LOTIS-9 Study of Lonca R in Previously Untreated DLBCL Discontinues

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The phase 2 LOTIS-9 clinical trial (NCT05144009) evaluating of loncastuximab tesirine-lpyl (Lonca; Zynlonta) and rituximab (Rituxan) or Lonca R in unfit or frail patients with previously untreated diffuse large B-cell lymphoma (DLBCL) has been discontinued, according to ADC Therapeutics.¹

With challenges for defining the addressable segment of the difficult-to-treat unfit or frail DLBCL patient population, including patients with significant active underlying comorbidities, the company has decided to discontinue the trial. The company does not believe that the benefit-risk profile supports continuation of the LOTIS-9 trial.

In early July 2023, the phase 2, open-label study assessing the efficacy and tolerability of a response-adapted treatment of Lonca-R in unfit and frail patients with previously untreated DLBCL voluntary paused the enrollment of new patients in the trial after a review of data assessing the 40 patients enrolled in the trial showed there to be potentially excessive respiratory-related, treatment-emergent adverse events (TEAEs) among patients treated with Lonca R, including 7 grade 5 fatal events and 5 grade 3 or 4 respiratory-related TEAEs.^2,3

Eleven of the TEAEs were individually assessed as unlikely or unrelated to study drugs. This included 6 of the 7 grade 5 fatal events. Among the 5 grade 3/4 events, 4 have been resolved and patients have completed treatment per protocol.²

All patients with fatal events had 1 or more significant active underlying respiratory and/or cardiac comorbidities. These included severe chronic obstructive pulmonary disease, pulmonary edema, chronic bronchiectasis, idiopathic pulmonary fibrosis, and recent COVID-19 infection.

Further, 2 of the 7 patients with fatal grade 5 AEs died within 30 days from the last doses of study medication. The other 5 patients died more than 30 days after the last dose of study drug (range, 41-86 days).

Then, a partial clinical hold was placed by the FDA for new patient enrollment while allowing patients already on therapy who were deriving clinical benefit to remain on therapy.¹

Once patients who reconsented receive therapy, the company plans to conduct the necessary steps to conclude the trial. There are no plans to continue studying this regimen in the unfit or frail previously untreated DLBCL patient population.

REFERENCES:

1. ADC Therapeutics announces plan to discontinue the phase 2 LOTIS-9 clinical trial of ZynlotaA® (loncastuximab tesirine-lpyl) and rituximab in unfit or frail previously untreated DLBCL patients. News release. ADC Therapeutics SA. July 20, 2023. Accessed July 25, 2023. https://tinyurl.com/4nzpsxr8

2. 1. ADC Therapeutics announces voluntary pause of enrollment in the phase 2 LOTIS-9 clinical trial of ZYNLONTA® (loncastuximab tesirine-lpyl) and rituximab in unfit or frail previously untreated DLBCL patients. News release. ADC Therapeutics SA. July 11, 2023. Accessed July 11, 2023. https://tinyurl.com/35sbzfzt

3. 2. A study of loncastuximab tesirine and rituximab (Lonca-R) in previously untreated unfit/frail participants with diffuse large b-cell lymphoma (DLBCL) (LOTIS-9). ClinicalTrials.gov. Updated June 22, 2023. Accessed July 11, 2023. https://clinicaltrials.gov/ct2/show/NCT05144009