Adding Adcetris (brentuximab vedotin) to Revlimid (lenalidomide) and Rituxan (rituximab) significantly improved survival and response rates versus Revlimid/Rituxan alone in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) treated with at least two prior lines of systemic therapy, as demonstrated in data from the phase 3 ECHELON-3 study presented during the 2024 SOHO Annual Meeting.
As presented at the 2024 ASCO Annual Meeting, at a median follow-up of 15.5 months for the Adcetris regimen (112 patients) and 18.9 months for Revlimid/Rituxan alone (118 patients), the median overall survival (OS; the time from the start of treatment when a patient with cancer is still alive) was 13.8 months versus 8.5 months, respectively, meeting the trial’s primary endpoint.
The triplet (Adcetris plus Revlimid/Rituxan) also resulted in a 47% reduction in the risk of disease progression or death versus the doublet (Revlimid/Rituxan alone). At a median follow-up of 11.1 months for the triplet and 8.8 months for the doublet, the median progression-free survival (PFS; how long a person lives without their disease getting worse) for the respective regimens was 4.2 months and 2.6 months. Notably, the OS and PFS benefits achieved with the Adcetris regimen continued across the several key subgroups that researchers analyzed.
The combination of drugs elicited an objective response rate (ORR; the percentage of people whose disease shrinks or disappears after treatment) of 64.3% versus 41.5% with the doublet; the respective complete response (CR; disappearance of all signs of cancer as a response to treatment) rates were 40.2% and 18.6%.
Study Highlights:
- The combination of Adcetris, Revlimid and Rituxan significantly increased overall survival compared with Revlimid/Rituxan alone in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
- The triplet therapy also reduced the risk of disease progression or death compared with the doublet therapy.
- The combination of drugs led to higher overall response rates, including a higher rate of complete responses.
- The benefits of Adcetris plus Revlimid/Rituxan were observed across different subgroups of patients, regardless of CD30 expression.
- This triplet therapy could be a promising option for patients with relapsed/refractory DLBCL, especially those who are not eligible for or have relapsed after other treatments like CAR T-cell therapy or bispecific antibodies.
The ORR improvement with the addition of Adcetris was observed irrespective of CD30 expression (a protein involved in cancer cell growth and survival). In those who were CD30 negative, the triplet (76 patients) elicited an ORR of 60.5% with the doublet (80 patients). In those who were CD30 positive, the respective ORRs with the triplet (36 patients) and doublet (38 patients) were 72.2% and 50%.
“This triplet combination, with its promising OS benefit, has the potential to address the high unmet need of patients with relapsed/refractory DLBCL, particularly those who are not able to receive CAR T-cell therapy or bispecific antibodies or who have relapsed/refractory disease following these treatments,” Dr. Christopher A. Yasenchak, said in an oral presentation of the data.
The randomized, phase 3 ECHELON-3 study enrolled patients with relapsed/refractory DLBCL who had received at least two prior lines of therapy. These patients were at least 18 years of age; had an ECOG performance status of 0 to 2 (0 meaning fully active and 2 meaning restricted in work activity); and fluorodeoxyglucose-avid (cancer cells that use a lot of sugar), measurable disease. They could not have been candidates for, or experienced disease relapse after, hematopoietic stem cell transplant or CAR T-cell therapy. If they had prior exposure to Adcetris or Revlimid, active cerebral or meningeal disease (disease affecting the brain or its protective coverings), or grade 2 or higher (considered moderate or worse) peripheral neuropathy (damage to the nerves outside of the brain and spinal cord), they were excluded.
Study participants were randomly assigned to receive intravenous Adcetris every three weeks or placebo (Revlimid/Rituxan alone) paired with oral Revlimid once daily and IV Rituxan every three weeks.
The primary focus of the study was OS. Secondary end points included PFS and ORR; CR rate; duration of response (DOR; the length of time a person's disease continues to respond to treatment); OS in the CD30-positive population; and safety and tolerability.
Of the total 230 patients who underwent randomization, 112 were assigned to the triplet arm and 118 were assigned to the doublet arm; 112 and 116 patients, respectively, comprise the safety population. At the time of presentation, 22 patients were still receiving the triplet and 14 patients were still receiving the doublet. The median duration of treatment with the Adcetris regimen was 3.6 months versus two months with Revlimid/Rituxan alone.
Subgroup analysis revealed that the median OS was longer with Adcetris plus Revlimid/Rituxan versus Revlimid/Rituxan alone across subgroups, including age, CD30 expression, cell of origin, previous CAR T-cell therapy, baseline International Prognostic Index (IPI) score (which can predict overall and progression-free survival in patients based on certain risk factors), status after last therapy, region, and whether they had double/triple-hit lymphoma.
Median PFS was also longer with the triplet versus the doublet across the subgroups, including age, CD30 expression, cell of origin, prior CAR T-cell therapy, baseline IPI score, status after last therapy, region, and double-/triple-hit lymphoma.
The median DOR with the triplet was 8.3 months versus three months with the doublet. In those who experienced a CR with the triplet or doublet, the median DOR was 18.9 months and not reached, respectively. Of note, when a median DOR is not reached in a trial, this means that at least half of the patients have not experienced disease progression or died. The median time to CR onset was 1.58 months with Adcetris versus 1.61 months without.
No new side effects were observed with the addition of Adcetris to Revlimid/Rituxan, Yasenchak noted. Any-grade side effects related to treatment occurred in 97% of patients in both arms; severe or worse side effects related to treatment occurred in 88% versus 77% of patients. Death from a treatment-related side effect occurred in 12% of those who received the Adcetris regimen versus 8% of those given the placebo arm.
The most common side effects from treatment reported in the triplet and doublet arms were neutropenia (lower-than-normal number of neutrophils [a type of white blood cell] in the blood), thrombocytopenia (lower-than-normal number of platelets in the blood), diarrhea, anemia, fatigue, COVID-19, weakness, constipation, reduced appetite, pneumonia, cough, fever, nausea, and itching. Any-grade peripheral neuropathy (nerve pain, numbness, tingling, swelling or muscle weakness) occurred in 31% of those given the Adcetris triplet and 24% of those given the doublet.
“AEs [adverse events; unwanted or harmful effects that occur as a result of a medical treatment] were manageable with dose modifications and consistent with the known safety profile of each individual drug,” Yasenchak said.
Subsequent anticancer therapies received were well balanced across the groups; 34% of those in the Adcetris arm and 47% of those in the placebo arm received subsequent treatment. The most common reason for doing so in the Adcetris arm was progressive disease (when a disease gets worse over time despite treatment) (27%), followed by relapsed disease (when a disease returns after a period of remission [when the disease is under control]) (5%) and other (4%). The most common reasons in the placebo arm were progressive disease (38%), other (7%), relapsed disease (4%), and secondary malignancies (cancerous growths) (2%). In the Adcetris arm, subsequent treatment included anti-CD20 therapy (8%), antibody-drug conjugates (antibodies linked to a cytotoxic drug, which can deliver the drug directly to cancer cells) (6%), bispecific antibodies (antibodies that bind to two different targets to help the immune system attack the tumor) (4%), CAR T-cell therapy (4%), Monjuvi (tafasitamab; 4%), or other (11%); these respective rates in the placebo arm were 9%, 5%, 9%, 4%, 1%, and 23%.
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