By: Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
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.
By: Madelyn Hanson, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health
Therapeutic approaches for acute myeloid leukemia (AML) have gone unchanged for several years. Most newly diagnosed patients achieve complete remission (CR) with a combination regimen of cytarabine plus an anthracycline (7+3 most commonly). However, the high rate of CR comes at the cost of a high level of toxicities with this regimen. This poses a significant problem for the multiple subsegments within AML that have a poor prognosis, such as elderly patients, those with specific molecular aberrations, and patients with various comorbidities. Often these patients cannot tolerate the high toxicities that accompany the 7+3 regimen, which leaves only less efficacious treatment options for these patient subsegments. Hypomethylating agents (HMAs) that are approved for the treatment of myelodysplastic syndromes (MDS) ‒ such as Dacogen® (decitabine, Eisai/Janssen) and azacitidine ‒ are often used to treat these patients.
More recently, these patients with high unmet need have become a hotbed for new therapy development. Exciting results presented at the 2015 annual meeting of the American Society of Hematology (ASH) demonstrated that the FLT3 inhibitor midostaurin (Novartis) combined with 7+3 was able to triple overall survival (OS) in newly diagnosed FLT3+ AML patients.1 Other agents currently being evaluated in Phase III trials for relapsed/refractory FLT3+ AML include quizartinib (Daiichi Sankyo) and enasidenib (AG-221, Agios/Celgene). While these agents have created a great deal of excitement for FLT3+ patients, even more development is ongoing for the treatment of elderly patients with AML. While the definition of “elderly” is not based strictly on chronological age but more often biologic age (which takes into account patient “fitness”), more than half of AML patients are still considered to be “elderly” (according to surveyed U.S. physicians2), signifying that this is a large patient population with a high unmet need. VYXEOS (CPX-351, Celator), ganetespib (Synta Pharmaceuticals), guadecitabine (SGI-110, Otsuka/Astex), sapacitabine (Cyclacel), vadastuximab talirine (SGN-CD33A, Seattle Genetics), and volasertib (Boehringer Ingelheim) are all in late-stage development for newly diagnosed, elderly patients.
Today at the annual meeting of the American Society for Clinical Oncology (ASCO), final results were presented from a Phase III trial (NCT01696084) evaluating VYXEOS in untreated, elderly AML patients considered at high risk for recurrence.3 VYXEOS is a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio. This formulation is administered intravenously at 100 u/m2 on days 1, 3 and 5 by approximately 90-minute infusion compared with the standard 7+3 regimen, which requires continuous infusion of cytarabine (100 mg/m2/day) for seven days as well as of daunorubicin (60 mg/m2) on days 1, 2 and 3.
In the trial, VYXEOS was compared with the standard 7+3 regimen of cytarabine and daunorubicin as first induction in untreated elderly patients with high-risk or secondary AML. The study enrolled 309 patients and OS was the primary endpoint. VYXEOS met its primary endpoint with mOS of 9.56 months compared with 5.95 months for patients receiving 7+3 therapy (HR=0.69, p=0.005). A 1.22-month improvement in event-free survival (EFS) also was observed in the VYXEOS arm (2.53 vs. 1.51 months, HR=0.74, p=0.021). VYXEOS was shown to improve the overall response rate (CR+CRi of 47.7% vs. 33.3%; p=0.016), with a significant improvement in CR (37.7% vs. 5.6%, p=0.040) and EFS (HR= 0.74, p=0.021).
Subanalysis of OS in patients with or without transplant was also performed. Although the sample was small (n=91), the mOS of patients who went on to receive a stem cell transplant following induction was significantly improved in the VYXEOS arm compared with the 7+3 arm (not reached vs. 10.25 months, HR=0.46, p=0.0046).
To begin to evaluate tolerability of VYXEOS, 60-day mortality favored VYXEOS versus 7+3 (13.7% vs. 21.2%). However, the presenter noted that while there was a significant reduction in deaths due to progressive AML (3.3% vs. 11.3%), there was no difference in deaths due to adverse events between the two arms (10.4% with VYXEOS vs. 9.9% with 7+3). Thus, the 60-day mortality improvement likely reflects the improvement in efficacy and not a difference in safety signals between the two regimens. In fact, there was no difference in Grade 3-5 adverse events between the two arms of the study. In addition, in patients achieving a CR after one induction, patients in the VYXEOS arm had a median six-day delay in absolute neutrophil count recovery compared with the 7+3 arm and a 7.5-day delay in platelet count recovery.
VYXEOS was awarded the U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation in May 2016, and Celator intends to submit a new drug application with the FDA later this year based on the data reported. Efficacy results from this study suggest that VYXEOS could quickly change the treatment approach for newly diagnosed, elderly AML patients that are deemed high risk. The fact that VYXEOS is a liposomal formulation of two agents (cytarabine and daunorubicin) that are currently standard of care for AML also supports rapid uptake by physicians. However, the issues of tolerability with the 7+3 regimen in elderly patients remain with VYXEOS. Physicians will have to decide whether the efficacy achieved along with the adverse-event profile warrants use of VYXEOS in individual patients. Although not discussed, additional subanalyses from this trial could provide physicians the information they need to select the patients most likely to benefit from VYXEOS. Although this trial was not performed in low-risk or younger patients, there may be a desire among physicians to use VYXEOS in these other patient types to improve the ability to reach stem cell transplant and improve OS, although such use would be considered off-label.
Thus, while VYXEOS sets a high survival benchmark in elderly, high-risk AML patients, this cytotoxic agent still leaves some room for targeted agents such as volasertib (which targets polo-like kinase), ganetespib (which targets heat-shock protein 90), and vadastuximab talirine (which targets CD33) with potentially less toxicity to enter into the same space if they too can demonstrate significant survival benefits, although notably these drugs are all being compared with low-intensity, single-agent therapies in their ongoing pivotal trials.