Combinations: The Future of Renal Cell Carcinoma Treatment?

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Several phase 3 clinical trials are likely to identify new frontline standards of care.
Several phase 3 clinical trials are likely to identify new frontline standards of care.

Renal cell carcinoma (RCC) is the most common form of kidney cancer, with an estimated 65,340 patients expected to be diagnosed in 2018 in the United States alone.1 Nearly a third of those patients will be diagnosed with advanced or metastatic disease.2

While understanding of RCC progression and metastasis improved over recent decades, biologic agents targeting the VEGF and mTOR pathways were developed and have moved into widespread clinical practice for disease management.3 Sunitinib has, for example, been a first-line standard of care for a decade. In 2017, the US Food and Drug Administration (FDA) approved a bevacizumab biosimilar — bevacizumab-awwb — for the treatment of metastatic RCC (mRCC) and other advanced solid tumors.4 These agents improve survival, but inevitably lead to acquired drug resistance, prompting efforts to develop combination regimens.3

Today, combination immunotherapy strategies are taking center stage.

In December 2017, the FDA granted Breakthrough Therapy designation to the PD-L1 immune checkpoint inhibitor, avelumab, plus the anti-VEGF tyrosine kinase inhibitor (TKI), axitinib, as a combination therapy for treatment-naive patients with advanced RCC.5 The approval was based on preliminary data from 55 patients enrolled in the phase 1b JAVELIN Renal 100 trial (ClinicalTrials.gov Identifier: NCT02493751).6

In January 2018, the agency granted the same designation to the multi-TKI, lenvatinib mesylate, plus the PD-1 immune checkpoint inhibitor, pembrolizumab, as another combination for mRCC.7

“The field of initial therapy for metastatic RCC is moving rapidly towards combination therapy,” said Brian I. Rini, MD, of the department of solid tumor oncology at the Cleveland Clinic Taussig Cancer Institute in Ohio. Dr Rini is a senior investigator for the JAVELIN Renal 100 trial and other studies of combination regimens in RCC.

There are 2 major types of combination regimens being tested in mRCC, Dr Rini told Cancer Therapy Advisor: the combination of 2 immunotherapy agents and combinations of an anti-VEGF agent and an immunotherapy agent.

“The major immunotherapy combination is ipilimumab plus nivolumab, which recently demonstrated clinical advantages over sunitinib, including an overall survival advantage, and a 9% complete response rate,” he explained. “This regimen is likely to be FDA-approved soon and become an initial standard of care.”

The phase 3 CheckMate-214 trial (ClinicalTrials.gov Identifier: NCT02231749) showed that frontline combination immunotherapy with the PD-1 and CTLA-4 immune checkpoint inhibitors nivolumab and ipilimumab outperformed sunitinib monotherapy for patients at intermediate and high risk of disease progression.8,9

More also needs to be learned about mitigating and managing toxicities, Dr Rini said. The safety profiles of combination immunotherapy regimens appear to be better than those of systemic cytotoxic chemotherapies, but it is crucial that immune-related adverse events (irAEs) be identified quickly because they can become severe and, in some cases, life-threatening.

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