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FDA Decision Alerts December 14, 2020

CDER-Approved NDA for BLENREP (belantamab mafodotin-blmf)

Christina Purpura and Elizabeth Dabrowski
Contributing writers, Aetion

On August 5, 2020, the FDA approved GlaxoSmithKline (GSK)’s BLENREP (belantamab mafodotin-blmf) for adults with relapsed or refractory multiple myeloma (RRMM). Here are the key findings from the FDA’s Multi-Discipline Review of the drug:

  • The agency’s approval is based on the results of a phase 2, single-arm study compared to a historical control. Study 205678 (DREAMM-2/NCT03525678; n=218) included two parallel dose cohorts: 2.5 or 3.4 mg/kg every three weeks up to disease progression or unacceptable toxicity. The sponsor used the overall response rate (ORR), which they define as partial response or better, as the major efficacy outcome. They drew on a historical control to evaluate the ORR magnitude. The sponsor prespecified the ORR boundary of 15 percent based on four publications. The sponsor then designed and executed its phase 2, single-arm study to exclude this ORR boundary from the 97.5 percent CI.
  • The FDA’s recommended dosage is 2.5 mg/kg. (The sponsor wrote: “there was no apparent evidence that the efficacy profile is different between the 2 dose cohorts.”) The ORR in the 2.5 mg/kg treatment group was 31 percent (97.5 percent CI: 20.8, 42.6).
  • The safety database included 291 patients from Study 205678 and a phase 1 study: BMA117159 (DREAMM-1/NCT02064387; n=73). The studies found ocular toxicity, including keratopathy, to be the key safety concern, especially for older adults. Among patients in the 2.5 mg/kg treatment group, the sponsor observed an increased incidence of ocular toxicity in older adults compared to younger adults.

The sponsor’s historical control is described below, as well as its postmarketing commitments (PMCs).

Historical control
Purpose: To support the efficacy outcomes of Study 205678, the sponsor drew on a historical control to evaluate the ORR magnitude. After discussion, the sponsor and the FDA agreed on this study design.

What was done: The sponsor conducted a literature search. They found an ORR of 15 percent in patients at fourth relapse, according to the literature (Hájek 2017; Kumar 2012; Durie 2012; Anderson 2008). Therefore, for the comparison with each belantamab mafodotin treatment group, the sponsor prespecified a lower bound of the CI that exceeded 15 percent.

Outcome: The sponsor’s approach won approval from the FDA, albeit with qualifiers. The FDA accepted the study design by pointing to the absence of an FDA-approved product for this population and the absence of published results on efficacy outcomes in this population. At the same time, it critiqued the study design. For example, the FDA noted that the sponsor reported two secondary endpoints, progression-free survival and overall survival, without context. The FDA writes that “comparisons to historical controls are prone to bias. Such biases include inconsistent definitions of time intervals across studies leading to biased estimates, and bias associated with comparison to historical controls due to differences in the study population, differences in the frequency and timing of assessments, and advances in medical care over time.”

A note on PMCs
In its review, the FDA wrote that the sponsor needs to submit an interim and final report, which should include results from clinical trials and RWE studies. For example, the sponsor needs to use real-world data to further characterize safety in older adults versus younger patients.

References
Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosinol L, Nagler, A, et al. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017;31: 107-114. https://pubmed.ncbi.nlm.nih.gov/27416912/

Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149-57. https://pubmed.ncbi.nlm.nih.gov/21799510/

Durie BG, Moreau P, Sonneveld P, et al. Regional differences in the treatment approaches for relapsed multiple myeloma: an IMF study. Journal of Clinical Oncology, 2012; 30: (suppl; abstr 8095). https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.8095

Anderson KC, Kyle RS, Rajkumar SV, et al. Clinically relevant end points and new drug approvals for myeloma, Leukemia, 2008;22: 231-9. https://pubmed.ncbi.nlm.nih.gov/17972944/

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