Abstract
In a phase III trial, the combination of nivolumab and ipilimumab yielded more and longer responses than sunitinib in patients with renal cell carcinoma at intermediate or high risk of progression. More than 41% of patients who received the immunotherapy combination responded, compared with 26.5% of patients who received sunitinib. Patients receiving the combination also experienced longer progression-free survival and fewer side effects.
Sunitinib (Sutent; Pfizer) has been a standard first-line treatment for patients with renal cell carcinoma (RCC) for more than a decade. For high- or intermediate-risk patients with advanced or metastatic RCC, however, the combination of nivolumab (Opdivo; Bristol-Myers Squibb) and ipilimumab (Yervoy; Bristol-Myers Squibb) outperforms sunitinib, according to results presented at the ESMO 2017 Congress, the annual meeting of the European Society for Medical Oncology, in Madrid, Spain.
Sunitinib, which inhibits multiple receptor tyrosine kinases such as VEGFR1, 2, and 3, can produce durable remissions in patients with advanced or metastatic RCC. However, the drug can cause side effects such as high blood pressure and diarrhea. Moreover, the cancer usually progresses, with patients at high risk for disease progression typically surviving less than a year. The combination of nivolumab and ipilimumab, which inhibit PD-1 and CTLA4, respectively, has shown promise against other cancers, such as melanoma. The phase III CheckMate 214 trial compared the checkpoint inhibitor combination to sunitinib in 996 patients with advanced or metastatic RCC.
Using standard criteria, Bernard Escudier, MD, of the Institut Gustave Roussy in Villejuif, France, and colleagues classified the patients as either low risk or intermediate to high risk. The scientists then randomly assigned the patients to receive either the checkpoint inhibitor combination or sunitinib.
After 17.5 months of follow-up, the researchers found that sunitinib was the superior drug for patients at low risk of disease progression. The objective response rate (ORR) was 52% among patients who received sunitinib, and 29% among those who received nivolumab and ipilimumab. Progression-free survival (PFS) was also longer in the sunitinib group, 25.1 months versus 15.3 months.
The results were reversed in the intermediate- and high-risk patients. The ORR in the nivolumab/ipilimumab group was 41.6%, compared with 26.5% in patients who received sunitinib. Similarly, PFS was 11.6 months in the patients treated with checkpoint inhibitors, versus 8.4 months in the sunitinib group.
Serious side effects were less common in the checkpoint inhibitor group. The rate of grade 3 or 4 adverse effects, such as nausea and liver toxicity, was 54% in the nivolumab/ipilimumab group and 63% in the sunitinib group.
Why these checkpoint inhibitors generate more and longer-lasting responses in intermediate- and high-risk patients isn't clear, says Escudier. But the results of the study indicate that “we have a signal that is good enough to make [the combination] a standard of care,” he says. Co-author Brian Rini, MD, of the Cleveland Clinic Taussig Cancer Institute in Ohio, adds that “A distinct advantage to this immune combo is the high rate of complete responses, many of which will be durable. This may provide unique benefits compared to other options.”
However, the large number of patients who required steroids to treat adverse effects of the checkpoint inhibitors is a concern, says Eric Jonasch, MD, of The University of Texas MD Anderson Cancer Center in Houston. Nonetheless, he says, this combination “deserves a place in our treatment algorithm.”
Four other phase III trials are testing checkpoint inhibitor/sunitinib combinations for metastatic RCC, says James Hsieh, MD, PhD, of Washington University in St. Louis, MO. The question for doctors and researchers may soon be, “How do you combine and sequence the drugs?” he says. –Mitch Leslie