Lurbinectedin Plus Doxorubicin Shows Early Efficacy and Safety in Soft Tissue Sarcomas

Gregory Michael Cote, MD, PhD

A full dose of lurbinectedin (Zepzelca) plus a low dose of doxorubicin was clinically active and tolerable in patients with advanced or metastatic soft tissue sarcomas, supporting its continued investigation in those with leiomyosarcoma (LMS), according to data from an ongoing phase 1b dose-expansion trial (NCT05099666) presented at the 2023 ASCO Annual Meeting.¹

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

Moreover, assessment of changes in baseline tumor size according to RECIST v1.1 criteria showed that a patient with retroperitoneal LMS who continued on dose level 2 achieved a PR, with a 53.7% reduction in baseline tumor size. The other patient that continued on dose level 2 progressed at 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) in 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 does appear to be an active combination,” said lead study author Gregory Michael Cote, MD, PhD, of Massachusetts General Hospital (MGH) Cancer Center, in a poster presentation of the data. “[Responses] tended to be within the first or second set of scans, and those responses were durable.”

Cote is a medical oncologist and investigator in 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 the median survival in is 2 years or less for those with metastatic and/or unresectable disease. “ORRs, PFS, and overall survival [OS] with up-front chemotherapy in soft tissue sarcomas, in particular LMS, remains poor, so there’s high interest in developing new therapies that will be both effective and tolerable in the up-front 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 who progressed on or after prior platinum-based chemotherapy. Moreover, data from a previous signal-seeking 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 were observed in this patient population (n = 20), 4 of which were in those with LMS. Eight patients went on to receive lurbinectedin monotherapy after 6 cycles of the combination regimen, and 2 of these patients had PRs while receiving the single agent.²

Based on these results, investigators that the use of lurbinectedin at a full dose plus a low dose of doxorubicin (less than 50 mg/m²) would be tolerable and have efficacy in patients with soft tissue sarcomas.

The open-label phase 1b/2 study followed a standard 3+3 design. Patients 18 years of age or older with locally advanced or metastatic, unresectable non-gastrointestinal stromal soft tissue sarcoma were enrolled in the phase 1b portion of the study. Other inclusion criteria for this portion of the research 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 greater than 2 or 1 cycles of cytotoxic chemotherapy for phase 1b or phase 2, respectively.

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

The study’s primary objective for phase 1b was to determine the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of lurbinectedin plus doxorubicin. Secondary and exploratory end points included the assessment of antitumor activity through disease control rate (DCR), PFS, OS, and ORR, as well as circulating tumor DNA/archival predictors of response or resistance to treatment.^1,3 Once the RP2D and MTD were identified, investigators planned to begin the randomized phase 2 study of comparing 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 median age population was 59 years (range 31-72), and the median ECOG performance status was 0 (range 0-1). Three patients were male and 7 were 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 number of 12.5 cycles (range 2-21). At a median follow-up of 344 days, 5 patients were still on treatment. Four patients remain on study to date.

Dose-limiting toxicities were observed in 2 patients who received dose level 2 at day 8. One patient experienced grade 2 alanine transaminase (ALT)/aspartate transaminase (AST) increase, and 1 experienced grade 3 neutropenia. After de-escalation to dose level 1, 1 patient experienced grade 3 ALT. Dose delays occurred due to neutropenia, small bowel obstruction/surgery, or a viral respiratory infection other than COVID-19. Dose reduction occurred in 2 patients originally given dose level 2 due to grade 2 liver function test elevation 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 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), white blood cell decrease (n = 3; n = 1), neutrophil decrease (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 increase (n = 1; n = 1), dehydration (n = 2; n = 0), lymphocyte count decrease (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 the RP2D, the phase 2 trial began accrual in August 2022. Investigators aim to enroll 50 patients aged 18 years of age or older with locally advanced or metastatic LMS. Patients will be excluded if they 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/m². Imaging will be performed once every 6 weeks for the first 8 cycles, and then once every 9 weeks. Serial assessment for left ventricular ejection function will also be conducted in these patients. In the experimental arm, patients who complete treatment will continue lifetime maximum doxorubicin therapy at 450 mg/m² and then lurbinectedin monotherapy at 3.2 mg/m². Patients in the initial monotherapy arm will proceed to lurbinectedin monotherapy at 3.2 mg/m² after disease progression.

Notably, patients randomly assigned to the combination arm will be allowed to cross over to lurbinectedin monotherapy. The primary end point of this portion of the study is PFS.

“The phase 2 study is open and is only focused on LMS… for logistical reasons, but we are interested in other histologies,” Cote concluded. “That could be an area of interest for future research.”

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

Disclosures: Dr Cote reported serving as a consultant or in an advisory role for BioAtla, C4 Therapeutics, Daiichi Sankyo/UCB Japan, Eisai, Foghorn Therapeutics, and Ikena Oncology. He 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 combination lurbinectedin (LURBI) + doxorubicin (DOX) from the phase 1B soft-tissue sarcoma (STS) lead-in to a randomized phase 2 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 phase II multi-strata study of lurbinectedin as a single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas. Eur 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