Zulassungsstudien

ASPIRE - In this study the triple combination Carfilzomib, lenalidomide and dexamethasone has been investigated against lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (KRd27 vs Rd).
    The primary analysis (Stewart et al. 2015) showed1
  • a significant prolonged progression free survival in the Carfilzomib arm compared to the lenalidomide arm (KRd vs Rd: 26.3 Mo vs 17.6 months; HR: 0.69; p 0.0001).
  • the number of patients, who achieved complete response, has been tripled by the addition of Carfilzomib to Rd to 32% (32 vs 9% CR in the Rd arm).
    The final analysis (Siegel et al. 2018) showed2
  • a likewise significantly prolonged overall survival by 8 months in the KRd arm compared to the Rd arm (KRd vs Rd: 48.3 vs 40.4 months; HR 0.79, 95% CI 0.667-0.945). The comparable survival post progression of study participants and the analysis of subsequent therapies showed that the observed survival advantage in the KRd arm is due to the addition of Carfilzomib.

Aspire

ASPIRE short explainer video

The primary and the longterm analysis of the safety data are consistent. The most common side effects are …

(all grade; KRd vs Rd): anemia (43.1 vs 40.6%), neutropenia (40.1 vs 35.0%) and thrombocytopenia (29.3 vs 24.2%). Adverse events of special interest ≥ grade 3 were (KRd vs Rd): acute renale failure (3.8 vs 3.3%), heart failure (4.3 vs 2.1%), ischemic heart disease (3.8 vs 2.3%), hypertension (6.4 vs 2.3%), hematopoietic thrombocytopenia (20.2 vs. 14.9%) and peripheral neuropathy (2.8 vs 3.1%).2 (Siegel et al. 2018)
ASPIRE Overall Survival as Oral at ASH 2017
The Oral presentation of the ASPIRE Overall Survival and the safety data is available for download.

The observed additional benefit by Carfilzomib to Rd regarding PFS and OS was consistent over the various subgroups of patients and was independent of the therapy line or prior therapy.

Patients in the second therapy line achieved in the KRd arm a median PFS of 29.6 months and a median OS of 47.3 months. In the comparative arm with Rd a median PFS of 17.6 months and a median OS of 35.9 months were achieved in a similar patient population. The difference in median PFS in patients in 3rd and 4th therapy line was 9.1 months (KRd vs Rd: 25.8 vs 16.7 mo, HR 0.72; 95% CI: 0.56, 0.92), resp. 6.5 months in median OS (KRd vs Rd: 48.8 vs. 42.3 mo; HR 0.79; 95% CI: 0.62, 0.99).2,3
The patients with a prior bortezomib therapy achieved with KRd as 2nd line therapy a median PFS of 29.3 months (vs 15.9 mo in the Rd arm; HR 0.58; 95% CI: 0.38, 0.88)4 and an OS of 45.9 months (vs 33.9 mo in Rd; HR 0.82; 95% CI: 0.56, 1.19): the progression free time has been doubled and the OS benefit prolonged by one year.2
Patients with a previous stem cell transplantation had with KRd as 2nd line therapy a PFS benefit of almost one year (KRd vs Rd: 29.7 vs 17.8 mo; HR 0.70 CI 95%: 0.46, 1.07) and an OS benefit of median 18.6 months (KRd vs Rd: 57.2 vs 38.6 mo; HR 0.71; 95% CI: 0.48, 1.05).2,5
The subanalyses of PFS and OS according to therapy lines and prior therapies are shown in this slidedeck.


ENDEAVOR - In this study the combination Carfilzomib and dexamethasone has been investigated against the doublet bortezomib and dexamethasone in patients with relapsed / refractory multiple myeloma (Kd56 vs Rd).
    The primary analysis (Dimopoulos et al. 2016) showed6
  • a significant prolonged progression free survival in the Kd56 study arm compared to the Vd arm (primary endpoint; Kd vs Vd: 18.7 mo vs 9.4 months; HR: 0.53; p <0.0001).
  • the number of patients, who achieved complete response, has been doubled by the addition of Carfilzomib to Rd to 13% (vs 6% CR in the Vd arm)
  • the incidence of peripheral neuropathies (≥ grade 2) was in the Vd arm five times higher compared to the Carfilzomib arm (6% vs 32% with Vd).
    The final analysis (Dimopoulos et al. 2017) showed7
  • a significantly prolonged overall survival by 7.6 months in the KRd arm compared to the Vd arm. (Kd vs Vd: 47.6 vs. 40 months ; HR 0.791; 95% CI, 0.648-0.964)

endeavor

ENDEAVOR – short explainer video

The safety data of the final analysis were comparable to the ones of the primary analysis. The incidence of Adverse events of ≥ grade 3 were 81% vs 71% in patients with Kd vs Vd, whereof patients with Kd were treated in median 21 weeks longer (48 weeks Kd vs 27 weeks Vd treatment duration). The most common side effects and adverse events of special interest were presented in detail in the Oral at IMW 2017, as well as in the subsequent publication in Lancet Oncology.
ENDEAVOR Overall Survival
The Oral presentation of the ENDEAVOR OS and of the safety analysis is available for download.

Further analyses of the ENDEAVOR study showed that the superiority of Kd vs Vd regarding progression free survival and overall survival is independent of Velcade-based prior therapies. The superiority of Kd56 vs Vd in elderly patients could also be confirmed.

In Velcade-pretreated patients the PFS with Carfilzomib in 2nd line was 18.7 months vs 8.7 months with Vd (HR 0.46 95% CI: 0.30, 0.72) and 13.1 vs 7.4 months in the 3rd & 4th line (HR 0.62; 95% CI: 0.45, 0.85).8 The overall survival was 47.6 months in patients who received Velcade in a prior therapy line, compared to the 32.8 months in the Vd arm (HR 0.84; 95% CI: 0.65, 1.08); OS could be prolonged by 14.7 mo with Kd.9
In elderly patients ≥75 years the median PFS with Carfilzomib could be doubled and the OS could be prolonged by almost one and a half year compared to Vd (Kd56 vs Vd: 18.7 vs 8.9 months PFS (HR 0.38, 95% CI: 0.23, 0.65) and by 42.4 vs. 25.9 months OS (HR 0.84, 95% CI: 0.52, 1.35)). In patients between 65 and 74 years the median PFS has been prolonged by half a year and the median OS has not been reached yet (Kd vs Vd: 15.6 vs 9.5 months PFS (HR 0.53, 95% CI: 0.38,0.73) and NE vs 37 months OS (HR 0.71 (95% CI: 0.51, 0.98).10
ENDEAVOR subanalyses Posters
Posters are available for download here or can be ordered as slides with Medinfo.

A.R.R.O.W.: the study compared the weekly dose of Kd 70 mg/m2 to the twice weekly dose of Kd 27 mg/m2, a dosage form that is registered only by the FDA in the USA.11
  • Multiple myeloma patients in relapse and/or refractory to their last treatment could be included in their 3rd or 4th therapy line, and they received Carfilzomib in 28-day cycles as Kd70 once-weekly on the days 1, 8 and 15 or as Kd27 on the days 1,2, 8,9 and 15, 16. 78% of the patients were refractory to lenalidomide in their previous therapy lines.
  • Therapy was given until progression or death or treatment intolerance.
  • The primary endpoints have been achieved; Kd70 prolonged median PFS versus Kd27 by 3.6 months (mPFS 11.2 mo (Kd70) vs 7.6 mo (Kd27); HR 0.69).
  • The safety profile of both study arms was comparable with a relatively small rate of adverse events ≥ grade 3 (68% vs 62%), and only in 8% resp. 5% of patients the therapy needed to be discontinued due to therapy-associated side effects.
  • In the frail patient population less «cardiac failures» events of ≥ grade 3 were reported in the Kd70 arm compared to the Kd27 Arm (4% vs. 8%).12
Subanalyses by frailty status, age, and previous therapy are available in the congress section.12-14 The Kd70 once-weekly data arm (A.R.R.O.W.) cannot be compared to Kd56 twice-weekly (ENDEAVOR), as the study population from A.R.R.O.W. was more advanced and with later therapy lines.
    Further subgroup analyses of ASPIRE, ENDEAVOR and ARROW can be found in the congress section.
All subgroup analyses are available as slides with Medinfo.
In a nutshell: both Carfilzomib pivotal studies - ASPIRE and ENDEAVOR - showed that not only the response and the progression free survival could been improved with Carfilzomib, but also that the overall survival could be significantly extended.
Abbreviations: Overall Survival (OS); Progression Free Survival (PFS); month (mo); Hazard Ratio (HR); versus (vs); week (we)
References:
  1. Stewart AK, et al. N Engl J Med 2015;372:142-152
  2. Siegel DS, et al. J Clin Oncol 2018;36(8):728-734
  3. Dimopoulos MA, et al. Blood Cancer J 2017; 7:e554
  4. Mateos MV, et al. ASH 2017 Poster (abstract 1840)
  5. Hari P, et al. Leukemia 2017; 31:2630-2641
  6. Dimopoulos MA, et al. Lancet Oncol 2016;17:27-38
  7. Dimopoulos MA, et al. Lancet Oncol 2017;18:1327-1337
  8. Moreau P, et al. Leukemia 2017;31: 115–22
  9. Weisel K, et al. ASH 2017 Poster (abstract 1850)
  10. Niesvizky R, et al. ASH 2017 Poster (abstract 1885)
  11. Moreau P, et al. Lancet Oncol. 2018 as doi: 10.1016/S1470-2045(18)30354-1.
  12. Mateos MV, et al. 17th International Myeloma Workshop 2019, abstract
  13. Dimopoulos MA, et al. 60th ASH Annual meeting 2018. Abstract and poster
  14. Moreau P, et al. 60th ASH Annual meeting 2018. Abstract and poster

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