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Phase III CANDOR Study | Primary Analysis

Dec 18, 2019

During the late-breaking abstracts (LBA) session at the 61 st American Society of Hematology(ASH) meeting, Orlando, US, on Tuesday 10 thDecember 2019, Saad Z. Usmani, Levine Cancer Institute, Atrium Health, Charlotte, US, presented the primary analysis from the phase III CANDOR study.

CANDOR ( NCT03158688) is a randomized phase III study comparing the combination of daratumumab (D), carfilzomib (K), and dexamethasone (d; DKd) to Kd alone in patients with relapsed/refractory multiple myeloma (RRMM). 1Previously, the EQUULEUS ( NCT01998971) phase Ib study demonstrated the DKd was safe and efficacious in patients with RRMM, leading to the instigation of the phase III CANDOR trial. 2

It was previously announced that the CANDOR study had met its primary endpointwith DKd improving progression-free survival (PFS) compared to Kd alone. 3This article summarizes the primary analysis data, as presented during the LBA session at the 61 stASH meeting. 1

Study design and patient characteristics 1

The study enrolled patients with RRMM who had received 1–3 prior lines of therapy with ≥ partial response (PR) to ≥ one line of therapy who had:

  • Eastern Cooperative Oncology Group (ECOG) performance status: 0–2
  • Creatinine clearance: ≥20mL/min
  • Left ventricular ejection fraction: ≥40%

Patients (N= 466) were randomized 2:1 to DKd (n= 312) or Kd (n= 154) and baseline characteristics were balanced as shown in Table 1.

Table 1.Baseline characteristics 1

 

DKd (n= 312)

Kd (n= 154)

Median age, years

64 (29–84)

65 (35–84)

International staging system (ISS) stage at baseline (I vsII vsIII), %

47.1 vs33.0 vs19.6

51.3 vs31.2 vs17.5

ECOG score (0 or 1 vs2), %

94.6 vs4.8

95.5 vs4.5

Cytogenetics by fluorescence in situhybridization (high vsstandard vsunknown), %

15.4 vs33.3 vs51.3

16.9 vs33.8 vs49.4

Number of prior therapies (1 vs≥2), %

46.2 vs53.8

45.5 vs53.9

Refractory to bortezomib, %

28.2

30.5

Refractory to lenalidomide, %

31.7

35.7

Dosing schedule: 28-day cycles

  • K: 30-minute intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16
    • On days 1 and 2 during cycle 1: 20mg/m 2
    • Thereafter: 56mg/m 2
  • D: IV infusion:
    • Day 1 and 2 of cycle 1: 8mg/kg
    • Once weekly for the remaining doses of first two cycles: 16mg/kg
    • Every two weeks for cycles 3–6 and every four weeks thereafter: 16mg/kg
  • d: IV or oral: 40mg weekly
    • Dose adjustment for patients ≥75 years: 20mg
  • Minimal residual disease (MRD) samples were taken at baseline, at 12-months (for MRD-negative complete response [CR] rate) and at 24 months (for sustained MRD-negative CR rate)
  • Treatment continued until disease progression

Endpoints

  • Primary endpoint: PFS
  • Secondary endpoints: overall response rate (ORR), MRD negative-CR at 12 months at a 10 -5 threshold, overall survival (OS), time to response, and safety

Efficacy 1

  • Primary endpoint of PFS was met at a median follow-up of 16.9 (DKd) vs3 (Kd) months as shown in Table 2
    • Read more on the MM hub here
  • Subgroup analysis showed the PFS benefit with DKd was maintained across subgroups including ISS stage I/II vsIII, age, region, baseline ECOG score, baseline creatinine clearance, and cytogenetic subgroup
  • The median time to first response was one month in both study arms
  • Median treatment duration was 70.1 weeks with DKd vs40.3 weeks with Kd
  • Additional efficacy measures are shown in Table 3

Table 2.Median PFS and OS for total cohort and by lenalidomide exposure status 1

 

DKd (n= 312)

Kd (n= 154)

Hazard ratio (HR) and pvalues for DKd versusKd

Median PFS

Not reached (NR)

15.8 months

HR= 0.63

95% CI, 0.46–0.85

p =0.0014

Median OS at median follow-up of 17 months

NR

NR

HR= 0.75

95% CI, 0.49–1.13

p=0.0836

Subgroup analysis of median PFS

Lenalidomide-exposed

NR

12.1

HR= 0.52

95% CI, 0.34–0.80

Lenalidomide-refractory

NR

11.1

HR= 0.45

95% CI, 0.28–0.74

Table 3.Additional efficacy measures 1

 

DKd (n= 312)

Kd (n= 154)

HR and pvalues

ORR

84.3%

74.7%

p=0.004

≥Very good PR (VGPR)

69.2%

48.7%

 

≥CR

28.5%

10.4%

 

MRD-negative CR at 12 months at 10 -5

12.5%

1.3%

p<0.0001

Safety 1

  • A summary of adverse events (AEs) is shown in Table 4and Table 5
  • Treatment-related fatal AEs (DKd vsKd): 5 vs0
    • Causes of death were pneumonia, sepsis, septic shock, Acinetobacterinfection and cardio-respiratory arrest
  • D infusion-related reactions occurred in 18.2% of patients, of which 2.3% were grade ³3
  • Treatment-emergent fatal AEs occurred in 30 patients (9.7%) in the DKd arm and 8 patients (5.2%) in the KD arm
    • The main cause was infection and cardiac disorders
    • Patients with fatal AEs in the DKd arm were older and more frail

Table 4.Treatment-emergent AEs 1 

 

DKd (n= 308)

Kd (n= 153)

≥Grade 3 AE

82.1%

73.9%

Serious AE

56.2%

45.8%

Fatal AE

9.7%

5.2%

Treatment discontinuation due to AE

22.4%

24.8%

Dose reduction due to AE

38.6%

34.6%

Cardiac failure event leading to discontinuation

3.9%

4.6%

  Table 5.≥Grade 3 AEs; A: occurring in ≥5% of patients in either arm or B: of interest 1

A

DKd (n= 308)

Kd (n= 153)

Hematologic

Thrombocytopenia

24.4%

16.3%

Anemia

16.6%

14.4%

Neutropenia

8.4%

5.9%

Lymphopenia

6.8%

7.2%

Non-hematologic

Hypertension

17.5%

13.1%

Fatigue

7.8%

4.6%

Pneumonia

13.3%

8.5%

B

Acute renal failure

2.9%

6.5%

Cardiac failure

3.9%

8.5%

Respiratory tract infection

28.9%

15.7%

Hypertension

17.9%

13.7%

Infusion related reaction (IRR) on same day as K administration

12.3%

5.2%

Viral infections

6.2%

2.0%

Conclusion 1

DKd provided a significant PFS benefit when compared to Kd alone, leading to a 37% risk of reduction in progression or death. There was an almost 10x higher MRD-negative CR rate at 12 months with DKd.

The PFS benefit was observed across subgroups, especially in patients who were refractory to lenalidomide. In relation to safety, the number of cardiac failure events was similar between arms, though there was a higher rate of respiratory tract infection in the DKd arm. The DKd regimen may represent a valuable option for patients with RRMM and pre-existing kidney disease, since there was a lower rate of acute renal failure with the DKd regimen.

  1. Usmani S.Z. et al., Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688). 2019 Dec 10. 61st American Society of Hematology Meeting, Orlando, US. Oral abstract #LBA-6 
  2. Chari A. et al., Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood134 (5): 421-431. 2019 May 21. DOI: 10.1182/blood.2019000722
  3. BioSpace. Amgen Announces Phase 3 CANDOR Study Combining KYPROLIS® (carfilzomib) And DARZALEX® (daratumumab) Meets Primary Endpoint Of Progression-Free Survival. https://www.biospace.com/article/releases/amgen-announces-phase-3-candor-study-combining-kyprolis-carfilzomib-and-darzalex-daratumumab-meets-primary-endpoint-of-progression-free-survival/[Accessed 2019 Dec 12]