Switzerland-based ADC Therapeutics SA (NYSE: ADCT) reported that a regimen of its CD19-targeted antibody drug conjugate (ADC) loncastuximab tesirine-lpyl (Zynlonta) combined with rituximab met the primary endpoint of progression-free survival in the Phase III LOTIS-5 confirmatory trial, focused on patients with relapsed or refractory diffuse large B-cell lymphoma. Although the trial outcome was positive, the benefit was accompanied by higher rates of serious adverse events, including a notable imbalance in serious and fatal adverse events compared with standard salvage chemotherapy. ADC nevertheless plans to use the data to support a supplemental regulatory filing aimed at converting Zynlonta's existing accelerated approval into full approval status.
LOTIS-5 is a randomized, open-label, multicenter study comparing Zynlonta plus rituximab against rituximab, gemcitabine, and oxaliplatin (R-GemOx) in patients with r/r DLBCL after one or more prior lines of systemic therapy. The trial enrolled patients who could not access or had progressed on CAR-T or other complex therapies.
The combination demonstrated a statistically significant improvement in PFS per independent review committee (HR 0.73; p = 0.008), with a median PFS of 6.1 months versus 4.7 months for R-GemOx. On the key secondary endpoint of overall survival, the hazard ratio of 0.96 indicated no detrimental effect, though the company noted that earlier and more frequent switching to subsequent therapies in the control arm likely compressed the OS signal. Response depth favored the Zynlonta arm: overall response rate was 58.1% versus 45.2%, complete response rate was 39.5% versus 26.7%, and — perhaps most clinically relevant — 48.5% of patients achieving a complete response remained in CR at 24 months, compared with 16.7% in the R-GemOx arm.
The safety profile warrants careful interpretation. Serious adverse events occurred in 49.0% of patients on the Zynlonta combination versus 34.5% on R-GemOx, and Grade 5 treatment-emergent adverse events were observed in 13.2% of the Zynlonta arm (27 patients) compared with 4.6% (9 patients) in the control arm. The company emphasized that the majority of Grade 5 events in the Zynlonta arm occurred in patients aged 75 or older, and that the longer adverse event observation window in the test arm — driven by earlier switching to subsequent therapies in the control arm — contributed to the higher reported rates. Grade ≥3 hematologic toxicity was actually lower in the Zynlonta arm (40.7% versus 59.4%), while infection, hepatotoxicity, and edema/effusion were higher. Treatment discontinuation due to adverse events occurred in 25.5% of patients on Zynlonta plus rituximab versus 9.1% on R-GemOx — a difference the company will need to contextualize carefully in its benefit-risk discussion with the US FDA.