ASH 2024: Merck’s new ADC posts positive results in first-line DLBCL

At the American Society of Hematology (ASH) annual meeting on 7 December, Merck and Co. presented results from its Phase II waveLINE-007 trial in first-line diffuse large B-cell lymphoma (DLBCL). The multicentre trial had two arms with two doses of zilovertamab vedotin in combination with rituximab, doxorubicin, cyclophosphamide, and prednisone (R-CHP). Zilovertamab vedotin is an ROR1-targeting antibody-drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload. The standard of care in this setting has historically been the R-CHOP regimen (R-CHP with vincristine). That has recently changed as another ADC, Roche’s Polivy, a CD79b-targeting therapy with an MMAE payload, gained US Food and Drug Administration (FDA) approval in 2023 off the back of positive Phase III data in the POLARIX trial comparing R-Pola-CHP (Polivy in combination with R-CHP) with R-CHOP.

At the data cut-off, 36 patients were enrolled to receive R-CHP in combination with zilovertamab vedotin. Complete response (CR) at the end of treatment (which lasted six or eight cycles) was 100% in the low-dose arm and 93% in the high-dose arm (one patient discontinued treatment due to a physician’s decision and was unable to be evaluated), for an overall CR of 94.4% (95% confidence interval [CI] 81-99%). In comparison, the R-Pola-CHP regimen achieved a CR of 78% in the POLARIX trial while the control arm, R-CHOP, achieved a CR of 74%. The POLARIX trial did cover a more difficult-to-treat population (ECOG score of 0-2, although only 15% had an ECOG score of 2) compared to the waveLINE-007 trial (ECOG score of 0-1). Of patients in the waveLINE-007 trial, 58% experienced grade 3 or higher adverse events (AEs); however, in the lower-dose arm of the trial, 33% of patients experienced grade 3 AEs, comparable to R-Pola-CHP in the POLARIX trial, where 34% of patients had grade 3 or above AEs. The lower dose of zilovertamab vedotin has been chosen for future trials.

With the positive results of the waveLINE-007 trial, Merck and Co. is planning a Phase III trial in first-line DLBCL to compete with the R-Pola-CHP regimen. However, there will be a debate about the appropriate control arm. Both regimens, R-CHOP and R-Pola-CHP, are the standard of care and a matter of the physician’s preference. Merck and Co. is planning to trial its newer ADC against the historical R-CHOP regimen. However, physicians might view the weaker control arm as a lack of confidence in zilovertamab vedotin’s effectiveness compared to Polivy, which would reduce uptake. By the time the data of any Phase III trial matures, R-Pola-CHP will likely have a larger market share in the first-line DLBCL setting than R-CHOP, and the FDA may not look too favourably on the out-of-date control arm. Merck and Co. would do well to use the stronger regimen R-Pola-CHP as the control arm in its upcoming Phase III trial.