New Agents in Advanced RCC Offer Novel Combinations, Sequences

With a number of therapies now available for treatment of renal cell carcinoma (RCC), research is now ongoing to determine the best possible sequencing and potential combinations of those therapies. The rise of immunotherapy offers promise but also complicates those questions further. Several experts discussed the combination and sequencing of VEGF inhibitors and immunotherapeutic agents at the 15^th International Kidney Cancer Symposium, held November 4–5 in Miami, Florida.

“Ultimately, the question with all these [therapy] combinations is… is this really immune therapy? Do these combinations achieve immune therapy endpoints? Do they lead to complete responses, and do they lead to durable overall survival? Can they lead to treatment-free survival, meaning benefit that lasts after drug is stopped?” asked David F. McDermott, MD, of Beth Israel Deaconess Medical Center in Boston.

He noted several trials combining VEGF and PD-1/PD-L1 inhibitors, including one recently presented at the European Society for Medical Oncology (ESMO) meeting in Copenhagen. In that study, the combination of axitinib and pembrolizumab yielded a response rate of 67.3% in metastatic RCC, with many deep responses seen. The progression-free survival in the trial was 15 months, and McDermott called it an encouraging early signal.

Another early phase study presented at ESMO this year combined the PD-L1 inhibitor avelumab with axitinib. Though it was a small phase I study, there was an overall response rate of 83.3% with the combination.

“At the moment, it’s too early to say that we’re seeing that with VEGF and PD-1 blockade,” McDermott said. “Most of what we’re seeing is with patients still on drug, and it would be very interesting to see what happens if you stop the treatment.”

Combining different immunotherapeutic agents is also under investigation in RCC. Hans Hammers, MD, PhD, of Johns Hopkins University in Baltimore, discussed some trials combining PD-1 and CTLA-4 inhibitors. For example, the CheckMate 214 trial is ongoing, comparing the combination of nivolumab and ipilimumab with sunitinib in previously untreated metastatic RCC. “The results are highly awaited, and may lead, if positive, to the approval of this combination as early as next year,” Hammers said.

He also noted the CheckMate 016 study, which Hammers presented results from at ESMO this year. In that trial, again combining ipilimumab and nivolumab, patients achieved a 40% response rate and most patients responded within 6 weeks of drug administration. Several other nivolumab/ipilimumab trials are also expected to report results in the near future, he said.

The sequencing of these various therapies from first-line to second-line therapy is also far from a settled question. Guru Sonpavde, MD, of the University of Alabama at Birmingham, discussed the various sequencing possibilities, and whether we can use various markers to select patients for specific therapies and specific sequences.

For example, it has been suggested that levels of PD-L1 expression could select for who might benefit from nivolumab as a second-line therapy. However, Sonpavde said a trial showed this was not the case. Genomic alterations have also been suggested as such a marker, but again, there is no solid data yet on this issue. “We don’t know how to use the alterations in RCC to guide therapy,” he said.

There are some factors that we do know can help guide therapy, though. Cabozantinib has been shown to have activity in bone, so perhaps this drug should be used in patients with bone-predominant metastases. In a trial comparing cabozantinib with everolimus, progression-free survival was markedly prolonged with cabozantinib specifically in patients with bone metastases, and skeletal-related events were reduced as well.

Performance status is another possibility, Sonpavde said. Given the better toxicity profile with nivolumab, he said that those with performance status of 2 should likely receive that drug, while performance status 0–1 could receive cabozantinib, lenvatinib/everolimus, or axitinib.

With a number of trials in this field ongoing, experts expect some of these questions to be answered to some extent in the coming years.