SUMMARY: The FDA on March 6, 2018 approved a supplemental Biologics License Application (sBLA) updating the OPDIVO® (Nivolumab) dosing schedule to include 480 mg infused every four weeks (Q4W) for a majority of approved indications. OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody approved by the FDA for multiple tumor types. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Under normal circumstances, Immune checkpoints or gate keepers, inhibit intense immune responses by switching off the T cells of the immune system. They therefore suppress antitumor immunity. OPDIVO® by targeting immune checkpoint PD-1, unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.
The clinical pharmacology of OPDIVO® is well established and the clinical data regarding the efficacy and safety of OPDIVO® when administered at 3 mg/kg Q2W (every 2 weeks) across multiple tumor types is well characterized. However, alternative dosing schedules would provide flexibility and other benefits both to patients as well as prescribers.
The authors in this study, using a combination of quantitative clinical pharmacology analyses and safety assessments, evaluated the feasibility of extending the dosing interval of OPDIVO®, and administering it every 4 weeks instead of every 2 weeks. They examined the predicted risk/benefit profile of OPDIVO® 480 mg Q4W compared to 3 mg/kg Q2W by
(1) Comparing OPDIVO® exposures produced by 3 mg/kg Q2W and 480 mg Q4W across tumor types
(2) Evaluating OPDIVO® exposure margins for safety, relative to the well-tolerated dose of 10 mg/kg Q2W
(3) Comparing the predicted risk of experiencing grade 3 adverse events with 480 mg Q4W relative to 3 mg/kg Q2W across the various tumor types for which it is indicated
(4) Comparing the predicted Objective Response Rate (ORR) and Overall Survival with OPDIVO® 480 mg Q4W compared to 3 mg/kg Q2W, in patients with Melanoma, Non Small Cell Lung Cancer (NSCLC), and Renal Cell Carcinoma (RCC).
The researchers noted that among patients with Melanoma, NSCLC, or RCC, there was a less than 1% difference in the predicted probability of achieving a response. The predicted 1 and 2-year survival probabilities were also similar among patients with these tumor types receiving either of the two dose schedules of OPDIVO®, with differences ranging between 0-4.6% at the end of the first year and 1.9-6.9% at the end of second year, across tumor types.
Based on this data, OPDIVO® 480 mg Q4W flat dose option was approved by the FDA for the following indications:
• Metastatic melanoma (monotherapy or monotherapy phase after combination treatment with YERVOY® (Ipilimumab)
• Previously treated metastatic Non Small Cell Lung Cancer
• Advanced Renal Cell Carcinoma following prior Anti-angiogenic therapy
• Previously treated locally advanced or metastatic Urothelial carcinoma following disease progression during or after Platinum-based chemotherapy
• Classical Hodgkin lymphoma following relapse/progression after autologous Hematopoietic Stem Cell Transplantation (HSCT) and Brentuximab vedotin, or three or more lines of systemic therapy that includes autologous HSCT
• Recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck following Platinum-based therapy
• Hepatocellular carcinoma after prior Sorafenib therapy
• Adjuvant therapy for patients with completely resected Melanoma with lymph node involvement or metastatic disease
It was concluded that based on the clinical pharmacology of OPDIVO® and well characterized Exposure-Response relationships for efficacy and safety, the differences in exposures produced by a OPDIVO® schedule of 480 mg Q4W relative to 3 mg/kg Q2W dosing schedule, should not result in clinically meaningful differences in the safety and efficacy of OPDIVO®. This alternate, flexible dosing option may further help tailor patient care. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types [abstract]. Zhao X, Ivaturi V, Gopalakrishnan M, et al. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract CT101. doi:10.1158/1538-7445.AM2017-CT101