LOTIS-9 Trial of Loncastuximab Tesirine/Rituximab in Untreated DLBCL Pauses Enrollment

ADC Therapeutics has voluntarily paused enrollment to the phase 2 LOTIS-9 trial (NCT05144009) investigating the combination of loncastuximab tesirine-lpyl (Zynlonta) and rituximab (Rituxan) for use in unfit or frail patients with previously untreated diffuse large B-cell lymphoma (DLBCL).¹

The decision was made following a consultation with the data monitoring committee regarding results observed from 40 patients enrolled thus far, which showed a potential signal for excessive respiratory-related adverse effects (AEs). Seven grade 5 respiratory-related, treatment-emergent AEs (TEAEs) have been reported, as well as 5 grade 3/4 respiratory TEAEs.

Notably, investigator assessment showed that 6 of the 7 fatalities, and 11 of the 12 respiratory TEAEs overall, were deemed to be unlikely related or unrelated to study drug. Moreover, 4 of the 5 grade 3/4 events resolved, and these participants completed treatment per trial protocol.

“Our top priority is the safety of every patient who participates in our clinical trials,” Ameet Mallik, chief executive officer of ADC Therapeutics, stated in a news release. “Given the aggregate of the respiratory-related events seen in the trial, we implemented a voluntary pause of enrollment to allow for a thorough investigation of the data set. This trial includes a very difficult-to-treat patient population with limited treatment options, and we will provide an update on next steps when available.”

The FDA and European Medicines Agency have been informed of the decision to pause the study. Additional data from the study are not expected to be reported in 2023.

Findings as of the data cutoff date of May 10, 2023, showed that among all patients evaluable for efficacy (n = 17), loncastuximab tesirine plus rituximab elicited an overall response rate (ORR) of 94.1% (95% CI, 71.3%-99.9%), including a complete response (CR) rate of 58.8% (95% CI, 32.9%-81.6%), a partial response (PR) rate of 35.3%, and a stable disease (SD) rate of 5.9%.

In unfit patients enrolled in cohort A (n = 10), the ORR was 100% (95% CI, 69.2%-100%) with CR and PR rates of 50% (95% CI, 18.7%-81.3%) and 50%, respectively. In those who were frail or had cardiac comorbidities in cohort B (n = 7), the ORR was 85.7% (95% CI, 42.1%-99.6%), and included a CR rate of 71.4% (95% CI, 29.0%-96.3%), a PR rate of 14.3%, and a SD rate of 14.3%.

In all patients evaluable for safety (n = 30), 20% experienced fatal TEAEs, including 1 instance each of pneumonia, acute respiratory failure, chronic obstructive pulmonary disease, dyspnea, hypoxia, and respiratory failure. Notably, the seventh grade 5 TEAE occurred following the data cutoff. Ten additional patients were enrolled and treated.

Two patients experienced grade 5 TEAEs within 30 days of their last dose of the study regimen, and the other 5 patients died between 41 and 86 days following last treatment.

In April 2023, the FDA granted accelerated approval to loncastuximab tesirine for the treatment of adult patients with relapsed/refractory LBCL following 2 or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma (HGBCL).²

LOTIS-9 is a non-randomized, open-label, phase 2 study evaluating the combination of loncastuximab tesirine and rituximab in patients with pathologically diagnosed stage I to IV DLBCL per 2016 World Health Organization classification, including those with DLBCL transformed from indolent lymphoma, HGBCL, or grade 3b follicular lymphoma.³

Key inclusion criteria included measurable disease per 2014 Lugano Classification, adequate organ function, and an ECOG performance status of 0 to 2. Notably, an ECOG performance status of 3 was allowed if the decline in status was deemed related to lymphoma and potentially reversible in the opinion of the treating physician.

In cohort A, patients needed to be at least 80 years of age with an activities of daily living (ADL) score of 6 and an interactive activities of daily living (IADL) score of 8. Patients could not have a Cumulative Illness Rating Scale-Geriatric (CIRS-G) score of 3 or 4, and they could not have 5 or more CIRS-G scores of 2.

In cohort B, patients needed to be frail or have cardiac comorbidities. Frailty was defined as being at least 80 years of age with an ADL score of less than 6, and/or an IADL score of less than 8, and/or at least 1 CIRS-G score of 3 or 4 and/or more than 5 scores of 2. Patients with cardiac comorbidities needed to be between 65 and 79 years of age with left ventricular ejection fraction of at least 30% and less than 50%, have a history of myocardial infarction within 6 months prior to screening, have ischemic heart disease, and have history of stroke within 12 months prior to screening.

Key exclusion criteria included having received prior therapy for DLBCL, HGBCL, or grade 3b follicular lymphoma, except for a corticosteroid course for symptom management of less than 14 days; prior treatment with loncastuximab tesirine and rituximab for any indication; and lymphoma with active central nervous system involvement, including leptomeningeal disease.

Patients received 375 mg/m² of rituximab on day 1 and 150 µg/kg of loncastuximab tesirine on day 2 of cycle 1. Next, 375 mg/m² of rituximab and 150 µg/kg of loncastuximab tesirine were given on day 1 of cycle 2. In cycle 3 and subsequent cycles, patients were administered 375 mg/m² of rituximab and 75 µg/kg of loncastuximab tesirine on day 1. Notably, 1400 mg per dose of subcutaneous rituximab was allowed in cycle 2 in beyond.

In both cohorts, patients who experienced a CR after 3 cycles received 1 additional cycle of treatment, and those with a PR were given 3 subsequent cycles. However, in cohort B, patients with SD were allowed to receive 3 additional cycles if they were deriving clinical benefit in the opinion of the investigator.

CR rate for the overall population and the percentage of patients in cohort B to complete 4 cycles of treatment were the primary end points. Secondary end points included ORR, 2-year progression-free survival, 3-year overall survival, duration of response, and safety.

In the 30 patients evaluable for safety at the May 10, 2023, data cutoff, the median age was 82 years (range, 72-92), and 66.7% of patients were male. Stage of disease included I (6.7%), II (23.3%), III (43.3%), and IV (26.7%).¹

Additional safety data showed that 30% of patients experienced grade 3 or higher TEAEs, including 6.7% who had cardiac disorders. Infections and infestations of grade 3 or higher (6.7%) included pneumonia (6.7%), COVID-19 pneumonia (6.7%), influenza (3.3%), and sepsis (3.3%). Respiratory, thoracic, and mediastinal disorders occurred in 13.3% of patients and consisted of acute respiratory failure (6.7%), pleural effusion (6.7%), dyspnea (3.3%), and respiratory distress (3.3%). Notably, vascular disorders were reported in 6.7% of patients.

References

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. July 11, 2023. Accessed July 11, 2023. https://ir.adctherapeutics.com/press-releases/press-release-details/2023/ADC-Therapeutics-Announces-Voluntary-Pause
2. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. News release. FDA. April 23, 2021. Accessed July 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma
3. 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