Daratumumab Combo Data Published as FDA Considers New Myeloma Indication

Jan van de Winkel, PhD

As the FDA considers a supplemental biologics license application (sBLA) for 2 daratumumab-based triplet regimens in multiple myeloma, the results for 1 of the pivotal phase III studies supporting the sBLA have been published in The New England Journal of Medicine (NEJM).

The sBLA, which is specifically for the use of daratumumab (Darzalex) in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone as a treatment for patients with multiple myeloma following at least 1 prior therapy, is based on data from 2 phase III trials.

The phase III CASTOR trial demonstrated that adding daratumumab to bortezomib (Velcade) and dexamethasone reduced the risk of progression or death by 61% in patients with recurrent or refractory multiple myeloma. In the phase III POLLUX trial, combining daratumumab with lenalidomide (Revlimid) and dexamethasone reduced the risk of disease progression by 63% versus lenalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma.

The CASTOR study results were published in NEJM in August,¹ and the journal has now published the findings from the POLLUX trial.²

"Following the publication of the phase III CASTOR data, we are pleased that the positive data from the phase III POLLUX study has now also been published in The New England Journal of Medicine," Jan van de Winkel, PhD, chief executive officer of Genmab, which codevelops daratumumab with Janssen, said in a statement.

"The data from this study formed the basis, along with data from the CASTOR study, of two regulatory submissions in August; the supplemental biologics license application submitted to the US Food and Drug Administration and the submission of the variation to the marketing authorization to the European Medicines Agency," added van de Winkel.

The international, open-label POLLUX trial randomized 569 patients with relapsed/refractory multiple myeloma to daratumumab combined with lenalidomide/dexamethasone (n = 286) or lenalidomide plus dexamethasone alone (n = 283). Patients characteristics were well balanced between the study arms. The median age across the trial was 65 years and the median number of prior treatment lines for each cohort was 1.

Daratumumab was dosed at 16 mg/kg IV once weekly during cycles 1 and 2, every 2 weeks during cycles 3 to 6, and once only (on day 1) of cycles 7 onward. Oral lenalidomide was administered at 25 mg daily for the first 3 weeks of each cycle and dexamethasone was dosed at 40 mg weekly (20 mg weekly in patients older than 75 or with a BMI <8.5). Treatment cycles for both study arms were 28 days. Patients were treated until progression or unacceptable toxicity.

At a median follow-up of 13.5 months, the median progression-free survival was not yet reached in the daratumumab arm versus 18.4 months with lenalidomide/dexamethasone alone (HR, 0.37; 95% CI, 0.27-0.52; P <.001). The overall response rate was 92.9% versus 76.4%, respectively (P <.001). The very good partial response or better rate was 75.8% with daratumumab versus 44.2% in the control arm (P <.001) and the compete response rates were 43.1% and 19.2%, respectively (P <.001).

The safety profile was consistent with previously report adverse events (AEs) for single-agent daratumumab and the combination of lenalidomide and dexamethasone. The most common grade 3/4 AEs were neutropenia (51.9% in the daratumumab arm vs 37% in the control arm), thrombocytopenia (12.7% vs 13.5%), and anemia (12.4% vs 19.6%). Infusion-related reactions associated with daratumumab were reported for 47.7% of patients and for the most part, were grade 1/2.

Daratumumab is a fully human monoclonal antibody that binds to glycoprotein CD38. Once bound, the antibody interacts with natural killer cells by mimicking the normal interaction between CD38 and CD31. This interaction elicits antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity resulting in antitumor activity.

In November 2015, the FDA granted an accelerated approval to daratumumab as a monotherapy for patients who have relapsed after ≥3 prior lines including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to those therapies.

References

1. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
2. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.