Subgroup analyses presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition held in San Diego, CA, support the clinical benefit of brentuximab vedotin (Adcetris; Pfizer) in heavily pretreated patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
Subgroup analyses data from the phase 3 ECHELON-3 trial (NCT04404283) continue to support the investigational triplet of brentuximab vedotin (BV) plus lenalidomide and rituximab (R) across subgroups compared with the doublet of lenalidomide and rituximab (R2) alone in patients with relapsed or refractory DLBCL who are ineligible for hematopoietic stem-cell transplant or CAR T-cell therapy.1-3
In one of the studies presented at the ASH meeting, investigators analyzed the safety and efficacy of the BV plus R2 regimen in a subgroup of patients aged ≥65 years. Previously reported results included data from patients between the ages of 21 and 89 years.1
More than half of the 230 patients enrolled in the overall ECHELON-3 study were included in this subgroup of data (n=155; median age, 75 years [range, 65-89]), with 79 of these patients randomly assigned to the triplet, and 76 to the doublet regimen.
Consistent with the interim analysis of the overall study population,4 this analysis revealed improvements in all key outcomes for the triplet versus the doublet regimen. At a 16.8-month median follow-up, median overall survival (OS) was 15.9 months versus 8.5 months (hazard ratio [HR], 0.540; 95% confidence interval [CI], 0.351-0.830; P=.0043), median progression-free survival (PFS) was 5.7 months versus 2.8 months (HR, 0.478; 95% CI, 0.318-0.718; P=.0003), overall response rate (ORR) was 70.9% versus 46.1% (P=.0020), and complete response (CR) rate was 45.6% versus 19.7%, respectively. The median time to CR was the same for both cohorts, at 1.61 months, but the median duration of CR differed, at 18.9 months (95% CI, 12.4-not estimable [NE]) for the triplet treatment versus 5.4 months (95% CI, 2.8-NE for the doublet (HR, 0.416; 95% CI, 0.139-1.250).
Certain adverse events were higher in the triplet versus the doublet groups, with grade ≥3 treatment-emergent adverse events (TEAEs) in 89% versus 76% of patients, serious TEAEs in 62% versus 47%, and TEAE-related study treatment discontinuation in 20% versus 8%, respectively. In addition, more patients (39%) receiving the triplet had peripheral neuropathy compared with the doublet group (27%), but most of these cases were grade 1.
The ECHELON-3 investigators also analyzed outcomes of the triplet therapy versus doublet therapy in subgroups of patients with relapsed or refractory DLBCL with 2 previous lines of therapy, refractory disease, or previous treatment with CAR T-cell therapy.2 Patients in the analyses could be included in ≥1 of the subgroups, but were analyzed separately.
The subgroup with 2 previous lines of therapy comprised more than one-third of patients in the overall ECHELON-3 study group (94 of 230), with 48 patients randomly assigned to receive BV plus R2 and 46 to R2 alone. Outcomes were improved for the triplet versus the doublet, with median OS nearly doubled at 16.3 months versus 8.5 months, respectively; a more-than-doubled median PFS of 7.1 months versus 2.7 months; an ORR of 68.8% versus 43.5%; and a CR rate of 52.1% versus 13.0%, respectively.
More than half (n=194) of the overall study population (n=230) comprised the subgroup with disease refractory to the most recent systemic therapy, with 98 patients randomized to the triplet and 96 to the doublet. BV plus R2 consistently showed improvement across efficacy outcomes versus the doublet (median OS, 11.7 vs 5.5 months; median PFS, 4.1 vs 1.5 months; ORR, 59.2% vs 29.2%; CR rate, 34.7% vs 11.5%).
The patients who previously received CAR T-cell therapy (n=67) comprised a smaller subgroup but also saw impressive improvements in outcomes. The median OS for patients in the BV plus R2 group (n=32) was 15.6 months versus 4.4 months for the R2 group (n=35), median PFS was 3.0 months versus 1.4 months, ORR was 65.6% versus 25.7%, and the CR rate was 37.5% versus 11.4%, respectively.
A third set of subgroup analyses focused on durability of CRs, with results favoring the combination of BV plus R2 versus placebo plus R2.3 The 67 patients in these subgroup analyses had a best overall response (BOR) of CR.
In the triplet group, 40.2% (45 of 112) of the patients had a BOR of CR versus 18.6% (22 of 118) of the doublet group. For the triplet versus doublet, respectively, the median duration of CR was 18.9 months (95% CI, 11.1-NE) versus not reached (NR; HR, 0.527; 95% CI, 0.200-1.389; P=.1891), and the median time to CR was 1.58 months (range, 1.2-7.3) versus 1.61 months (range, 0.7-4.6).
At a median 14.3-month follow-up, the median OS in this subgroup was 31.5 months (95% CI, 20.3-NE) for BV plus R2 versus NR for placebo plus R2 (HR, 1.044; 95% CI, 0.331-3.298; P=.9407). The triplet group had a median PFS of 21.5 months (95% CI, 12.6-NE) versus NR (95% CI, 5.4-NE) in the doublet group (HR, 0.6333; 95% CI, 0.256-1.567; P=.3198). The NR results in the doublet group “are likely attributable to limited follow-up and small sample size,” the investigators noted.3
Fewer patients in the BV plus R2 group (6.7%) than in the placebo plus R2 group (22.7%) received subsequent systemic anticancer therapy, with BV more than doubling the CR rate versus placebo.
Based on these CR subgroup analyses, investigators called BV plus R2 a “promising option” for complete and durable responses in patients with relapsed or refractory DLBCL receiving third- or later-line therapy.
Previously reported results from ECHELON-3 demonstrated OS benefit in a patient population with relapsed or refractory DLBCL who have received ≥2 previous lines of systemic therapy.
References
- Bartlett NL, Kim JA, Hahn U, et al. Outcomes in older patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) from the ECHELON-3 study. Blood. 2024;144(suppl 1):4483-4485.
- Hahn U, Bartlett NL, Kim JA, et al. Outcomes by refractory status and prior therapies received in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) from the ECHELON-3 study. Blood. 2024;144(suppl 1):4489-4490.
- Yasenchak C, Bartlett NL, Kim JA, et al. Durability of complete responses in patients from the ECHELON-3 study. Blood. 2024;144(suppl 1):3101-3102.
- Kim JA, Hahn U, Kim WS, et al. Brentuximab vedotin in combination with lenalidomide and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma: results from the phase 3 ECHELON-3 study. J Clin Oncol. 2024;42(17 suppl):Abstract LBA7005.