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Supplemental BLA for New Nivolumab Dosing Schedule Accepted by FDA

Jason Harris
Published Online:11:46 AM, Thu July 27, 2017

Elizabeth Plimack, MD
Supplemental Biologics License Applications (sBLAs) were sent to and accepted by the FDA for a new dosing schedule for nivolumab (Opdivo) across all of the agent's indications as a montherapy, according to Bristol-Myers Squibb (BMS), the manufacturer of the PD-1 inhibitor. 

If approved, doctors would be able to prescribe the new dosing schedule of 480 mg of nivolumab every 4 weeks. Nivolumab is currently approved as a single-agent for:
  • Advanced melanoma 240 mg IV infused over 1 hour every 2 weeks
  • Advanced non–small cell lung cancer (NSCLC) 240 mg IV infused over 1 hour every 2 weeks
  • Advanced renal cell carcinoma (RCC) 240 mg IV infused over 1 hour every 2 weeks
  • Metastatic Urothelial carcinoma 240 mg IV infused over 1 hour every 2 weeks
  • Hodgkin lymphoma 3 mg/kg IV infused over 1 hour every 2 weeks
  • Advanced head & neck squamous cell carcinoma 3 mg/kg IV infused over 1 hour every 2 weeks
  • The FDA is scheduled to issue a final approval decision by March 5, 2018.

“Less often is better—patients don’t like to travel and have their veins accessed every 2 weeks,” Elizabeth Plimack, MD, chief of the division of genitourinary medical oncology and director of genitourinary research at Fox Chase Cancer Center in Philadelphia, commented to Targeted Oncology. “Every 4 weeks is better, and presumably their data shows that it works just as well.”

In an email to Targeted Oncology, BMS spokesperson Tara DiFlumeri said the move is intended improve flexibility and convenience for patients and providers.

“Based on dose/exposure efficacy and safety relationships, there are no clinically significant differences in safety and efficacy between a nivolumab dose of 240 mg or 3 mg/kg every 2 weeks,” she said. “The currently approved 2-week dosing schedule at 240 mg is not being replaced. The sBLAs pending are to add the 4-week dosing at 480 mg as an option for patients for whom physicians feel it is appropriate.”

The drug was most recently approved to treat previously-treated, locally-advanced or metastatic urothelial cancer in February 2017 based on results from the CheckMate-275 trial.1

In results presented at the 2016 ESMO Annual Meeting, the objective response rate (ORR) was 19.6% for nivolumab in patients with platinum-refractory metastatic urothelial carcinoma (n = 270). The complete response rate was 3%. Across the study, the median progression-free survival was 2.0 months and the median overall survival (OS) was 8.74 months.

The FDA approved nivolumab in May 2016 for classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and posttransplantation brentuximab vedotin (Adcetris). The ORR was 65% (95% CI, 55-75; n = 62) in a combined analysis of 95 patients from the phase II CheckMate-205 trial or the phase I CheckMate-039 trial.2,3

The drug was approved for second-line squamous cell NSCLC in March 2015. That indication was expanded in October of that year to include patients with nonsquamous NSCLC who progressed on or following platinum-based chemotherapy, or EGFR- or ALK-targeted agents, based on data from the phase III CheckMate-057 trial. In the study, second-line nivolumab reduced the risk of death by 27% versus docetaxel in patients with nonsquamous NSCLC, including a 60% risk reduction among patients with the highest levels of PD-L1 expression.4

The approval for HNSCC, which occurred in November 2016, was based data from CheckMate-141. The median OS with nivolumab was 7.5 months compared with 5.1 months with investigator's choice (HR, 0.70; 95% CI, 0.52-0.92; P = .0101). The ORR was 13.3% with nivolumab and 5.8% for investigator's choice.5

The FDA used data from pivotal phase III CheckMate-025 trial to approve nivolumab for metastatic renal cell carcinoma in November 2015. In the study, nivolumab reduced the risk of death by 27% versus everolimus (Afinitor), representing a 5.4-month improvement in median OS.6

The FDA first approved nivolumab as a single agent for advanced melanoma in 2014, and that indication was expanded to include BRAF V600 mutation–positive unresectable or metastatic melanoma in January 2016, based on data from CheckMate-067. In the three-arm CheckMate-067 study, single-agent nivolumab reduced the risk of progression by 43% versus ipilimumab (HR, 0.57; P <.0001).7
  1. Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate-275 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA31.
  2. Younes A, Santoro A, Zinzani PL, et al. Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A phase 2 study. J Clin Oncol. 34, 2016 (suppl; abstr 7535).
  3. Ansell S, Armand P, Timmerman JM, et al. Nivolumab in patients (Pts) with relapsed or refractory classical Hodgkin lymphoma (R/R cHL): clinical outcomes from extended follow-up of a phase 1 study (CA209-039). Blood. 2015;126(23):583.
  4. Horn L, Brahmer J, Reck M, et al. Phase 3, randomized trial (CheckMate 057) of nivolumab (NIVO) vs docetaxel (DOC) in advanced non-squamous (non-SQ) non-small cell lung cancer (NSCLC): Subgroup analyses and patient reported outcomes (PROs). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3010.
  5. Ferris RL, Blumenschein GR, Fayette J, et al. Further evaluations of nivolumab (nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. J Clin Oncol. 2016;34 (suppl; abstr 6009).
  6. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma [published online September 25, 2015]. N Engl J Med. 2015;373:1803-1813.
  7. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.

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