Lurbinectedin Active in Endometrial Cancer as Monotherapy and in Combination Regimens

Martin David Forster, MD, PhD

Lurbinectedin (PM01183) shows activity as a single agent as well as in combination with doxorubicin or paclitaxel in patients with advanced endometrial cancer, according to findings presented during the 2017 ASCO Annual Meeting.

“First of all, the single agent has some activity; 50% of patients have some response. The response even as a single agent is quite durable, which is reassuring. The other standout point is the combination with doxorubicin is really quite impressive in response rate and durability of response,” according to Martin David Forster, MD, PhD, of University College London Hospitals in the United Kingdom, the lead author on the poster.

Lurbinectedin blocks trans-activated transcription, induces DNA double-strand breaks, and modulates the tumor microenvironment. The results of 3 clinical trials of lurbinedectin in patients with endometrial cancer were reported. These trials included a phase Ib study of lurbinectedin in combination with doxorubicin, a phase I study in combination with paclitaxel, and a phase II basket trial with lurbinectedin as a single-agent.

The phase II trial was a multicenter, open-label, exploratory basket trial with response rate as the primary objective. Initial recruitment included 15 patients with endometrial carcinoma who had 1 prior line of chemotherapy. If 1 response was seen in the first cohort of 15 patients, accrual was to continue to 50 evaluable patients; otherwise, single-agent lurbinectedin would be considered to have no activity in this indication. Patients were to receive 3.2 mg/m²lurbinectedin as a 1-hour intravenous infusion on day 1 every 3 weeks.

The phase Ib trial of the combination of lurbinectedin plus doxorubicin used a 3+3 dose-escalation scheme followed by dose expansion at the recommended dose in selected diseases, including endometrial carcinoma. Patients included those with fewer than 3 prior lines of chemotherapy for advanced disease. Cohort A received a flat dose of lurbinectedin from 3 mg to 5 mg plus 50 mg/m²doxorubicin on day 1 every 3 weeks, and continuing with a 7-mg flat dose of lurbinectedin after a cumulative doxorubicin dose of 450 mg/m². Cohort B received the recommended dose of 2 mg/m²lurbinectedin plus 40 mg/m²doxorubicin on day 1 every 3 weeks, continuing with 4 mg of lurbinectedin after a cumulative doxorubicin dose of 450 mg/m².

The phase I lurbinectedin plus paclitaxel combination study started with a 3+3 dose expansion at the recommended dose in patients with selected diseases, including endometrial carcinoma, who had fewer than 3 prior lines of chemotherapy for advanced disease. The recommended dose for this trial was lurbinectedin 2.2 mg/m²on day 1 and 80 mg/m²paclitaxel on days 1 and 8 every 3 weeks, continuing with lurbinectedin alone after 18 weeks of treatment with the combination.

There were 103 patients enrolled across the 3 studies: 34 receiving lurbinectedin plus doxorubicin, 13 receiving lurbinectedin plus paclitaxel, and 56 receiving single-agent lurbinectedin. Median age was similar between the 3 studies. The most frequent histology was endometrioid. Median of prior chemotherapy lines was 1 for all the studies, except the median number of prior lines of chemotherapy was 2 (range, 1-3) in the lurbinectedin plus paclitaxel trial. All patients had received prior platinum chemotherapy.

Responses were observed in all 3 studies. Complete responses were seen in 2 patients (14%) in Cohort A of the lurbinectedin plus doxorubicin trial and in 1 patient receiving single-agent lurbinectedin.

The overall response rate (ORR) was 28% in Cohort A (n = 14 evaluable) and 44% in Cohort B (n = 18 evaluable) of the lurbinectedin plus doxorubicin trial. The duration of response (DOR) was 19.5 and 6.8 months for the 2 cohorts, respectively, and progression-free survival (PFS) was 7.8 and 7.7 months, respectively.

ORR was 27% for the 11 evaluable patients in the lurbinectedin plus paclitaxel trial; DOR was 6.1 months, and PFS was 1.9 months. For the 56 patients in the lurbinectedin single-agent trial, ORR was 12.5%, DOR was at least 6.8 months, and PFS was at least 2.6 months.

Forster observed that for “the combination with doxorubicin, the main toxicity is myelosuppression.” He said that toxicity was too high in Cohort A, resulting in the lower dose for Cohort B.

Grade 3/4 myelosuppression included anemia, neutropenia, febrile neutropenia, and thrombocytopenia. Grade 3/4 febrile neutropenia occurred in 40% of patients in Cohort A, in 15.8% of patients in Cohort B, in 3.6% of patients receiving single-agent lurbinectedin, and was not seen in the lurbinectedin plus paclitaxel trial. Myelosuppression was managed with dose reductions and administration of colony-stimulating factors.

Non-hematological toxicities were mostly grade 1/2, and included fatigue, nausea, vomiting, and elevated levels of transaminases. The investigators felt that safety was acceptable for patients in the lurbinectedin plus doxorubicin second cohort, and for patients receiving lurbinectedin plus paclitaxel or single-agent lurbinectedin.

Forster concluded, “The plan now will be to take lurbinectedin into a randomized study in combination with doxorubicin with a lower dose, which is more deliverable, so I think it should be really exciting.”

Reference:

Forster MD, Moreno V, Boni V, et al. Activity of lurbinectedin (PM01183) as single agent and in combination in patients with endometrial cancer.J Clin Oncol35, 2017 (suppl; abstr 5586).