Lurbinectedin plus doxorubicin shows initial efficacy and safety in soft tissue sarcomas

Lurbinectedin plus doxorubicin shows initial efficacy and safety in soft tissue sarcomas

Gregory Michael Cote, MD, PhD

A full dose of lurbinectedin (Zepzelca) plus a low dose of doxorubicin has been found to be clinically active and tolerable in patients with advanced or metastatic soft tissue sarcomas, supporting its continued research in those with leiomyosarcoma (LMS), according to data from a ongoing phase 1b dose-expansion trial (NCT05099666) submitted to the ASCO Annual Meeting 2023.1

Patients receiving the combination regimen (n = 10) had an overall response rate (ORR) of 60% consisting entirely of partial responses (PR); 3 patients who achieved a PR had LMS. Three patients experienced improved stable disease response (SD). Notably, 2 patients had prolonged SD who remained in the study. One patient with uterine LMS experienced disease progression.

In addition, assessment of baseline tumor size changes using RECIST v1.1 criteria showed that a retroperitoneal LMS patient who continued on dose level 2 achieved PR, with a 53.7% reduction in baseline tumor size. The other patient who continued on dose level 2 progressed on the first scan.

The median time to response was 81 days (range 43-207) and the median duration of response (DOR) was 169 days (range 63-279) across all responders. The median progression-free survival (PFS) in patients who remained on treatment (n = 5) was 322 days (95% CI, 175 days – not determined).

The full dose of lurbinectedin with a low dose of doxorubicin is feasible, well tolerated, and appears to be an active combination, said study lead author Gregory Michael Cote, MD, PhD, of Massachusetts General Hospital (MGH) Cancer Center. in a data presentation poster study. [Responses] they tended to fall into the first or second set of scans, and those responses were durable.

Cote is a physician oncologist and researcher at the Henri and Belinda Termeer Center for Targeted Therapies (Phase I), the Center for Sarcoma and Connective Tissue Oncology, and the Stephan L. Harris Center for Chordoma, at MGH Cancer Center. He is also an assistant professor of medicine at Harvard Medical School.

Doxorubicin has been a standard of care in sarcoma for several years, but median survival is 2 years or less for those with metastatic and/or unresectable disease. ORR, PFS and overall survival [OS] with initial chemotherapy in soft tissue sarcomas, particularly LMS, remaining scarce, so there is great interest in developing new therapies that will be both effective and tolerable in the initial setting, Cote explained.

Although lurbinectedin has not yet been approved for use in soft tissue sarcoma, the agent is indicated for the treatment of patients with metastatic small cell lung cancer that has progressed during or after prior platinum-based chemotherapy. Furthermore, data from a previous signal-finding study (NCT02448537) indicated that the combination of lurbinectedin and doxorubicin showed preliminary signs of clinical activity in patients with soft tissue sarcomas. A total of 7 PRs (n = 20) were observed in this patient population, 4 of which were in those with LMS. Eight patients continued to receive lurbinectedin monotherapy after 6 cycles of the combination regimen, and 2 of these patients experienced PR while receiving the single agent.2

Based on these results, the researchers demonstrated that the use of full dose lurbinectedin plus a low dose of doxorubicin (less than 50 mg/m22) would be tolerable and effective in patients with soft tissue sarcomas.

The Phase 1b/2 open label study followed a standard 3+3 design. Patients 18 years of age and older with locally advanced or metastatic, unresectable non-gastrointestinal stromal soft tissue sarcoma were enrolled in phase 1b of the study. Other inclusion criteria for this part of the study included an ECOG performance status of less than 3, measurable disease according to RECIST v1.1 criteria, and normal organ function.1.3 Patients were excluded if they had previously received an anthracycline, lurbinectedin, or trabectedin (Yondelis) or more than 2 or 1 cycles of cytotoxic chemotherapy for phase 1b or phase 2, respectively.

In the dose escalation portion of the study, patients received lurbinectedin at a fixed dose of 3.2 mg/m22 with 25 mg/m2 of doxorubicin on day 1 or days 1 and 8 of each 21-day cycle. All patients received granulocyte colony-stimulating factor (G-CSF) prophylaxis. Tumor assessments were conducted every 2 cycles.

The primary objective of the Phase 1b study was to determine the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of lurbinectedin plus doxorubicin. Secondary and exploratory endpoints included assessment of antitumor activity through disease control rate (DCR), PFS, OS, and ORR, as well as circulating tumor DNA/archival predictors of treatment response or resistance.1.3 Once RP2D and MTD were identified, the investigators planned to begin the randomized Phase 2 study to compare the combination regimen with doxorubicin monotherapy in patients with advanced LMS.

The dose escalation portion of the study enrolled a total of 10 patients. The mean age of the population was 59 years (range 31-72) and the median ECOG performance status was 0 (range 0-1). Three patients were male and 7 female. Regarding histology, 5 patients had LMS, 1 patient had myxofibrosarcoma, 1 had undifferentiated pleomorphic sarcoma, 1 had dedifferentiated liposarcoma, 1 had endometrial stromal sarcoma, and 1 had a solitary fibrous tumor. The median number of prior lines of therapy received was 0.5 (range, 0-1).

Patients completed a median of 12.5 cycles (range 2-21). At a median follow-up of 344 days, 5 patients were still on treatment. Four patients remain in the study to date.

Dose-limiting toxicities were observed in 2 patients who received the tier 2 dose on Day 8. One patient experienced increased alanine transaminase (ALT)/aspartate transaminase (AST) and 1 experienced grade 3 neutropenia. After reduction to dose level 1, 1 patient experienced Grade 3 ALT. Dose delays have occurred due to neutropenia, small bowel obstruction/surgery, or respiratory viral infection other than COVID-19. Dose reduction occurred in 2 patients originally on dose level 2 due to Grade 2 liver function test elevations and Grade 3 neutropenia, respectively. At dose level 1, two patients required dose reduction due to neutropenia and fatigue, respectively.

Most treatment-emergent adverse effects (TEAEs) were less than grade 3, with only 1 patient experiencing a grade 4 lymphocyte count decrease. Common TEAEs included fatigue (grade 2, n = 7; grade 3, n = 0), hypertension (n = 6; n = 0), infection (n = 6; n = 0), nausea (n = 5; n = 0), decrease in white blood cells (n = 3; n = 1 ), decreased neutrophils (n = 3; n = 1), anemia (n = 2; n = 1), vomiting (n = 3; n = 0), alopecia (n = 3; n = 0), anorexia ( n = 2; n = 0), dyspnea (n = 2; n = 0), alanine aminotransferase increased (n = 1; n = 1), dehydration (n = 2; n = 0), blood count decreased lymphocytes (n = 0; n = 1), duodenal obstruction (n = 0; n = 1), and gastric outlet obstruction (n = 0; n = 1).

After dose level 1 was chosen as RP2D, the Phase 2 study began rolling up in August 2022. The investigators aim to enroll 50 patients 18 years of age and older with locally advanced or metastatic LMS. Patients will be excluded if they have received 1 or more prior lines of cytotoxic chemotherapy. Other inclusion/exclusion criteria are consistent with phase 1b.

Patients will be randomly assigned 1:1 to the RP2D of lurbinectedin and doxorubicin or single agent doxorubicin at 75 mg/m22. Imaging will be performed once every 6 weeks for the first 8 cycles, then once every 9 weeks. A serial assessment for left ventricular ejection function will also be conducted in these patients. In the experimental arm, patients who complete treatment will continue doxorubicin therapy at most for life at 450 mg/m22 and then lurbinectedin monotherapy at 3.2 mg/m22. Patients in the initial monotherapy arm will proceed to lurbinectedin monotherapy at 3.2 mg/m22 after disease progression.

Notably, patients randomly assigned to the combination arm will be able to switch to lurbinectedin monotherapy. The primary endpoint of this part of the study is PFS.

The Phase 2 study is open-ended and focused only on LMS for logistical reasons, but we are interested in other histologies, Cote concluded. This could be an area of ‚Äč‚Äčinterest for future research.

A correlational study analysis is planned after completion of the Phase 2 study. The study is currently open and enrolling.

Disclosures: Dr. Cote reported having served as a consultant or in an advisory role for BioAtla, C4 Therapeutics, Daiichi Sankyo/UCB Japan, Eisai, Foghorn Therapeutics and Ikena Oncology. He has received institutional research funding from Agios, Bavarian Nordic, Bayer, BioAtla, C4 Therapeutics, CBA Research, Eisai, Epizyme, Foghorn Therapeutics, Ikena Oncology, Jazz Pharmaceuticals, Kronos Bio, Macrogenics, Merck KGaA, PharmaMar, Rain Therapeutics, Repare Therapeutics, Servier, Springworks Therapeutics and Sumitomo Dainippon Pharma Oncology.

References

  1. GM, Cote, Haddox CL, Choy E, et al. Efficacy of lurbinectedin (LURBI) + doxorubicin (DOX) combination from phase 1B soft tissue sarcoma (STS) introducing to a phase 2 randomized trial in leiomyosarcoma (LMS). J Clin Oncol. 2023;41(suppl 16):11507. 10.1200/JCO.2023.41.16_suppl.11507
  2. Cote GM, Choy E, Chen T, et al. A multilayered phase II study of lurbinectedin as single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas.Euro J Cancer. 2020;126:21-32. doi:10.1016/j.ejca.2019.10.021
  3. Lurbinectedin + doxorubicin in leiomyosarcoma. ClinicalTrials.gov. Updated March 20, 2023. Accessed June 8, 2023. https://clinicaltrials.gov/ct2/show/NCT05099666

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