CASTOR Shines in Relapsed/Refractory Multiple Myeloma
| Jun 5, 2016
Co-authored by Greg Wolfe, Ph.D.
The armamentarium of treatment options available for patients with multiple myeloma continues to grow as the result of several recent, successful novel therapeutic agents in development. In November 2015, three novel agents received approval from the U.S. Food and Drug Administration (FDA) for treatment of relapsed/refractory disease: Darzalex® (daratumumab, HuMax-CD38; Genmab/Janssen Biotech), a human monoclonal antibody directed against CD38 that is highly expressed on the surface of multiple myeloma cells and indicated for patients who have received at least three prior lines of therapy; Empliciti™ (elotuzumab; Bristol-Myers Squibb/Abbvie), a SLAMF7-directed immunostimulatory antibody indicated in combination with Revlimid® (lenalidomide, Celgene) and dexamethasone for the treatment of patients who have received one to three prior lines of therapy; and Ninlaro® (ixazomib, Takeda) an orally administered proteasome inhibitor (PI) indicated in combination with Revlimid and dexamethasone for the treatment of patients who have received at least one prior line of therapy.
Darzalex targets and mediates destruction of CD38+ immunosuppressive regulatory cells and promotes T-cell expansion and activation. This agent has multiple mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent, cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis. Darzalex received accelerated approval for use as a single agent in the United States in November 2015 for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. In April 2016, Darzalex was also granted conditional marketing approval by the Europe Commission as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. The design of the clinical trial upon which Darzalex’s approval is based relegates Darzalex utilization to later lines of therapy.
In March 2016, Johnson & Johnson announced that the randomized Phase III CASTOR trial (NCT02136134) achieved its primary endpoint and was stopped early as recommended by the Independent Data Monitoring Committee. Today at the annual meeting of the American Society for Clinical Oncology (ASCO), data were presented from the prespecified interim analysis of the CASTOR trial that compared the safety and efficacy of Darzalex, Velcade (bortezomib; Takeda) and dexamethasone (DVd) versus Velcade and dexamethasone (Vd) in subjects with relapsed or refractory multiple myeloma.1 Patients (n=498) with progressive disease after at least one prior line of therapy were randomized (1:1) to receive Darzalex (16 mg/kg IV QW in cycles 1-3, Q3W in cycles 4-8, Q4W thereafter), Velcade ( 1.3 mg/m2 SC on Days 1, 4, 8 and 11 of cycles 1-8) and dexamethasone (20 mg PO on Days 1, 2, 4, 5, 8, 9, 11 and 12 of cycles 1-8) or VelDex (1.3 mg/m2 Velcade SC on Days 1, 4, 8 and 11 of cycles 1-8; 20 mg dexamethasone PO on Days 1, 2, 4, 5, 8, 9, 11 and 12 of cycles 1-8) alone. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints included time to progression, overall survival (OS), overall response rate, very good partial response and complete response rates, and percentage of patients with minimal residual disease. Patients in the trial had received a median of two prior therapies.
Treatment with DVd yielded superior clinical activity compared with treatment with VelDex alone. Darzalex significantly improved PFS with the median not reached in DVd treated patients and a median PFS of 7.2 months in the Vd arm (HR=0.31; p<0.0001). PFS at one year was 60.7% for DVd versus 26.9% for Vd, and for patients who received just one prior line of therapy PFS at one year was 77.5% versus 29.4%, respectively. Treatment with DVd also improved median time to progression: not reached for DVd versus 7.3 months for Vd (HR=0.30; p<0.0001). Darzalex improved objective response rate to 83% from 63% for Vd (p<0.0001), and treatment with DVd doubled rates of complete responses or better (19% versus 9%) and very good partial responses or better (59% versus 29%) compared with Vd alone. Just 3% of Vd patients were MRD-negative compared with 14% MRD-negative for DVd. Median OS data are immature as the median follow-up was only 7.4 months. Darzalex was well tolerated and was not associated with additional cumulative toxicity.
Darzalex utilization is currently reserved for fourth-line; however, results from the CASTOR trial are practice changing, and these data suggest that DVd should be considered a new standard of care for relapsed/refractory multiple myeloma patients currently receiving Vd alone. The 78% PFS at one year for patients who had received only one prior therapy supports early Darzalex utilization.
While impressive results from the CASTOR trial bode well for Darzalex VelDex combination, a triplet combination of Darzalex plus a PI and an immunomodulatory agent such as Revlimid (lenalidomide, Celgene) may be an even more important regimen to evaluate in the future. More imminent are the results of the randomized Phase III POLLUX trial comparing Darzalex, Revlimid, and dexamethasone (DRd) versus Revlimid and dexamethasone (Rd) in relapsed/refractory multiple myeloma patients that will be reported next week at the 21st Congress of the European Hematology Association (EHA). Preliminary data from this trial (Genmab press release, May 18, 2016) reported a significant improvement in mPFS, which was not reached for DRd versus 18.4 months for Rd (HR = 0.37, p < 0.0001). Notably, the mPFS in the Rd control arm of POLLUX is longer than the Vd control arm in CASTOR. It will be interesting to see whether this is a result of a difference in median number of prior therapies for patients between the two trials. Potential future competition for Darzalex is on the horizon from isatuximab (Sanofi), another CD38-directed monoclonal antibody, and from checkpoint inhibitor-based combinations such as Keytruda plus Revlimid. Nonetheless, the results of CASTOR clearly suggest DVd provides a highly efficacious option for relapsed/refractory patients, further increasing the crowdedness of the multiple myeloma landscape.
- Palumbo A, Chanan-Khan AAA, Weisel K, et al.; “Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study;” J Clin Oncol 34, 2016 (suppl; abstr LBA4).