by Dr. C.H. Weaver M.D. updated 3/2021
Opdivo (nivolumab) is a precision cancer immunotherapy medicine that belongs to a class of medicines called PD-1 inhibitors that have generated great excitement for their ability to help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 may enhance the ability of the immune system to fight cancer. Opdivo works by blocking PD-1. PD-1 inhibitors are approved for the treatment of many kinds of cancer and can often have their effectiveness improved when used in combination with another medication. (8)
About Renal Cell Carcinoma
Each year in the United States, more than 61,000 people are diagnosed with kidney cancer. The most common type of kidney cancer is renal cell carcinoma (RCC), which starts in the lining of very small tubes (tubules) in the kidney. For people with advanced RCC (cancer that has spread to other parts of the body), targeted therapies can play an important role in treatment. Approximately 20-30% of patients with RCC will have metastases at diagnosis and as many as 40% will demonstrate metastasis after primary surgical treatment for localized RCC. With a 5-year survival rate ranging from 5-10%, the prognosis for these patients is poor.
Opdivo can be used alone or in combination to treat advanced RCC. The initial approval in RCC was based on the results of a comparative clinical study known as CheckMate 025. Of 821 patients with advanced RCC who stopped responding to anti-angiogenic therapies, patients were assigned to receive Opdivo or Afinitor (everolimus) a standard therapy in this setting.
The median overall survival was 25 months with Opdivo compared to 19.6 months with Afinitor. In addition, more patients responded to the immunotherapy: the objective response rate was 21.5% for Opdivo versus 3.9% for Afinitor. And they responded longer: the median duration of response was 23 months for patients on Opdivo versus 13.7 months for those on Afinitor. With an extended minimum follow-up of 64 months, patients treated with Opdivo continued to demonstrate survival benefit with 26% of patients alive compared to 18% of patients treated with Afinitor.
Opdivo Combination Therapy
Because the initial effectiveness reported for Opdivo used as a single agent researchers are combining Opdivo with other medicines known to be effective against RCC to evaluate whether outcomes can be further improved with combination therapies. The combination of Opdivo + Cabometyx was approved by the FDA in January 2021. (8)
Opdivo + Cabometyx
The CheckMate -9ER Phase 3 clinical trial directly compared treatment with Cabometyx combined with the immunotherapy drug Opdivo (nivolumab) to treatment with Sutent alone in patients with previously untreated advanced or metastatic RCC.
Both Opdivo and Cabometyx are FDA approved for treatment of RCC and research suggests that Cabometyx may create a more immune-permissive environment that may enhance response to immune checkpoint inhibitors.(3) Opdivo is designed to help the body’s immune system recognize and attack cancer cells. Cabometyx is a small-molecule inhibitor of tyrosine kinases including c-Met and VEGFR2, which are implicated in cancer cell growth.
The CheckMate -9ER Phase 3 clinical trial directly compared treatment with Cabometyx combined with the immunotherapy drug Opdivo (nivolumab) to treatment with Sutent alone in patients with previously untreated advanced or metastatic RCC. Both Opdivo and Cabometyx are FDA approved for treatment of RCC and research suggests that Cabometyx may create a more immune-permissive environment that may enhance response to immune checkpoint inhibitors. (6)
The results of the CheckMate -9ER clinical trial were featured at the Presidential Symposium at the European Society for Medical Oncology (ESMO) Virtual Congress 2020, on September 19, 2020 and published in the New England Journal of Medicine in March 2021. (9)
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Opdivo in combination with Cabometyx reduced the risk of death by 40% and doubled the survival duration without cancer progression from 8.3 months with Sutent to 16 months with the Opdivo-Cabometyx combination. Twice as many patients responded to treatment with the combination leading to an average 20.2 months response duration compared to 11.5 months with Sutent. (3)
Opdivo + Yervoy (ipilimumab)
Yervoy is a monoclonal antibody that targets a molecule known as CTLA4. CTLA4 is found on the surface of T cells and is thought to inhibit immune responses. By targeting this molecule, Yervoy may enhance the immune system’s response against tumor cells. Yervoy was approved in March 2011 for the treatment of melanoma and appears active in a number of cancers.The FDA approval for advanced renal cell carcinoma was based on the CheckMate 214 clinical trial that compared the Opdivo and Yervoy combination to Sutent, a standard treatment for advanced renal cell cancer.
The combination improved response rates and prolonged survival compared to treatment with Sutent alone. Follow up data was published in February 2020 with patients on the Checkmate 214 trial now having been followed for an average of 42 months. At 42 months 52% for patients treated with Opdivo plus Yervoy survive compared to 39% for patients treated with Sutent.Overall 28% of patients treated with the combination survived without cancer progression at 30 months from initiation of treatment compared to only 12% for those treated with Sutent alone. The adverse event profile was said to be manageable, with no new safety signals emerging.
Salvage Opdivo + Yervoy also has anti-tumor activity with acceptable toxicity in patients with metastatic RCC previously treated with immune checkpoint inhibitor (ICI) therapy - producing an objective response rate of 20%. ()
The most common adverse reactions (reported in at least 20% of patients treated with the combination) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite and no new side effects have emerged as problematic with longer follow up. “These results show the long-term benefits of Opdivo plus Yervoy in patients with previously untreated advanced renal cell carcinoma. The long-term overall survival benefits, high proportions of complete response and ongoing response, and paucity of chronic toxicity with nivolumab plus ipilimumab after extended follow-up compares favorably with available reports of other combination regimens in first-line advanced renal cell carcinoma,” the researchers wrote. (4-6)
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- Motzer R, Escudier B, McDermott D, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. New England Journal of Medicine. 2015. 2015DOI: 10.1056/NEJMoa1510665.
- Updated CheckMate -025 Results Show 26% of Patients Treated with Opdivo are Alive at Five Years in Patients with Previously Treated Advanced or Metastatic Renal Cell Carcinoma
- Cabometyx Treatment of Advanced Renal Cell - Kidney Cancer
- Motzer RJ, Rini BI, McDermott DF, et al. [Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomized, controlled phase 3 trial](https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19%2930413-9/fulltext) [published online August 16, 2019]. Lancet Oncol. doi: 10.1016/S1470-2045(19)30413-9
- Opdivo (nivolumab) Plus Yervoy (ipilimumab) Demonstrates Continued Survival Benefit at 42-Month Follow-up in Patients with Previously Untreated Advanced or Metastatic Renal Cell Carcinoma
- J Clin Oncol. 2020 Jun 3. Epub ahead of print.
- US Food and Drug Administration. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. Updated January 22, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma. Accessed January 22, 2021.