ADC Therapeutics' LOTIS-5 Trial Meets PFS Endpoint but Safety Concerns Cloud Zynlonta Combination in DLBCL
核心洞察
The Phase 3 LOTIS-5 trial met its primary endpoint with ZYNLONTA plus rituximab showing statistically significant PFS improvement over R-GemOx (HR=0.73, p=0.008) in relapsed/refractory DLBCL.
Grade 5 treatment-emergent adverse events were higher in the ZYNLONTA arm (13.2%) versus the control arm (4.6%), with the majority of deaths occurring in patients aged 75 years or older.
ADC Therapeutics plans a pre-sBLA meeting with the FDA in August 2026 and a supplemental Biologics License Application submission in Q4 2026.
ADC Therapeutics announced topline results from its Phase 3 LOTIS-5 confirmatory trial, revealing that ZYNLONTA (loncastuximab tesirine-lpyl) in combination with rituximab met its primary endpoint of progression-free survival (PFS) in patients with relapsed or refractory diffuse large B-cell lymphoma (搜索) (r/r DLBCL). However, elevated rates of Grade 5 adverse events in the experimental arm triggered a sharp market reaction, with shares falling more than 50% following the disclosure.
Trial Design and Efficacy Results
LOTIS-5 is a randomized, open-label, two-arm, multicenter study comparing ZYNLONTA plus rituximab against standard immunochemotherapy with rituximab plus gemcitabine-oxaliplatin (R-GemOx) in patients with r/r DLBCL after one or more lines of systemic therapy.
The study met its primary endpoint with statistical significance, demonstrating a hazard ratio of 0.73 for PFS per independent review committee (p=0.008, two-sided). Median PFS was 6.1 months for the ZYNLONTA-rituximab combination versus 4.7 months for R-GemOx, representing a 27% improvement.
Overall response rate (ORR) favored the ZYNLONTA arm at 58.1% compared to 45.2% for the control. The complete response (CR) rate was 39.5% versus 26.7%, with median duration of response (DOR) of 9.2 months versus 7.7 months. Notably, median duration of complete response (DoCR) reached 16.8 months for ZYNLONTA plus rituximab compared to 12.3 months for R-GemOx. Among patients achieving CR, 48.5% in the ZYNLONTA arm remained in CR at 24 months versus 16.7% in the control arm.
Overall survival showed no detrimental effect with the ZYNLONTA combination (HR=0.96), though the company noted this was impacted by earlier use and a higher rate of new anti-lymphoma treatment switching in the control arm.
Safety Profile Raises Concerns
Overall treatment-emergent adverse event (TEAE) rates were similar between arms (98.5% vs. 97.5%). However, serious adverse events (SAEs) were higher in the ZYNLONTA plus rituximab arm at 49.0% compared to 34.5% in the control arm.
Grade ≥3 TEAEs observed in more than 5% of patients included hematologic events (40.7% vs. 59.4%), infections/infestations (24.5% vs. 15.7%), hepatotoxicity (17.2% vs. 8.1%), and edema/effusion (7.4% vs. 0.5%) for ZYNLONTA plus rituximab versus R-GemOx, respectively.
The most concerning finding was the rate of Grade 5 TEAEs: 27 patients (13.2%) in the ZYNLONTA plus rituximab arm versus 9 patients (4.6%) in the R-GemOx arm. The majority of Grade 5 TEAEs in the test arm occurred in patients aged 75 years or older. TEAEs leading to any drug withdrawal were also higher in the ZYNLONTA arm (25.5% vs. 9.1%).
ADC Therapeutics noted that the TEAE reporting window was defined as 105 days after the last dose of study treatment or the start of new anticancer therapy, whichever was earlier. The company attributed the disparity in TEAE rates partly to a longer overall TEAE observation time in the test arm versus the control arm, driven by a higher rate of and earlier switching to subsequent therapies in the control arm.
Regulatory Path Forward
"In the context of a positive study, based on the totality of the data, we plan to discuss the benefit-risk profile of this combination with the U.S. FDA as we prepare for the planned supplemental Biologics License Application (sBLA) filing," said Ameet Mallik, Chief Executive Officer of ADC Therapeutics.
Mohamed Zaki, MD, PhD, Chief Medical Officer of ADC Therapeutics, indicated the company intends to conduct a pre-sBLA meeting in August 2026 and is preparing for a planned sBLA submission in the fourth quarter of 2026.
Mehdi Hamadani, MD, Professor of Medicine at Medical College of Wisconsin and principal investigator for the trial, noted: "LOTIS-5 was designed to address a clear unmet need in r/r DLBCL in patients who cannot access or who progress on a CAR-T or other complex therapies. Based on these results, I believe this combination may provide an additional option in treating relapsed or refractory DLBCL."
Market Context
ZYNLONTA received accelerated approval from the FDA in 2021 for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, based on response rates in the LOTIS-2 study. The LOTIS-5 trial serves as the confirmatory study required to convert this accelerated approval to full approval, while also aiming to move ZYNLONTA into the second-line setting—a market ADC Therapeutics has estimated at approximately $3 billion in the U.S. alone. Sales of ZYNLONTA were just under $74 million in the prior year.
It is worth noting that ADC Therapeutics discontinued a separate trial of ZYNLONTA in previously untreated DLBCL (LOTIS-9) in 2023 after several deaths, which may have heightened sensitivity to safety signals in the current readout. Analysts suggested the deaths could overshadow the PFS results, and the safety trade-off may make it harder for ADC Therapeutics to build a position for the drug earlier in treatment, if approved, and may not be strong enough to convert later-line use to full approval.
The company also stated it will continue to evaluate a broad range of value-maximizing alternatives, including near-term cost reduction initiatives.