ECHELON-3: Brentuximab vedotin ticks another box on the lymphoma treatment board

A triplet regimen comprising the anti-CD30 antibody-drug conjugate (ADC) brentuximab vedotin (BV) plus lenalidomide and rituximab (R²) inches its way into the R/R DLBCL* treatment path in the prespecified interim analysis of the ECHELON-3 trial, further reinforcing the role of BV in lymphoma treatment.

Approved in the US as monotherapy or in combination with chemotherapy for the treatment of seven** lymphomas, BV now tackles R/R DLBCL – a type of lymphoma with a high unmet need. [https://www.pfizer.com/news/press-release/press-release-detail/pfizers-adcetrisr-regimen-produces-clinically-meaningful]

When added to the R² regimen, BV conferred statistically significant and clinically meaningful improvements in overall survival (OS; median 13.8 vs 8.5 months; hazard ratio [HR], 0.63; p_log-rank=0.0085) and progression-free survival (PFS; median 4.2 vs 2.6 months; HR, 0.53; p_log-rank<0.0001). For OS, the prespecified efficacy boundary was crossed.

“ECHELON-3 is the first randomized, placebo-controlled, phase III study to demonstrate an OS benefit in a contemporary population of patients with R/R DLBCL who have received ≥2 prior lines of systemic therapy,” said Dr Jeong-A Kim from St Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea, during her presentation at ASCO 2024.

The OS and PFS benefits were consistently seen across the evaluated subgroups, especially among participants who had received prior CAR*** T-cell therapy (median OS, 15.6 vs 4.4 months; HR, 0.38) and those who had relapsed following their last prior treatment (median PFS, 15.1 vs 5.6 months; HR, 0.29). [ASCO 2024, abstract LBA7005]

“Importantly, the OS benefit was seen in meaningful high-risk disease subsets, such as those with a high IPI^# score, advanced age, non-germinal centre phenotype, and those with prior CAR [T-cell] exposure,” said discussant Dr Peter Riedell from the University of Chicago in Illinois, US, at ASCO 2024.

Moreover, overall response rate (ORR) was significantly higher in the BV vs placebo arm overall (64 percent vs 42 percent; p=0.0006) and among those who were CD30-negative (60 percent vs 38 percent; p=0.0063) and CD30-positive (72 percent vs 50 percent; p=0.0602). Across these groups, about 40 percent of ORRs with BV were complete responses, as opposed to only about 20 percent in the placebo arm.

Manageable AEs

Neutropenia was the most common treatment-emergent adverse event (TEAE) in both arms. Compared with the placebo arm, the BV arm had higher incidences of grade ≥3 TEAEs (88 percent vs 77 percent), grade 5 TEAEs (12 percent vs 8 percent), and any-grade peripheral neuropathy TEAEs (31 percent vs 24 percent). Kim however pointed out that most of the neuropathy cases were grade 1.

“There were no new safety signals with the addition of BV to R² … Overall, BV plus R² was tolerable, demonstrated by the high relative dose intensity for BV of nearly 95 percent,” Kim said. “The AEs were manageable with dose modifications and consistent with the known safety profile of each drug.”

At end of treatment, a third of participants in the BV arm received any subsequent therapy^##; nearly half did in the placebo arm. The most common reason for subsequent therapy was disease progression.

High unmet need

DLBCL is the most frequent type of lymphoma that is aggressive and difficult to treat, with over a third of patients having disease progression following frontline treatment. [https://www.ncbi.nlm.nih.gov/books/NBK557796; https://www.lls.org/research/diffuse-large-b-cell-lymphoma-dlbcl, accessed June 20, 2024]

Riedell noted that R-CHOP^###, one of the two standards of care for DLBCL, does not serve all patients equally. “The curability of R-CHOP diminishes, as patients acquire some high-risk features such as high IPI, advanced age, non-germinal centre cell of origin, along with the double-expressor (DE) phenotype.”

“DE lymphoma is [a type of] lymphoma with increased expression of both MYC and BCL2 … but importantly, without the gene arrangements. This is seen in approximately 20–30 percent of DLBCL patients, and it is an indicator of poor prognosis,” Riedell added.

“Despite recent advances, including T-cell directed therapies, there remains a high unmet need for readily available and tolerable regimens for patients with later-line DLBCL,” Kim said, noting that the current real-world OS rate in the third-line setting or beyond is less than a year. [Adv Ther 2024;41:1226-1244; Cancer Med 2024;13:e7173]

Kim and colleagues included R/R DLBCL patients who had received ≥2 prior lines of therapy who were ineligible to receive, or relapsed after, hematopoietic stem cell transplantation or CAR T-cell therapy. A total of 230 participants (median age 72 years, 56 percent men, 26 percent Asian) were randomized 1:1 to receive IV BV 1.2 mg/kg Q3W or placebo on top of oral lenalidomide 20 mg daily and IV rituximab 375 mg/m² Q3W.

Nearly all patients received anthracycline and anti-CD20 antibodies as prior systemic therapies. More than half of participants had DLBCL not otherwise specified while a quarter had transformed DLBCL. Over 80 percent were refractory to their last prior DLBCL therapy.

An encouraging Tx option

“This triplet combination, with its promising OS benefit, has the potential to address the high unmet need in patients with R/R DLBCL, particularly those who are not able to receive CAR T-cell therapy or bispecific antibodies, have relapsed, or whose disease has remained refractory following these treatments,” Kim said.

“[Hence,] this triplet regimen represents a novel treatment option for patients with heavily pretreated R/R DLBCL,” she concluded.

Also, Riedell underlined that the characteristics of the study participants are reflective of real-world clinical practice. “This may represent an encouraging treatment [alternative] in CAR T transplant- or bispecific ineligible-patients due to factors like access issues, comorbidities, and prior treatment exposure.”

“Questions do remain regarding the long-term safety and duration of response with this therapy,” Riedell added.