The U.S. Food and Drug Administration (FDA) has agreed to review applications requesting the approval of Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) for people with advanced renal cell cancer, the most common type of kidney cancer in adults.
The applications — requests to extend the indications for Opdivo by Bristol Myers Squibb and Cabometyx by Exelixis — were given priority review status, which accelerates FDA review time from 10 to six months. A decision is expected by Feb. 20, 2021.
The filings were based on results from the CheckMate -9ER trial (NCT03141177), which showed that the combination significantly extends survival, delays disease progression, and increases the rate of positive responses, compared to standard treatment with Sutent (sunitinib), among people newly diagnosed with advanced renal cell cancer.
“Based on strong supporting data from CheckMate -9ER, the acceptance of our application is important progress in our efforts to make Cabometyx in combination with Opdivo available to patients with advanced kidney cancer who need additional treatment options,” Gisela Schwab, MD, Exelixis’ president of product development and medical affairs, and chief medical officer, said in a press release.
“We look forward to working with the FDA throughout the ongoing review process,” she added.
Cabometyx is an approved therapy for people with advanced kidney cancer that works by blocking the activity of tyrosine kinases, enzymes that fuel key cancer processes, including the formation of new blood vessels as well as tumor cell migration and invasiveness.
Evidence supports that Cabometyx also induces changes in tumors that make them more permissive to the entry of immune cells. This had led researchers to believe that combining Cabometyx with immune checkpoint inhibitors, such as Opdivo, would lead to better outcomes.
Immune checkpoint inhibitors block the activity of proteins used by cancer cells to avoid being targeted and destroyed by immune cells. In the case of Opdivo, it prevents a protein receptor, called PD-1, found on the surface of immune cells from interacting with the PD-L1 protein on cancer cells. This allows immune cells to recognize and eliminate cancer cells more effectively.
Opdivo is approved for people with advanced renal cell cancer who received prior therapies.
“With their complementary mechanisms of action and evidence that Cabometyx may promote a more immune-permissive environment, we believe there is opportunity for additive or synergistic effects with this potential combination regimen,” said Schwab.
In CheckMate -9ER, a total of 638 patients newly diagnosed with advanced or metastatic renal cell cancer were randomly assigned to oral Cabometyx plus Opdivo — given via intravenous (into-the-vein) infusions — or standard Sutent treatment.
The trial’s main goal was to determine whether the combination outperformed Sutent at extending the time patients lived without signs of disease worsening. Secondary measures included overall survival, the proportion of patients responding to treatment, and safety.
Results shared at the European Society for Medical Oncology Virtual Congress 2020 showed that the combination doubled the time patients lived without disease progression, from 8.3 months with Sutent to 16.6 months. This represented a 49% reduction in the risk of death or disease worsening.
The Opdivo-Cabometyx combination also lowered the risk of death by 40%, and doubled the proportion of patients responding to treatment (56% vs. 27%). Responses also lasted longer with the combo therapy (20.2 months) compared to Sutent (11.5 months).
Notably, the benefits were consistent across pre-specified risk categories (favorable, intermediate, poor risk) and regardless of PD-L1 status — though cancers producing high levels of the PD-L1 factor are usually predicted to have better responses to immune checkpoint inhibitors like Opdivo.
Patients on the combination also reported significantly better health-related quality of life than those given Sutent at most assessments throughout the trial.
“These results, along with a favorable tolerability profile and superior health-related quality of life, highlight this regimen’s potential importance among combinations of immunotherapies and tyrosine kinase inhibitors,” Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and professor at Harvard Medical School, said in a press release announcing the results.
The combination therapy showed a favorable safety profile, in agreement with the known safety profiles of each therapy. While more patients receiving it experienced an adverse event (97%) than those on Sutent (93%), the combo led to fewer treatment discontinuations due to such adverse events (3% vs. 9%).
“In the CheckMate -9ER trial, combining Opdivo and Cabometyx, two proven agents with strong clinical legacies in advanced renal cell carcinoma, led to superior efficacy across all endpoints,” said Mark Rutstein, vice president of Opdivo development at Bristol Myers Squibb.
“We look forward to working with the FDA to bring this potential treatment option to physicians and their patients who choose an immunotherapy plus tyrosine kinase inhibitor regimen,” he added.
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