Merck Advances ROR1-Directed ADC in Lymphoma Treatment

Merck & Co. has made significant strides in the development of zilovertamab vedotin, a ROR1-directed antibody-drug conjugate (ADC), for the treatment of diffuse large B cell lymphoma (DLBCL). Recent phase 2 data highlights both the potential and challenges of this innovative therapy.

Phase 2 Results Show Promise and Pitfalls

In a phase 2/3 study involving 40 patients with relapsed or refractory DLBCL, Merck tested three dosage levels of zilovertamab vedotin in combination with standard rituximab and gemcitabine-oxaliplatin therapy. The middle dose of 1.75 mg/kg emerged as the most promising, demonstrating an overall response rate of 56.3% and a median duration of response of 8.7 months at a median follow-up of 9.9 months.

Interestingly, increasing the dosage to the highest level did not significantly improve efficacy, with a 57.1% response rate observed. However, the high-dose arm had not yet reached the median duration of response after 9.3 months of follow-up.

Safety Concerns Guide Dose Selection

The selection of the middle dose for further development was largely influenced by safety and tolerability data. At the highest dose, three out of seven patients discontinued treatment due to adverse events, including treatment-related sepsis and respiratory failure. In contrast, the middle dose showed a lower discontinuation rate, with only one patient dropping out due to a physician's decision and seven due to disease progression.

Dose-limiting toxicities were observed across all three dosage levels, with the middle-dose cohort experiencing a grade 3 increase in liver enzyme and a case of intestinal obstruction. The high-dose group saw multiple grade 3 and 4 adverse events, underscoring the delicate balance between efficacy and safety in ADC development.

Merck's Strategic Approach to ADC Development

This latest data builds on Merck's previous decision to advance the 1.75 mg/kg dose in patients with previously untreated DLBCL, following observations of discontinuations at higher doses. The company is now conducting phase 3 trials in both previously untreated and relapsed or refractory DLBCL populations.

Merck's investment in zilovertamab vedotin stems from its $2.75 billion acquisition of VelosBio, highlighting the pharmaceutical giant's commitment to expanding its oncology portfolio. As the ROR1-directed ADC landscape evolves, Merck faces competition from other industry players, including Ipsen's recent partnership with Sutro Biopharma in the ROR1 space.