Loncastuximab Tesirine Plus Rituximab Meets PFS End Point in R/R DLBCL

Topline data from the phase 3 LOTIS-5 trial (NCT04384484) demonstrate that loncastuximab tesirine-lpyl (Zynlonta) combined with rituximab (Rituxan; Lonca-R) significantly improved progression-free survival (PFS) compared with standard immunochemotherapy in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).¹

The combination met the trial's primary end point of PFS per independent review committee (HR, 0.73; 2-sided P =.008), yielding a median PFS of 6.1 months vs 4.7 months for the comparator regimen of rituximab, gemcitabine, and oxaliplatin (R-GemOx).

On the key secondary efficacy end point of overall survival (OS), the combination demonstrated no detrimental effect compared with R-GemOx (HR, 0.96). The sponsor noted the OS hazard ratio was affected by earlier use and a higher rate of new antilymphoma treatment switching in the control arm.

Response rates also favored the Lonca-R arm. The overall response rate was 58.1% with Lonca-R vs 45.2% with R-GemOx. Complete response (CR) rates were 39.5% vs 26.7%, respectively. Median duration of response was 9.2 months vs 7.7 months, and median duration of CR was 16.8 months vs 12.3 months. Among patients who achieved a CR, 48.5% in the Lonca-R arm remained in remission at 24 months, compared with 16.7% in the R-GemOx arm.

"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," said Mehdi Hamadani, MD, of Medical College of Wisconsin and trial principal investigator, in a news release. "Based on these results, I believe this combination may provide an additional option in treating R/R DLBCL."

About LOTIS-5

LOTIS-5 is a global, randomized, open-label, 2-arm study evaluating the efficacy and safety of Lonca-R vs R-GemOx in 440 patients with R/R DLBCL who had received 1 or more prior lines of systemic therapy.² The trial was designed specifically to address a treatment gap for patients who cannot access or have progressed on chimeric antigen receptor (CAR) T-cell therapy or other complex treatment approaches.

Patients in the experimental arm received loncastuximab tesirine 150 µg/kg plus rituximab 375 mg/m² every 3 weeks for 2 cycles, followed by loncastuximab tesirine-lpyl 75 µg/kg plus rituximab 375 mg/m² every 3 weeks for up to 6 additional cycles. Patients in the control arm received R-GemOx administered every 2 weeks for up to 8 cycles, consisting of rituximab 375 mg/m², gemcitabine 1000 mg/m², and oxaliplatin 100 mg/m².

Safety Profile

Overall treatment-emergent adverse event (TEAE) rates were similar across arms (98.5% vs 97.5%). Grade ≥3 TEAEs occurring in more than 5% of patients included hematologic events, which were more common in the R-GemOx arm (40.7% vs 59.4%), while infection/infestation (24.5% vs 15.7%), hepatotoxicity (17.2% vs 8.1%), and edema/effusion (7.4% vs 0.5%) were more frequent with Lonca-R compared with R-GemOx.

Serious adverse events occurred in 49.0% of patients in the Lonca-R arm vs 34.5% in the R-GemOx arm. Grade 5 TEAEs were observed in 27 patients (13.2%) receiving Lonca-R compared with 9 patients (4.6%) in the R-GemOx arm; the majority of grade 5 TEAEs in the Lonca-R arm occurred in patients aged 75 years or older. TEAEs leading to any drug withdrawal were reported in 25.5% vs 9.1% of patients, respectively.

Regulatory Outlook

Loncastuximab tesirine is a CD19-directed antibody-drug conjugate currently approved by the FDA and the European Medicines Agency for the treatment of adult patients with R/R large B-cell lymphoma after 2 or more prior lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. The current FDA approval is under accelerated approval based on overall response rate from the LOTIS-2 trial (NCT03589469); continued approval may be contingent on verification of clinical benefit in a confirmatory trial.

The sponsor has stated it plans to discuss the benefit-risk profile of the combination with the FDA in preparation for a supplemental biologics license application (sBLA) filing. A pre-sBLA meeting is planned for August 2026, with a formal sBLA submission targeted for the fourth quarter of 2026.

REFERENCES

1. ADC Therapeutics Announces Results From LOTIS-5 Phase 3 Confirmatory Clinical Trial of ZYNLONTA® in Combination with Rituximab in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. News release. ADC Therapeutics. June 3, 2026. Accessed June 5, 2026. https://tinyurl.com/54wm9c5m

2. Study to Evaluate Loncastuximab Tesirine With Rituximab Versus Immunochemotherapy in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS 5). ClinicalTrials.gov. Updated April 28, 2026. Accessed June 5, 2026. https://clinicaltrials.gov/study/NCT04384484