The FDA ( U.S. Food and Drug Administration ) has approved Opdivo ( Nivolumab ) 240 mg injection for intravenous use every two weeks or 480 mg every four weeks in combination with CaboMetyx ( Cabozantinib ) 40 mg once daily tablets, for the first-line treatment of patients with advanced renal cell carcinoma ( RCC ).
The approval is based on the Phase 3 CheckMate -9ER trial, which compared Nivolumab in combination with Cabozantinib ( n=323 ) versus Sunitinib ( n=328 ) in patients with advanced renal cell carcinoma.
In the CheckMate -9ER trial, the primary endpoint was progression-free survival ( PFS ) assessed by Blinded Independent Central Review ( BICR ), and the secondary endpoints included overall survival ( OS ) and BICR-assessed objective response rate ( ORR ).
In the trial, patients treated with Nivolumab in combination with Cabozantinib lived twice as long without their tumors progressing as patients who were treated with Sunitinib ( median PFS was 16.6 months [ 95% Confidence Interval [ CI ]: 12.5-24.9 ] versus median PFS of 8.3 months [ 95% CI: 7.0-9.7 ]; [ Hazard Ratio [ HR ]: 0.51 [ 95% CI: 0.41–0.64 ], P less than 0.0001; median follow-up of 18.1 months ]; range: 10.6-30.6 months ).
Nivolumab in combination with Cabozantinib has also reduced the risk of death by 40% compared to Sunitinib ( HR: 0.60 [ 98.89% CI 0.40–0.89 ]; P=0.0010; median overall survival was not reached for Nivolumab in combination with Cabozantinib and not available for Sunitinib [ range: 22.6-NR months ] ).
Additionally, more patients responded to Nivolumab in combination with Cabozantinib than Sunitinib, with an ORR of 55.7% ( n=180/323 ) ( 95% CI: 50.1 to 61.2 ) versus 27.1% ( n=89/328 ) ( 95% CI: 22.4 to 32.3 ); P less than 0.0001, respectively.
In the combination arm, 8.0% (n=26/323) of patients experienced a complete response and 47.7% ( n=154/323 ) experienced a partial response versus 4.6% ( n=15/328 ) and 22.6% ( n=74/328 ) of those treated with Sunitinib.
Among patients who responded, the median duration of response was 20.2 months for Nivolumab in combination with Cabozantinib ( 95% CI: 17.3 to NA ) and 11.5 months for Sunitinib ( 95% CI: 8.3 to 18.4 ).
Consistent results for progression-free survival were observed across pre-specified subgroups of International Metastatic Renal Cell Carcinoma Database Consortium ( IMDC ) risk categories and PD-L1 tumor expression status.
Adverse reactions greater than grade 3 in the trial were similar with Nivolumab in combination with Cabozantinib versus Sunitinib ( 75% versus 71% ).
All-cause adverse reactions leading to discontinuation of either Nivolumab or Cabozantinib occurred in 19.7% of patients; 6.6% of Nivolumab only, 7.5% of Cabozantinib only and 5.6% of the combination due to same adverse reaction at the same time.
CheckMate -9ER is an open-label, randomized, phase 3 trial evaluating patients with previously untreated advanced renal cell carcinoma.
A total of 651 patients ( 22% favorable risk, 58% intermediate risk, 20% poor risk ) were randomized to Nivolumab in combination with Cabozantinib ( n=323 ) versus Sunitinib ( n=328 ).
Patients were randomized to receive 240 mg of Nivolumab every two weeks intravenously and 40 mg of Cabozantinib orally daily or Sunitinib 50 mg orally daily for the first four weeks of a six-week cycle.
Treatment with Nivolumab continued until disease progression per Response Evaluation version 1.1 ( RECIST v1.1 ) or unacceptable toxicity.
The recommended dosing for Nivolumab and Cabozantinib is 240 mg of Nivolumab every two weeks or 480 mg every four weeks in combination with 40 mg of Cabozantinib once daily administered orally without food.
The recommended treatment for Nivolumab is until disease progression, unacceptable toxicity or up to two years.
Treatment with Cabozantinib is until disease progression or unacceptable toxicity.
Adverse reactions leading to dose interruption or reduction of either Nivolumab or Cabozantinib occurred in 83% of patients: 3% Nivolumab only, 46% Cabozantinib only, 21% both drugs due to same adverse reaction at the same time and 6% both drugs, sequentially.
Serious adverse reactions occurred in 48% of patients receiving Nivolumab in combination with Cabozantinib ( n=320 ).
The most frequent ( greater than or equal to 2% ) serious adverse reactions in those patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection and hyponatremia.
Fatal intestinal perforations occurred in 3 ( 0.9% ) patients.
The most common ( greater than or equal to 20% ) adverse reactions of any grade in patients receiving Nivolumab and Cabozantinib were diarrhea ( 64% ), fatigue ( 51% ), hepatotoxicity ( 44% ), palmar-plantar erythrodysaesthesia syndrome ( 40% ), stomatitis ( 37% ), rash ( 36% ), hypertension ( 36% ), hypothyroidism ( 34% ), musculoskeletal pain ( 33% ), decreased appetite ( 28% ), nausea ( 27% ), dysgeusia ( 24% ), abdominal pain ( 22% ), cough ( 20% ) and upper respiratory tract infection ( 20% ).
Renal cell carcinoma is the most common type of kidney cancer in adults, accounting for approximately 15,000 deaths in the United States each year.
Renal cell carcinoma is approximately twice as common in men as in women.
In the United States, the five-year survival rate, based on data from 2010 to 2016, for those diagnosed with metastatic ( or advanced ) kidney and renal pelvis cancer is 13%. ( Xagena )
Source: BMS, 2021