Carfilzomib extends survival in RRMM: OS analysis of the ENDEAVOR trial

The phase III ENDEAVOR clinical trial was the first clinical trial to compare two proteasome inhibitors head to head: carfilzomib plus dexamethasone versus bortezomib plus dexamethasone, in patients with Relapsed and Refractory Multiple Myeloma (RRMM). A previous interim analysis assessed progression free survival (PFS), but in the latest analysis, published in Lancet Oncology in August 2017, the overall survival (OS) data was revealed. The open-label, multi-center study was conducted across 198 hospitals in 27 countries, and was led by Professor Meletios Dimopoulos and Professor Philippe Moreau. For details of the clinical trial set-up and patient characteristics see previous MM Hub article.

Key Findings:

All data is given as carfilzomib group vs bortezomib group:

• Patients (pts) were randomly assigned to either the carfilzomib (n = 464) or bortezomib (n = 465) group
• Median pt age = 65 years in both groups; baseline clinical and treatment characteristics were balanced between groups
• Number of deaths at time of this analysis (January 3^rd 2017) = 398 deaths; 189 vs 209
• Median follow-up = 37.5 (IQR 34・4–41・9) vs 36.9 (33.4–40.6) months
• Median OS = 47.6 (95% CI 42.5–not evaluable) vs 40.0 (95% CI 32.6–42.3) months;
• HR = 0.791 (95% CI 0.648–0.964; one-sided p = 0.010
• Discontinuation of study drug (due to progression, toxicity, or other) = 262/391 (67%) vs 291/413
• Median duration of long-term follow-up = 15.4 (IQR 5.8–25.6) vs 16.9 months (6.4–28.1)
• Median time to next treatment (TTNT) (ITT population) = 26.3 (95% CI 24.2–30.6) vs 14.4 months (12.6–16.6)
• OS from time of progression = 21.5 in both groups
• Median duration of treatment = 48 weeks (IQR 24.1–88.7) vs 27 weeks (15–50)
• Average number of cycles of treatment = 12 cycles (IQR 6–22) vs 8 cycles (5–15)
• Median relative dose intensity = 91% (IQR 81–98) vs 85% (IQR 70–96)

Safety Data:

• Grade 3 or worse adverse events (AEs)= 377/463 pts (81%) vs 324/456 pts (71%) of 456
• Serious AEs = 273 (59%) vs 182 (40%)
• Most frequent grade 3 or worse AEs:
  • Anaemia = 76 pts (16%) vs 46 pts (10%)
  • Hypertension = 67 pts (15%) vs 15 pts [3%])
  • Pneumonia = 42 pts (9%) vs 39 pts (9%)
  • Thrombocytopenia = 41 pts (9%) vs 43 pts (9%)
  • Fatigue = 31 pts (7%) vs 35 pts (8%)
  • Dyspnoea = 29 pts (6%) vs 10 pts (2%)
  • Decreased lymphocyte count = 29 pts (6%) vs 9 (2%)
  • Diarrhoea = 18 pts (4%) vs 39 (9%)
  • Peripheral neuropathy = 6 pts (1%) vs 28 pts (6%)
• Treatment-related deaths = 5 pts (1%) vs 2 pts (<1%)
• Grade 2 or worse peripheral neuropathy = 32 pts (7%) vs 159 pts (35%) (OR 0.139, 95% CI 0.092–0.208; p<0.0001)
• Exposure-adjusted incidence of overall grade 3 or worse AEs was similar between the two groups

Conclusion:

This study provides more encouraging data for the use of a carfilzomib and dexamethasone combo in the relapsed setting, with a clear improvement in OS compared to the bortezomib and dexamethasone combo. This builds on the data from earlier interim analyses that revealed a significantly improved PFS compared to the bortezomib regimen, and that the carfilzomib regimen was also beneficial in patients with high-risk cytogenetics. The first interim analysis is detailed here, and the second sub-group analysis of patients with high risk cytogenetics is detailed here. The safety profiles between the two regimens, were remarkably similar, although there were a higher number of grade 3 AEs and serious AEs in the carfilzomib group, but these were deemed to be manageable and may be accounted for due to a longer average treatment exposure than the bortezomib group. However, the authors note that they were unable to account for all subsequent treatments when assessing OS, and that this is a limitation. The effect of using one PI over the other on subsequent treatment responses to other PIs was also not studied. However, this new data is likely to further support the use of carfilzomib and dexamethasone as a standard of care regimen for RRMM patients.

 Abstract

BACKGROUND:

The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups.

METHODS:

ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive carfilzomib and dexamethasone (carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m2) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients.

FINDINGS:

Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47·6 months (95% CI 42·5-not evaluable) in the carfilzomib group versus 40·0 months (32·6-42·3) in the bortezomib group (hazard ratio 0·791 [95% CI 0·648-0·964], one-sided p=0·010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 [16%] of 463 patients in the carfilzomib group vs 46 [10%] of 456 patients in the bortezomib group), hypertension (67 [15%] vs 15 [3%]), pneumonia (42 [9%] vs 39 [9%]), thrombocytopenia (41 [9%] vs 43 [9%]), fatigue (31 [7%] vs 35 [8%]), dyspnoea (29 [6%] vs ten [2%]), decreased lymphocyte count (29 [6%] vs nine [2%]), diarrhoea (18 [4%] vs 39 [9%]), and peripheral neuropathy (six [1%] vs 28 [6%]). Treatment-related deaths occurred in five (1%) of 463 patients in the carfilzomib group (pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown [n=1]) and two (<1%) of 456 patients in the bortezomib group (cardiac arrest [n=1] and pneumonia [n=1]).

INTERPRETATION:

Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease.