Five-year follow-up of the AETHERA phase III trial: brentuximab vedotin for cHL patients

On 28 September 2018, Dr Craig H. Moskowitz from the Sylvester Comprehensive Cancer Center, University of Miami Health System, Florida, US, and colleagues, published in Blood the five year follow-up results from the phase III trial AETHERA (NCT01100502). Results of that global randomized study demonstrated that brentuximab vedotin (BV) significantly improves progression-free survival (PFS), as compared to placebo plus best supportive care alone, in adults with classical Hodgkin lymphoma (cHL) at high risk of relapse or progression following autologous hematopoietic stem cell transplant (auto-HSCT).

At five-years follow-up, the authors sought to examine whether BV was still efficacious and safe for adult cHL patients who fail to be cured by auto-HSCT. The primary outcomes of the study included PFS and safety, with a specific focus on the incidence of neuropathy.

Study overview

• Eligible cHL patients needed to be BV-naïve, must have received auto-HSCT before randomization and have been at high risk of relapse after auto-HSCT
• N = 329 patients randomized to receive BV (n = 165) or placebo (n =164)
• Intravenous BV (1.8 mg/kg) or placebo was administered once every three weeks for up to 16 cycles (start date 30−45 days post auto-HSCT)
• In the initial AETHERA trial, PFS by independent review was significantly improved in BV than placebo patients (HR = 0.57; 95%, CI 0.40−0.81; P = 0·0013), while median PFS was 42.9 months (95% CI, 30.4−42.9) for patients in the BV group versus1 months (11.5−not estimable) for those in the placebo group

Key findings

• At the five-year data cut off (November 2017), patients initially randomized to BV continued to have a significantly longer PFS than those in the placebo arm.
• Median 5-year PFS: BV: not reached versus placebo: 15.8 months
• Five-year PFS rate: BV: 59% (95% CI, 51−66) versus 41% (95% CI, 33−49) [HR =0.521; 95% CI, 0.379−0.717]
• At the three-, four- and five-year follow-up, patients receiving BV presented with a reduction in PFS events of 30%, 28% and 30%, respectively, when compared to the placebo group
• BV benefit was more pronounced in patients with pre-auto-HSCT risk factors
• In general, significantly fewer patients in the BV arm received further anti-cancer therapy (32%, n = 53) than those in the placebo arm (54%, n = 89; P < 0.0001)
• Interestingly, 87% of the placebo patients, received BV monotherapy later on as subsequent therapy
• Overall survival analysis is not planned until 2020

Safety

• At the 5-year data cut off:
  • Reported deaths in the BV and placebo groups were 40 and 37, respectively
  • Patients who received ≥ 2 subsequent therapies for HL or died in the BV and placebo groups were 36% and 46%, respectively (HR = 0.656; 95% CI, 0.467−0.922)
  • The need for subsequent auto-HSCT was lower in the BV (12%) than the placebo group (21%)
• At the latest follow-up, in 90% of patients in the BV arm, peripheral neuropathy (PN) resolved or improved and in 73% resolved completely
• Median time to PN resolution in the BV group was 37.6 weeks, compared to 9.1 weeks in the placebo group
• Secondary malignancies excluding PN in the BV arm occurred in 6 patients:
  • Myelodysplastic syndromes (n = 2), acute myelogenous leukemia (n =1), pancreatic, lung, and bladder cancer (n = 1 each)
• Secondary malignancies excluding PN in the placebo arm occurred in 3 patients:
  • Mantle cell lymphoma, acute myelogenous leukemia, and myelodysplastic syndromes in the placebo arm (n = 1 each)

Conclusion

The authors concluded that even five years after the first patient randomization, BV treatment maintained its initial efficacy and tolerability when treating cHL patients with high risk of relapse or progression after auto-HSCT.