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Lurbinectedin Shows Promise in Endometrial Cancer

Lynne Lederman, PhD
Published: Sunday, Jun 18, 2017

Martin David Forster, MD, PhD

Martin David Forster, MD, PhD

Lurbinectedin (PM01183) induced a high rate of response as monotherapy and with doxorubicin or paclitaxel in patients with advanced endometrial cancer, according to findings presented during the 2017 ASCO Annual Meeting.

“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,” said lead author Martin David Forster, MD, PhD, of University College London Hospitals in the United Kingdom. “The other standout point is the combination with doxorubicin is really quite impressive in response rate and durability of response.

“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,” added Forster.

Lurbinectedin blocks trans-activated transcription, induces DNA double-strand breaks, and modulates the tumor microenvironment.

Researchers presented results from 3 clinical trials of lurbinectedin in patients with endometrial cancer, including a phase Ib study of lurbinectedin in combination with doxorubicin, a phase I study in combination with paclitaxel, and a multicenter, open-label, exploratory phase II basket trial with lurbinectedin monotherapy.

Response rate was the primary objective in the basket trial. 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/m2 lurbinectedin as a 1-hour IV infusion on day 1 every 3 weeks.

In the phase Ib trial, two cohorts of patients were assigned the combination of lurbinectedin plus doxorubicin in 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/m2 doxorubicin 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/m2 lurbinectedin plus 40 mg/m2 doxorubicin 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. Recommended dose was lurbinectedin 2.2 mg/m2 on day 1 and 80 mg/m2 paclitaxel on days 1 and 8 every 3 weeks, continuing with lurbinectedin alone after 18 weeks of treatment with the combination.

A total of 103 patients were 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.

Researchers observed responses in all 3 studies. Two 2 patients (14%) in Cohort A of the lurbinectedin plus doxorubicin trial complete responses, as well as 1 patient receiving single-agent lurbinectedin.

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.

“The combination with doxorubicin, the main toxicity is myelosuppression.” Forster said. He added 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.

Most nonhematological toxicities were grade 1/2, and included fatigue, nausea, vomiting, and elevated levels of transaminases. 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 MD, Moreno V, Boni V, et al. Activity of lurbinectedin (PM01183) as single agent and in combination in patients with endometrial cancer. J Clin Oncol. 35, 2017 (suppl; abstr 5586).


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