Merck & Co. has posted phase 2 data on zilovertamab vedotin in lymphoma, providing more evidence of the narrow safety and efficacy window that is open to the ROR1-directed antibody-drug conjugate (ADC).
The first part of the phase 2/3 study enrolled 40 people with relapsed or refractory diffuse large B cell lymphoma (DLBCL). Participants received one of three doses of zilovertamab vedotin in combination with standard of care rituximab and gemcitabine-oxaliplatin. In light of the data, Merck has moved the middle dose into the phase 3 portion of the trial.
At a median follow-up of 9.9 months, Merck reported an overall response rate of 56.3% on the middle dose of 1.75 mg/kg. The median duration of response was 8.7 months. Increasing the dose had little effect on response rate, with 57.1% of people responding to the high dose. The high-dose arm was yet to reach the median duration of response after 9.3 months of follow-up.
Safety and tolerability data informed the selection of the middle dose. On the high dose, three of the seven patients stopped taking the ADC because of adverse events, namely treatment-related sepsis and respiratory failure. A fourth patient dropped out based on the decision of the physician. The other three people completed treatment.
The discontinuation rate because of adverse events was lower on the middle dose. Eight of the 16 people taking 1.75 mg/kg of the ADC completed treatment. Seven patients discontinued because of disease progression. One person dropped out based on the physician’s decision.
Merck saw seven dose-limiting toxicities across the three doses. In the middle-dose cohort, one patient had a grade 3 increase in a liver enzyme and one person had intestinal obstruction. Merck saw a grade 4 case of febrile neutropenia, a serious condition in which a patient with low white blood cells develops a fever, on the low dose. There were multiple grade 3 and 4 adverse events on the high dose.
The drugmaker has needed to balance the pursuit of higher efficacy against safety and tolerability issues as it has selected its phase 3 doses. Last year, Merck picked 1.75 mg/kg as the phase 3 dose in patients with previously untreated DLBCL after seeing discontinuations at two higher doses.
Merck is running phase 3 trials in previously untreated and relapsed or refractory DLBCL as it seeks to generate a return on an asset it acquired in its $2.75 billion VelosBio buyout.
Last year, Ipsen joined Merck in the ROR1 race by striking a deal with Sutro Biopharma. In 2023, Boehringer Ingelheim terminated a phase 1 trial of its contender.