Lurbinectedin induces response in small cell lung cancer

CHICAGO — Lurbinectedin improved overall response rate and survival outcomes for patients with small cell lung cancer, according to findings from the phase 2 BASKET trial presented at ASCO Annual Meeting.

Perspective from Rami Manochakian, MD

Topotecan has been the only treatment approved for second-line, platinum-sensitive small cell lung cancer for over 2 decades. However, the agent has modest clinical benefit, with an ORR ranging from 5% to 24% and median OS of 6 to 8 months.

“Lurbinectedin is an active single-agent treatment alternative for second-line small cell lung cancer where, until now, no progress has been made for more than 2 decades. Lurbinectedin has now emerged as a potential new treatment alternative for these patients,” Luis G. Paz-Ares, MD, PhD, chair of the department of medical oncology at Hospital 12 de Octubre, associate professor at Universidad Complutense, and head of the lung cancer unit at the National Oncology Research Center in Madrid, said during the presentation.

A previous phase 1/phase 2 trial showed the combination of lurbinectedin (PM1183, PharmaMar) — a RNA polymerase II inhibitor — and doxorubicin induced a 37% ORR rate with a 5.2-month duration of response among patients with small cell lung cancer.

In March, the FDA granted orphan drug status to lurbinectedin.

For the current trial, investigators assessed 3.2 mg/m² lurbinectedin IV every 3 weeks among 105 patients (median age, 60 years; 60% men) with small cell lung cancer. Forty-three percent of patients (n = 45) had a chemotherapy-free interval of less than 90 days, which researchers considered resistant disease. Fifty-seven percent (n = 60) had a chemotherapy-interval of 90 days or longer, indicating sensitive disease.

Patients received a median four cycles (range, 1-24) of lurbinectedin therapy.

ORR served as the primary endpoint. Secondary endpoints included PFS and OS.

Median follow-up was 17.1 months.

ORR was 35.2% (95% CI, 26.2-45.2) among all patients, 45% (95% CI, 32.1-58.4) among those with sensitive disease, and 22.2% (95% CI, 11.2-37.1) among those with resistant disease.

Overall, 65% of patients showed some degree of tumor shrinkage on trial.

Median PFS was 3.9 (95% CI, 2.6-4.6) months among all patients, 4.6 months (95% CI, 3-6.5) among those with sensitive disease, and 2.6 months (95% CI, 1.3-3.9) among those with resistant disease. Median OS was 9.3 months (95% CI, 6.3-11.8) among all patients, 11.9 months (95% CI, 9.7-16.2) among those with sensitive disease, and 5 months (95% CI, 4.1-6.3) among those with resistant disease.

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Moreover, the overall disease control rate was 68.6% (95% CI, 58.5-77.3), including 81.7% (95% CI, 69.6-90.5) among those with sensitive disease and 51.1% (95% CI, 35.8-66.3) among those with resistant disease.

Median duration of response was 5.3 months (95% CI, 4.1-6.4) among all patients, 6.2 months (95% CI, 3.5-7.3) among those with sensitive disease, and 4.7 months (95% CI, 2.6-5.6) among those with resistant disease.

The most common grade 3 or higher adverse events included febrile neutropenia (4.8%), anemia (6.7%) and thrombocytopenia (4.8%). – by Jennifer Southall

Reference:

Paz-Ares, et al. Abstract 8506. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Paz-Ares reports honoraria from Adacap, Amgen, AstraZeneca, Bayer, Blueprint, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Incyte, Ipsen, Merck, Merck Sharpe & Dohme, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, and Sysmex; research grants to his institution from AstraZeneca, Bristol-Myers Squibb, Merck Sharpe & Dohme and Pfizer; serving on the board for Genomica; and being a co-founder of Altum Sequencing. Please see the abstract for all other authors’ relevant financial disclosures.

Perspective

Rami Manochakian, MD

Small cell lung cancer accounts approximately for 15% of all lung cancer cases. It is an aggressive malignancy with very dismal prognosis. At least two-thirds of patients with small cell lung cancer have extensive-stage (ie, metastatic) disease at the time of diagnosis, with an estimated 5-year survival rate of 2%. Although most patients with extensive-stage disease respond to first-line systemic therapy — historically a platinum-etoposide regimen and, more recently, with the addition of atezolizumab (Tecentriq, Genentech) immunotherapy to the chemotherapy regimen — the majority of patients experience progression or relapse.

Chemotherapy agents such as topotecan are used for second-line line treatment; however, they have limited activity.

Immune checkpoint inhibitors have shown modest activity in small cell lung cancer, but no other agent has shown meaningful activity over the last few decades.

Lurbinectedin is a selective inhibitor of oncogenic transcription that inhibits active transcription in tumor-associated macrophages, leading to downregulation of interleukin-6, interleukin-8, CCL2 and VEGF.

In this phase 2 study, investigators assessed lurbinectedin for patients with small cell lung cancer whose disease progressed or relapsed after at least one line of systemic therapy. The results — including ORR (35%), median duration of response (5.3 months), disease control rate (68%), median PFS (3.9 months), 6-month PFS rate (33%), median OS (9.3 months) and 12-month OS (34%) — represent unprecedented numbers in the management of progressive or relapsed small cell lung cancer.

It is noteworthy that lurbinectedin showed activity among patients deemed to have sensitive disease (defined by chemotherapy-free interval of 90 days or more) and patients deemed to have resistant disease (defined by chemotherapy-free interval of less than 90 days), with better outcomes in the former population. In addition, patients who received prior immunotherapy also benefitted from lurbinectedin. This is a key point, as immunotherapy with atezolizumab has become standard of care in first-line settings in combination with platinum and etoposide, and both pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb) received FDA approval for patients with small cell lung cancer whose disease progressed after at least two lines of treatment.

Lurbinectedin was well-tolerated with low incidence of treatment-related adverse events and discontinuation due to adverse events. Lurbinectedin was given via IV in a friendly schedule, once every 3 weeks over 1-hour infusion.

Overall, I believe lurbinectedin is a novel drug with a mechanism of action that is very relevant to small cell lung cancer, a transcription-addicted cancer. Lurbinectedin has shown very promising activity and a favorable toxicity profile, and it may be the next breakthrough therapy for an aggressive disease with a high unmet need.

Rami Manochakian, MD

Mayo Clinic

Jacksonville, Florida

Disclosures: Manochakian reports advisory board roles with AstraZeneca, Guardant Health, Novocure and Takeda.