Merck & Co. has shown off data on its ROR1-directed antibody-drug conjugate (ADC), trumpeting a 100% complete response rate but also reporting safety signals that informed the decision to take the low dose into phase 3.
The study evaluated zilovertamab vedotin, the ADC Merck acquired in its $2.75 billion VelosBio buyout four years ago. Investigators enrolled 36 people with previously untreated diffuse large B-cell lymphoma (DLBCL) to receive one of three doses of the ADC on top of cyclophosphamide, doxorubicin, prednisone and rituximab (R-CHP).
All 15 patients who received 1.75 mg/kg of the ADC had a complete response. The complete response rates in the 2-mg/kg and 2.25-mg/kg cohorts were 93.3% and 100%, respectively. However, Merck also saw patients stop treatment after receiving the higher doses.
One of the 15 patients on the middle dose discontinued after the first cycle because of the decision of their physician. A physician also decided to stop the treatment of one of the six patients who received the high dose of the ADC. The authors of the American Society of Hematology (ASH) abstract said a patient discontinued one of the components of R-CHP because of “an all-cause” adverse event.
None of the discontinuations were tied to the ADC, and no patients died of drug-related adverse events. Four patients, including one at the low dose, had serious treatment-related adverse events (TRAEs). The investigators saw grade 3 or 4 TRAEs in 21, or 58%, of the patients. The most common adverse events were neutropenia, nausea, anemia and diarrhea.
The data informed Merck’s decision to advance the low dose of the ADC into a phase 3 trial. The study will compare the combination of the ADC and R-CHP to R-CHOP. The standard of care R-CHOP contains the same four medicines as R-CHP plus the chemotherapy drug vincristine.
About 10% to 15% of patients treated with R-CHOP have an incomplete response or relapse within six months. A further 20% to 25% of patients relapse later, typically within the first two years. The figures set a high bar, with more than 60% of patients being cured by the regimen, which some other candidates have failed to clear but do leave room for a molecule that can provide broader, more durable responses.
Merck was yet to reach the median duration of response (DOR) in its ADC trial as of the data cutoff. The 12-month DOR was 93.5%. Merck’s phase 3 trial is using progression-free survival as its primary endpoint and is assessing complete response at the end of treatment and overall survival as secondary endpoints.
The phase 3 trial could validate an approach that has attracted the attention of multiple drugmakers. Boehringer Ingelheim took a ROR1 ADC candidate into the clinic in 2020 but terminated the trial after enrolling 12 patients. Ipsen entered the race in April by committing $90 million in near-term payments to Sutro Biopharma.
Merck’s ASH abstract says lymphoid cancers are responsive to ADCs that deliver monomethyl auristatin E (MMAE). Zilovertamab vedotin has a MMAE payload. STRO-003, the candidate licensed by Ipsen, uses the topoisomerase I inhibitor exatecan.