A phase 2, randomized trial evaluating the combination of dalantercept plus axitinib in patients with advanced clear cell renal cell carcinoma

Abstract

Background: In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC).

Methods: In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate.

Results: Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group.

Conclusions: Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.

Trial registration: ClinicalTrials.gov NCT01727336.

Keywords: angiogenesis; antiangiogenic agents; chemotherapy; drug therapy; randomized controlled trial; renal cell carcinoma.

Conflict of interest statement

Conflicts of interest:

1. MHV: research funding: BMS and Genentech/Roche; honoraria: Novartis; travel: Eisai, Novartis and Takeda; consulting: Alexion Pharmaceuticals, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, GlaxoSmithKline, Natera, Novartis and Pfizer.

2. RSB: research funding: Acceleron; patent: dalantercept

3. NJV: Speaker for BMS, Exelixis, Roche; consultant to Norvartis, Pfizer and Cerulean

4. MF: honoraria/speaking: Exelixis, Pfizer, Prometheus, Ipsen; data safety monitoring board: Immatics; research funding: Acceleron, Alkermes, BMS, Calithera, Eisai, Merck, Nektar, Pfizer, Prometheus; consulting: Alkermes, Eisai, Novartis, Pfizer

5. RSA: honoraria/speaking: AstraZeneca, Astellas, Eisai, Pfizer, Merck, Genentech, Exelexis, Bayer, BMS, Janssen, Sanofi, Amgen; consulting: Eisai, Pfizer, Astellas

6. BIR: research funding and consulting: Pfizer

7. JTB: research funding (institutional): Alexion, Novartis, Lilly, Genentech, AstraZeneca, Calithera, Pfizer, Acceleron, Janssen, BMS, Merck Serono, Vaccinex, Tesaro, IBM

8. MJ: consulting: Sanofi; research grant: AstraZeneca, Pfizer

9. RH: no disclosures

10. MBA: consulting: BMS, Novartis, Merck, Genentech/Roche, Pfizer, Exelixis, Eisai, Alexion; advisory board: Novartis, Merck, X4 Pharma, Arrowhead

11. EB: honoraria/speaking: Roche, Exelixis, Janssen; consulting/advisory board: Roche, Exelixis, Janssen, Takeda; research funding: Astellas, Pfizer

12. TFL: research funding: Acceleron, Abbott Laboratories, Abraxis BioScience, Amgen, Argos, AstraZeneca, Aveo, Biovex, BMS, Eisai, Lilly, GSK, Roche, Immatics, Merck, Novartis, Pfizer, Synta, Threshold Pharmaceuticals, Millenium, Tracon, Cerulean, EMD Serono, Prometheus Laboratories, Macrogenics, Peloton, Iovance Biotherapeutics, Medimmune; Dynavax; consulting: Prometheus Laboratories

13. DS: no disclosures

14. RP: no disclosures

15. NM: no disclosures

16. XZ: employment and equity through Acceleron

17. CG: employment and equity through Acceleron

18. MLS: employment and equity through Acceleron

19. ERP: research funding: Merck, Novartis, Pfizer, Genentech/Roche, AstraZeneca, BMS, Eli Lilly, Pfizer; consulting: Acceleron, AstraZeneca, BMS, Clovis, Exelixis, Genentech/Roche, Horizon Pharma, Incyte, Inovio, Janssen, Merck, Novartis; DSMB: Eli Lilly, Pfizer

© 2019 American Cancer Society.

Figures

Figure 1:. Trial profile

CONSORT diagram summarizing enrollment and randomization of subjects and discontinuation from study treatment.

Figure 2:. Overall progression-free survival

Data are from the all-treated cohort (all randomized patients who received study drug). Kaplan Meier curves depicting progression-free survival for patients treated with axitinib + dalantercept (blue line) vs. axitinib + placebo (red line). CI=confidence interval. HR=hazard ratio. PFS=progression-free survival.

Figure 3:. Overall survival

Data are from the all-treated set (all randomized patients who received study drug). Kaplan Meier curves depicting overall survival for patients treated with axitinib + dalantercept (blue line) vs. axitinib + placebo (red line). Median follow-up on both arms was 17.8 months at time of analysis. CI=confidence interval. HR=hazard ratio. NE=not estimable. OS=overall survival.