Nivolumab versus Cabozantinib: Second-Line Therapy for Metastatic Renal-Cell Carcinoma Still Unresolved

Anaheim, CA—As options for second-line therapy for patients with metastatic renal-cell carcinoma continue to expand, so does the controversy surrounding optimal treatment selection. At the 2017 Hematology/Oncology Pharmacy Association (HOPA) Annual Conference, presenters debated the evidence for using targeted therapy and immunotherapy in the second-line setting.

“Nivolumab or cabozantinib could be the correct choice for second-line therapy. Cabozantinib appears to be more effective in patients with bone metastases, but the toxicity is greater. Nivolu­mab could offer patients a break from tyrosine kinase inhibitor [TKI] side effects, but both agents offer benefits in terms of overall survival,” said Jocelyn Mohs, PharmD, BCOP, Oncology/Specialty Clinical Pharmacist, St. Cloud VA Health Care System, MN.

“Ultimately, selection should be based on patient-specific factors. It’s about making a strategic choice for your individual patient,” she added.

Targeted Therapy

According to Anne Spengler, PharmD, BCOP, Clinical Oncology Pharmacist, University of Washington Seattle Cancer Care Alliance, there are several benefits to using a TKI compared with immunotherapy:

1. Faster response. Although specific time-to-response data have not been recorded for cabozantinib, TKIs that target vascular endothelial growth factor (VEGF), such as sunitinib, have shown a median time to response of 10.6 weeks (earliest, 2.7 weeks). Nivolumab, however, has shown a time to response of approximately 15 weeks (earliest, 6 weeks).
   “In patients who need a more rapid response to get their disease under control, another VEGF-targeted therapy should be the treatment of choice over immunotherapy,” said Dr Spengler.
2. Patient convenience. Rather than coming in for an infusion of nivolu­mab every 2 weeks, oral TKI therapy involved just 1 pill taken daily on an empty stomach at home, which may be more conducive to certain patients’ lifestyles, said Dr Spengler.
3. Toxicity management of immune-related adverse events. Because VEGF-targeted treatments have been around longer, said Dr Spengler, providers—especially those in community settings—are better equipped to manage common toxicities, such as diarrhea, hypertension, and hand-foot syndrome.

“Oncologists who are prescribing immunotherapies are becoming more familiar with the management of immune-related toxicities, but since they’re so new to the armamentarium of treatment, overall awareness of those toxicities and management of immune-related adverse events hasn’t trickled out to other members of the healthcare system yet,” said Dr Spengler.

Nevertheless, she added, because head-to-head trials comparing TKIs and immunotherapy in the second-line setting have not been conducted, only generalizations can be made.

“Cabozantinib and nivolumab have both demonstrated overall survival of approximately 20 months. I would argue that treatment with either of these therapies in the second-line setting is a reasonable option and depends on the individual patient,” she said.

Immunotherapy

Although cabozantinib and nivolu­mab have not been compared in head-to-head trials, according to Rebecca Greene, PharmD, BCOP, Oncology Pharmacy Program Manager, Orlando VA Medical Center, FL, it is still useful to examine the similarities and differences.

“There is certainly greater ease of administration with oral cabozantinib versus intravenous infusion every 2 weeks on nivolumab, but there may be issues with adherence to therapy. There also may be differences in cost to patients of these therapies, depending on their insurance and copay situation,” said Dr Greene.

Duration of treatment, speed of response, overall survival, tolerability of the therapy, and patient quality of life are additional factors that may guide treatment decisions.

“The speed of response to cabozantinib was not actually reported, so we have no data to confirm that time to response would be similar to other TKIs,” said Dr Greene.

Both cabozantinib and nivolumab had improved objective response rates in comparison with everolimus, but the degree of difference between nivolumab and everolimus (25% vs 5%, respectively) in the CheckMate-025 trial was greater than the difference between cabozantinib and everolimus (17% vs 3%, respectively) in the METEOR trial, Dr Greene reported. However, the real difference between agents emerges with respect to tolerability of therapy.

“It’s important to keep in mind that only 20% of patients receiving nivolu­mab had grade 3 or 4 toxicity compared with 70% of patients who received cabozantinib. There were more dose reductions with cabozantinib than even everolimus in the METEOR trial,” said Dr Greene.

“While providers and patients may not be as familiar with immune-mediated toxicities that can occur with nivolumab, it’s a low rate of toxicities. The more we see these drugs being used in many different tumors, the better equipped we’ll be to treat them,” she added.

Finally, said Dr Greene, quality of life was improved with nivolumab versus everolimus, but the effect of cabozantinib on quality of life for this patient population remains unknown.

Future Considerations

Ongoing clinical trials may complicate the issue further, said Dr Mohs.

CABOSUN, a randomized, multicenter phase 2 trial, compared cabozantinib with sunitinib in the first-line setting of metastatic renal-cell carcinoma in patients with poor- and intermediate-risk disease. Although cabozantinib surpassed standard first-line sunitinib in terms of progression-free survival (8.2 vs 5.6 months, respectively), the therapy was not well-tolerated, said Dr Mohs. Grade 3 or higher adverse events occurred in >70% of patients in both treatment arms, and 16 patients in each arm actually stopped treatment because of toxicity.

“Nevertheless, if cabozantinib emerges as a first-line option for this particular patient population, that would potentially shift sunitinib into the second-line role,” said Dr Mohs.

However, CheckMate-214, a phase 2 trial combining immunotherapies, could also shift lines of therapy. The trial, comparing nivolumab plus ipilimumab versus sunitinib in the first-line setting, could potentially take nivolu­mab out of its second-line role, Dr Mohs concluded.