Renal cell carcinoma (RCC) - combination treatment with cabozantinib

The recommended dose is nivolumab administered intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks in combination with 40 mg cabozantinib administered orally every day.

Duration of treatment

Treatment with nivolumab, either as a monotherapy or in combination with other therapeutic agents, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient (and up to maximum duration of therapy if specified for an indication).

Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment with nivolumab or nivolumab in combination with ipilimumab for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

Dose escalation or reduction is not recommended for nivolumab as monotherapy or in combination with other therapeutic agents. Dosing delay or discontinuation may be required based on individual safety and tolerability. When nivolumab is administered in combination with other therapeutic agents, refer to the SmPC of these other combination therapeutic agents regarding dosing.

Nivolumab as monotherapy or in combination with other therapeutic agents should be permanently discontinued for:

• Grade 4 or recurrent Grade 3 adverse reactions;
• Persistent Grade 2 or 3 adverse reactions despite management.

If any agents are withheld, the other agents may be continued. If dosing is resumed after a delay, either the combination treatment, nivolumab monotherapy or chemotherapy alone could be resumed based on the evaluation of the individual patient.

Nivolumab in combination with cabozantinib in RCC

For liver enzyme elevations, in patients with RCC being treated with nivolumab in combination with cabozantinib:

• If ALT or AST >3 times ULN but ≤10 times ULN without concurrent total bilirubin ≥2 times ULN, both nivolumab and cabozantinib should be withheld until these adverse reactions recover to Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or rechallenge with both medicines after recovery may be considered. If rechallenging with cabozantinib, refer to cabozantinib SmPC.
• If ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, both nivolumab and cabozantinib should be permanently discontinued and corticosteroid therapy may be considered.

Recommended doses for nivolumab solution for injection in combination with cabozantinib for the treatment of RCC:

^* For nivolumab in combination with cabozantinib, nivolumab should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Cabozantinib should be continued until disease progression or unacceptable toxicity. Refer to the Summary of Product Characteristics (SmPC) for cabozantinib.

Duration of treatment

Treatment with nivolumab, either as a monotherapy or in combination with other therapeutic agents, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient (and up to maximum duration of therapy if specified for an indication).

Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment with nivolumab or nivolumab in combination with ipilimumab for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

Dose escalation or reduction is not recommended for nivolumab as monotherapy or in combination with other therapeutic agents. Dosing delay or discontinuation may be required based on individual safety and tolerability. When nivolumab is administered in combination with other therapeutic agents, refer to the SmPC of these other combination therapeutic agents regarding dosing.

Nivolumab as monotherapy or in combination with other therapeutic agents should be permanently discontinued for:

• Grade 4 or recurrent Grade 3 adverse reactions;
• Persistent Grade 2 or 3 adverse reactions despite management.

If any agents are withheld, the other agents may be continued. If dosing is resumed after a delay, either the combination treatment, nivolumab monotherapy or chemotherapy alone could be resumed based on the evaluation of the individual patient.

Nivolumab in combination with cabozantinib in RCC

For liver enzyme elevations, in patients with RCC being treated with nivolumab in combination with cabozantinib:

• If ALT or AST >3 times ULN but ≤10 times ULN without concurrent total bilirubin ≥2 times ULN, both nivolumab and cabozantinib should be withheld until these adverse reactions recover to Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or rechallenge with both medicines after recovery may be considered. If rechallenging with cabozantinib, refer to cabozantinib SmPC.
• If ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, both nivolumab and cabozantinib should be permanently discontinued and corticosteroid therapy may be considered.

Administer the full contents of the syringe of nivolumab solution for injection into the subcutaneous tissue of the abdomen or thigh over a period of 3 to 5 minutes. The dose should not be split between two syringes or between two sites of administration. Alternate injection sites for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of nivolumab solution for injection is interrupted, it can be resumed at the same site, or at an alternate site.

During the treatment course with nivolumab solution for injection, other medicinal products for subcutaneous administration should preferably be injected at different sites.