ADC Therapeutics lays off staff after 27 patient deaths mar Zynlonta readout

ADC Therapeutics Announces Layoffs After Zynlonta Trial Deaths

ADC Therapeutics is implementing layoffs for approximately 30 workers, or 17% of its team, following disappointing results from its LOTIS-5 Phase 3 trial for the blood cancer drug Zynlonta. The trial, which tested Zynlonta plus rituximab for relapsed or refractory diffuse large B cell lymphoma (DLBCL), showed no overall survival benefit. Furthermore, 27 patients in the Zynlonta arm died, compared to nine in the control group. This reorganization aims to save $10 million annually and extend the company's cash runway into 2028. Despite the setbacks, ADC Therapeutics plans to submit Zynlonta to the FDA for expanded approval based on LOTIS-5 before year-end, maintaining belief in its benefit-risk profile.

• The Phase 3 LOTIS-5 trial, evaluating Zynlonta plus rituximab for relapsed or refractory DLBCL, failed to demonstrate an overall survival benefit. Critically, the Zynlonta arm reported 27 patient deaths, significantly higher than the nine deaths in the control group, raising concerns about the drug's safety profile, particularly in older patients.
• In response to the trial outcomes and to conserve resources, ADC Therapeutics is laying off approximately 17% of its workforce, impacting around 30-32 roles. This restructuring is projected to save $10 million annually and is expected to cost about $3 million in severance, extending the company's cash runway into 2028.
• Despite the negative LOTIS-5 results, ADC Therapeutics remains committed to pursuing expanded regulatory approval for Zynlonta. The company plans to submit Zynlonta to the FDA for an expanded approval based on the LOTIS-5 data before the end of the year and anticipates a pre-supplemental Biologics License Application (sBLA) meeting with the FDA in August.

The Persistent Challenges in Treating Relapsed/Refractory DLBCL

Despite meaningful advances in frontline immunochemotherapy, a substantial proportion of DLBCL patients continue to face poor outcomes, underscoring the unmet need for more effective and individualized treatment strategies. Approximately 30–40% of patients experience relapse following first-line R-CHOP, and 10% exhibit primary refractory disease — trajectories associated with markedly diminished survival and limited therapeutic options.

• High relapse and refractory disease burden: While R-CHOP achieves initial responses in approximately 80% of patients, 30–40% ultimately relapse and 10% are primarily refractory. Of those eligible for second-line salvage chemotherapy followed by autologous stem-cell transplantation (ASCT), around 50% experience further relapse — and the median overall survival for patients refractory to advanced lines of therapy or ineligible for ASCT is less than six to twelve months.

• Diminished efficacy of salvage therapy in the rituximab era: Salvage chemotherapy and autotransplantation demonstrate reduced effectiveness in patients with prior rituximab exposure. Intensified salvage regimens followed by high-dose therapy and ASCT have shown only limited benefit, and no standard salvage therapy has been established to date.

• Disproportionate impact on older and comorbid patients: Relapse or refractory disease occurs more frequently in older patients (40% vs. 27%, P = .0019). Two-year progression-free survival is 78% in patients under 65 versus 64% in those 65 and older (P = .004), with corresponding overall survival rates of 87% and 76% (P = .001). Toxicity and restricted tolerability further limit treatment options in this population, which remains underrepresented in clinical trials.

• Biological heterogeneity complicating treatment decisions: DLBCL is characterized by significant clinical, pathologic, and biologic heterogeneity. Treatment failure remains particularly prevalent in the non-germinal center B-cell (non-GCB) subset, while rituximab-based regimens have more substantially reduced failure rates in the GCB-like subset. Despite advances in gene expression profiling and next-generation sequencing, incorporating biologic heterogeneity into individualized treatment decisions is not yet standard of care.

• Molecular resistance mechanisms limiting chemotherapy efficacy: Overexpression of drug efflux transporters and anti-apoptotic proteins — including MRP1/ABCC1, survivin, and BCRP/ABCG2 — has been significantly associated with relapsed and refractory disease (p < 0.05 vs. remission). ECOG performance status combined with these molecular markers was significantly predictive of R-CHOP treatment response, highlighting the need for biomarker-guided patient stratification.

• Immunosuppressive tumor microenvironment impairing therapeutic response: DLBCL is a highly metabolically active malignancy that depletes vital nutrients and generates immunosuppressive metabolites — including lactate, adenosine, and kynurenine — thereby impairing effective anti-tumor immune responses. Treatment failure is further compounded by tumor antigen loss and T-cell dysfunction, factors that undermine the durability of both conventional and novel immunotherapeutic approaches.

• Evolving resistance landscape with novel therapies and unresolved sequencing questions: As advanced therapies — including CAR-T cell therapy and bispecific antibodies — move earlier in the treatment paradigm, the biology of relapse is expected to evolve. Critical questions regarding optimal therapeutic sequencing, patient selection criteria, and mechanisms of resistance to novel immunotherapies and targeted agents remain unanswered, necessitating ongoing reevaluation of treatment algorithms in the relapsed/refractory setting.

Unpacking the LOTIS-5 Trial Results for Zynlonta in DLBCL

Recent clinical investigation in DLBCL has produced a breadth of evidence spanning novel combinations, bispecific antibodies, CAR-T platforms, and salvage regimens. The studies summarized below represent a cross-section of 2025–2026 publications, encompassing both early-phase and retrospective analyses across treatment-naïve and relapsed/refractory settings.

• ZR2-CHOP (NCT05200312): A multicenter Phase 2 study evaluating zanubrutinib (160 mg twice daily) plus lenalidomide (25 mg on Days 1–7) in combination with standard R-CHOP for newly diagnosed non-GCB DLBCL (N=34). The best ORR was 100%, with a CR rate of 94.1% at end of treatment and a 2-year PFS of 84.8%. Plasma ctDNA negativity was achieved in 84% of evaluable patients. Grade 3–4 adverse events occurred in 67.6% of patients, predominantly hematologic in nature.

• BGB-3111-110 (NCT04436107): A Phase 1 multicenter dose-escalation and expansion study of zanubrutinib (160 mg twice daily) plus lenalidomide in relapsed/refractory DLBCL (N=66). At the recommended Phase 2 dose of lenalidomide 25 mg daily, ORR was 58% and CR rate was 42%, with a median duration of response of 14.9 months and median PFS of 5.5 months (95% CI, 2.9–11.1). No dose-limiting toxicities were observed; however, Grade ≥3 treatment-emergent AEs occurred in 74% of patients, most commonly decreased neutrophil count (58%) and decreased white blood cell count (29%).

• L-MIND Trial vs. SMC-LCS Registry (Tafasitamab + Lenalidomide vs. ICE): An external control arm comparison evaluating tafasitamab plus lenalidomide against ICE (ifosfamide, carboplatin, etoposide) in second- to fourth-line R/R DLBCL. After inverse probability of treatment weighting (IPTW), median OS was 34.1 months (95% CI, 18.6–NR) versus 6.4 months (95% CI, 0.3–13.9) for ICE (HR 0.33; 95% CI, 0.20–0.53). Tafasitamab plus lenalidomide also demonstrated significantly superior PFS (HR 0.33), duration of response (HR 0.17), ORR (OR 3.17), and CRR (OR 2.87).

• Pola-ZR/G (NCT06203652): A prospective observational study of polatuzumab vedotin combined with zanubrutinib plus rituximab (Pola-ZR) or obinutuzumab (Pola-ZG) in R/R DLBCL (N=22; median age 68 years). At a median follow-up of 16.1 months, best ORR was 70% and CR rate was 45%. Median PFS was 8.3 months, comparing favorably to traditional salvage therapy cohorts, and median OS had not been reached. The most common Grade 3–4 AEs were infections and hematological toxicities.

• Orelabrutinib + Lenalidomide + Sintilimab: A study of 34 R/R DLBCL patients treated with orelabrutinib 150 mg daily, lenalidomide 25 mg on Days 1–10, and sintilimab 200 mg IV on Day 1 of each 21-day cycle. Best ORR was 58.8% with a CR rate of 38.2%; 1-year PFS and OS were 41.9% and 77.8%, respectively. TRAEs occurred in 82% of patients, with Grade ≥3 events in 20.6%; the most frequent Grade 1 TRAEs were neutropenia (64.7%), thrombocytopenia (44.1%), skin rash (32.4%), and fatigue (29.4%).

• Epcoritamab vs. Axicabtagene Ciloleucel — EPCORE NHL-1 (NCT03625037) vs. ZUMA-1 (NCT02348216): A matching-adjusted indirect comparison for R/R DLBCL with two or more prior lines of therapy. Epcoritamab demonstrated comparable efficacy to axi-cel, with ORR of 73.5% versus 74.3% (adjusted absolute difference −0.7%; P=.933) and CR rates of 48.7% versus 54.5% (P=.599). No statistically significant differences were observed for PFS (adjusted HR 1.009; P=.975) or OS (adjusted HR 0.826; P=.546), suggesting epcoritamab as a viable off-the-shelf alternative to CAR-T in this setting.

• R-CHOP vs. R-DA-EPOCH — Multicenter Retrospective Analysis: A comparative analysis in 148 young, treatment-naïve, high-risk DLBCL patients (R-CHOP n=98; R-DA-EPOCH n=50). CR rates were 36.7% versus 46.0% (P=0.313) and ORR was 61.2% versus 58.0% (P=0.313), with no statistically significant efficacy difference between arms. However, R-DA-EPOCH was associated with significantly greater toxicity burden, including higher rates of dose reduction (52.0% vs. 18.4%; P<0.001), treatment delay (46.0% vs. 18.4%; P=0.001), G-CSF use (50.0% vs. 31.6%; P=0.033), platelet transfusions (28.0% vs. 8.2%; P=0.003), and longer median hospital stay (7.1 vs. 4.9 days; P<0.001).

Navigating Zynlonta's Path in the Evolving DLBCL Landscape

Over the past five years, the DLBCL treatment landscape has undergone substantial expansion across both frontline and relapsed/refractory settings, driven by the regulatory approval and clinical investigation of multiple mechanistically distinct agents. Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate with a pyrrolobenzodiazepine dimer payload, received FDA approval for relapsed DLBCL after two or more prior lines of therapy on the basis of a 48.3% overall response rate in a Phase 2 study, with durable responses observed across high-risk subgroups. CAR-T cell therapy, polatuzumab vedotin, and tafasitamab also achieved regulatory approval during this period, collectively reshaping the relapsed/refractory treatment algorithm. Despite these advances, approximately one-third of patients continue to experience relapse or refractory disease following first-line anthracycline-based immunochemotherapy, and outcomes remain particularly poor for those with primary refractory disease or early relapse, with 2-year overall survival rates of 27% and 25%, respectively — underscoring that a significant unmet medical need persists.

In the frontline setting, chemotherapy-free and targeted combination regimens have generated compelling efficacy data, particularly in non-GCB and older patient populations. The Smart Start trial demonstrated that rituximab, lenalidomide, and ibrutinib (RLI) administered prior to chemotherapy yielded an 86.2% ORR after two induction cycles and a 94.5% complete response rate at end of combined treatment, translating to 2-year PFS and OS rates of 91.3% and 96.6%, respectively, in a cohort enriched for high-risk features including 62% double expressors. For patients aged ≥75 years, both the iR2 (ibrutinib, rituximab, lenalidomide) and ZR2 (zanubrutinib, rituximab, lenalidomide) regimens demonstrated feasibility, with ZR2 achieving a 65.0% complete response rate at end of induction, 2-year PFS of 67.1%, and 2-year OS of 82.4%, with no atrial fibrillation events — a notable tolerability distinction from ibrutinib-based regimens. The ZR2-CHOP combination in newly diagnosed non-GCB DLBCL further demonstrated a 100% best ORR, 94.1% end-of-treatment complete response rate, and 2-year PFS of 84.8%, with ctDNA negativity achieved in 84% of evaluable patients.

In the relapsed/refractory setting, bispecific antibody-based strategies and novel combination regimens have produced some of the most clinically significant data of the period. The Phase 3 STARGLO trial established that glofitamab plus gemcitabine-oxaliplatin significantly improved overall survival versus R-GemOx, with an updated median OS of 25.5 months versus 12.9 months (HR 0.62; 95% CI 0.43–0.88). Glofitamab also demonstrated activity post-CAR-T, with a median OS of 14.7 months and a best complete metabolic response rate of 45.7% in a dedicated study. Additional regimens — including acalabrutinib plus lenalidomide and rituximab (ORR 54.5%, CR 31.8%), penpulimab plus lenalidomide and R-GemOx (ORR 66.7%, median PFS 30.4 months), and zanubrutinib plus lenalidomide (ORR 58%, median duration of response 14.9 months at the RP2D) — have collectively demonstrated that targeted combination strategies can achieve clinically meaningful response depths in heavily pretreated populations, albeit with grade ≥3 adverse event rates frequently exceeding 60–70%, predominantly driven by hematologic toxicity. Emerging computational and machine learning approaches to dissecting DLBCL molecular heterogeneity are anticipated to further refine patient selection and inform the transition toward personalized therapeutic strategies.

Zynlonta's Combination Setback: A Strategic Reassessment

The treatment landscape for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remains challenging, with a significant unmet need for effective therapies, particularly for heavily pretreated patients. Loncastuximab tesirine (Zynlonta), a CD19-directed antibody-drug conjugate, emerged as a promising option, demonstrating substantial single-agent antitumour activity and durable responses with an acceptable safety profile in pivotal Phase 2 studies. Research indicates it offered a new therapeutic avenue, showing improved efficacy compared to older chemoimmunotherapy and a potentially more favorable safety profile than some newer combination regimens in indirect comparisons.

However, the recent announcement regarding the LOTIS-5 Phase 3 trial marks a significant inflection point. This trial, which explored Zynlonta in combination with rituximab, failed to demonstrate an overall survival benefit, and critically, reported a higher number of deaths in the Zynlonta treatment arm. This outcome presents a complex challenge for Zynlonta's future. While the drug has established efficacy as a monotherapy, the combination data introduces a substantial risk. Physicians may view these results with caution, potentially impacting the broader perception of Zynlonta's benefit-risk profile, even in its approved single-agent use.

The company's intent to still pursue FDA submission for expanded approval based on LOTIS-5, despite these results, highlights a strategic gamble. This path will likely face intense scrutiny from regulatory bodies, given the lack of OS benefit and the safety signal. For ADC Therapeutics, this necessitates a sharp focus on its core strengths and a re-evaluation of its clinical development strategy. While cost-saving measures are in place to extend the cash runway, the long-term success of Zynlonta will depend on navigating these regulatory and market perception challenges, potentially by reinforcing its established role as a single agent or exploring different, more synergistic combination partners. The evolving R/R DLBCL landscape demands robust evidence, and this setback underscores the inherent complexities of developing new combination therapies.