Loncastuximab tesirine

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. Loncastuximab tesirine is a CD19-directed antibody-drug conjugate that delivers a pyrrolobenzodiazepine payload, inducing DNA crosslinking and cell death in CD19-expressing B-cells. The drug received an accelerated FDA approval in 2021 for r/r DLBCL. In the crowded r/r DLBCL space, it competes most directly with other non-CAR-T options including Genentech’s Polivy (polatuzumab vedotin), which received full FDA approval in 2023, and the CD3×CD20 bispecific antibodies Genmab and AbbVie’s Epkinly (epcoritamab) and Genentech’s Columvi (glofitamab), both granted accelerated approval in 2023 for patients after two or more prior lines. Pfizer’s Adcetris (brentuximab vedotin) in combination with lenalidomide and rituximab has also entered the DLBCL space based on the ECHELON-3 trial. What LOTIS-5 does establish is that the Zynlonta-rituximab combination can deliver a statistically significant PFS benefit over a standard salvage chemotherapy backbone in patients who lack access to cellular therapies — a population that remains large globally. ADC plans a pre-sBLA meeting with the FDA in August 2026 and a supplemental BLA submission in Q4 2026, with conversion from accelerated to full approval contingent on the agency’s benefit-risk assessment of the complete dataset. This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: https://allsci.com/news/ Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Privacy Terms About Us Copyright © 2026. AllSci Corp. All rights reserved.

ADC Therapeutics said its blood cancer drug met the main goal of a confirmatory trial, but the experiment recorded more deaths among patients treated with the drug, sending shares down more than 50% Thursday morning.The Switzerland-based company unveiled data from its Phase 3 trial testing an antibody-drug conjugate called Zynlonta in combination with the medicine rituximab among people with a type of hard-to-treat blood cancer. The pairing extended progression-free survival in trial participants compared to a standard treatment combination, meeting the studys primary endpoint.But the results were overshadowed by the number of deaths in the study, leaving investors to question the drugs chances of gaining full approval. The Food and Drug Administration granted accelerated approval to Zynlonta in 2021 based on the results of a trial in which it wasnt compared to a placebo.Given other available options to patients, the number of deaths may be difficult to accept for physicians, patients and regulators, wrote RBC Capital Markets analyst Leonid Timashev in a note Thursday.Zynlonta, used to treat large B-cell lymphoma in people whose disease hasnt responded to at least two treatments, is ADCs only asset.The Phase 3 trial paired the drug with rituximab and tested it against an immunotherapy cocktail of rituximab plus the chemotherapy drugs gemcitabine and oxaliplatin across 440 participants.ADCs treatment extended progression-free survival by 1.4 months, with enrollees receiving Zynlota surviving 6.1 months without progression compared with 4.7 months for those on the immunotherapy regimen, a statistically significant difference. The company did not meet its secondary endpoint for overall survival, but said there was no detrimental effect on that measure.However, 27 deaths were recorded for those given Zynlonta, compared to the nine deaths recorded for the immunotherapy arm. The company noted a majority of deaths occurred in patients aged 75 years or older.Eric Schmidt, from investment firm Cantor Fitzgerald, wrote in a client note that while the death total is likely to temper both investors' and physicians' views towards these results, there are some explanations for why the rate was higher than what was previously seen for Zynlonta.Schmidt explained that the Phase 3 trial included deaths up to 105 days after treatment, compared to a previous trial that recorded events up to 30 days. Additionally, he argued its worth noting that most of these events occurred in elderly patients, with a high portion of them having advanced, aggressive disease and poorer overall health.Based on the data, ADC plans to meet with the FDA in August to discuss next steps. It is preparing for a regulatory submission in the fourth quarter.Analysts such as Timashev, though, remain unsure of the drugs future.In his note, Timashev wrote that while the trial did win on progression-free survival, the benefits were modest, with no clear overall survival trend, and the significant death imbalance makes the benefit/risk profile difficult to accept and adds considerable regulatory risk.Others still remain bullish. Schmidt wrote that despite the safety hiccup, management expressed confidence in the regulatory path.We believe these data will support conversion from accelerated to full FDA approval, he added. '