Phase III CANDOR Study | Primary Analysis

During the late-breaking abstracts (LBA) session at the 61^st American Society of Hematology (ASH) meeting, Orlando, US, on Tuesday 10^th December 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).¹ Previously, 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 endpoint with DKd improving progression-free survival (PFS) compared to Kd alone.³ This article summarizes the primary analysis data, as presented during the LBA session at the 61^st ASH meeting.¹

Study design and patient characteristics¹

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 characteristics¹

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/m²
  • Thereafter: 56mg/m²
• 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

Efficacy¹

• Primary endpoint of PFS was met at a median follow-up of 16.9 (DKd) vs3 (Kd) months as shown in Table 2
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• Subgroup analysis showed the PFS benefit with DKd was maintained across subgroups including ISS stage I/II vs III, 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 vs 40.3 weeks with Kd
• Additional efficacy measures are shown in Table 3

Table 2. Median PFS and OS for total cohort and by lenalidomide exposure status¹

Table 3. Additional efficacy measures¹

Safety¹

• A summary of adverse events (AEs) is shown in Table 4 and Table 5
• Treatment-related fatal AEs (DKd vs Kd): 5 vs 0
  • Causes of death were pneumonia, sepsis, septic shock, Acinetobacter infection 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 AEs¹  

 Table 5. ≥Grade 3 AEs; A: occurring in ≥5% of patients in either arm or B: of interest¹

Conclusion¹

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.