggests it improves progression-free survival compared with doublet regimens -- but at the expense of significant toxicity. Longer-term overall survival outcomes are still maturing. "Patient selection will be crucial in finding those in whom the risk-benefit ratio favors aggressive therapy," the authors concluded.

In the following interview, Haas, director of the Prostate and Kidney Cancer Program, discussed the evidence and issues relevant to triplet therapy in more detail.

The COSMIC-313 study is the first phase III trial of triplet therapy for ccRCC. Can you highlight some of the key results so far?

Haas: Combination ipi/nivo/cabo [ipilimumab/nivolumab/cabozantinib] improved progression-free survival over ipi/nivo alone, but demonstrated less complete responses than ipi/nivo alone and also higher incidence of side effects.

What are the most important factors to consider when choosing between double or triplet therapy for patients with advanced ccRCC?

Haas: For now, we recommend participation in triplet clinical trials if a patient is in good health and meets eligibility criteria. I would not recommend triplet therapy with cabo/ipi/nivo unless an overall survival benefit is seen.

One therapy with a completely novel mechanism of action being evaluated as part of frontline triplet therapy is CBM588, a bifidogenic live bacterial product. How does this new therapy work?

Haas: CBM588 is a probiotic that showed improvement in progression-free survival in two small trials so far, in combination with ipi/nivo and in combination with cabozantinib and nivolumab (both at City of Hope).

CBM588 is thought to improve the immune microenvironment for patients receiving IO [immune oncology] therapy by providing favorable bacteria noted to be in the fecal material from patients responding to IO therapy. The mechanism is being explored, although a recent identified some pathways that might play a role.

What is depth of response (DepOR), and how is it useful as a biomarker in this setting?

Haas: Depth of response (defined by RECIST [Response Evaluation in Solid Tumors] shrinkage) that is in some cases 75% or 90% at a predetermined time point (such as 6 months into therapy) has had similar promising improved progression-free survival as is seen in patients who achieved a complete response. So if a patient achieves a deep response quickly, it might indicate that he/she might be likely to have a superior outcome (such as improved overall survival) compared to patients who only have stable disease (or progressive disease).

Is there anything else you would like to make sure oncologists understand about triplet therapy for advanced ccRCC?

Haas: Read our chapter in the ASCO Educational Book!

Read the chapter here.