Lurbinectedin, a selective inhibitor of oncogenic transcription, had encouraging activity when given as second-line therapy in patients with relapsed small-cell lung cancer (SCLC) for whom few treatment options currently exist, an open-label, phase II trial found.
In February 2020, the FDA granted lurbinectedin Priority Review, and the agency is expected to hand down a decision on approval Aug. 16, 2020.
In a cohort of 105 patients, 35.2% (95% CI, 26.2-45.2%) responded to treatment at a median follow-up of 17.1 months (interquartile range (IQR), 6.5-25.3 months), Jose Trigo, MD, Instituto de Investigacion Biomedica de Malaga in Spain, and colleagues reported in The Lancet Oncology .
All responses were partial responses (PR), but response rates were higher in patients who had chemotherapy-sensitive disease compared to those with chemotherapy-resistant disease.
Chemotherapy-sensitive disease was defined by a chemotherapy-free interval equal to or greater than 90 days while chemotherapy-resistant disease was defined by an interval of less than 90 days, investigators noted.
The median duration of response was 5.3 months (95% CI, 4.1-6.4 months) and almost two-thirds of the group at 65% had a reduction in target lesions, the authors added.
"At present, the only evidence-based second-line treatment approved for SCLC is topotecan, a topoisomerase 1 inhibitor with moderate activity in patients with sensitive disease, although its effect is much less evident in patients with resistant SCLC," Oscar Arrieta, MD, Instituto Nacional de Cancerologia (INCan), Mexico City, Mexico, and colleagues observed in a commentary on the findings.
"[T]he importance of having a potential treatment option for patients with sensitive and resistant SCLC should not be understated," they emphasized.
Patients with a pathologically proven diagnosis of SCLC were included in the study, but only if they had received just one prior line of a chemotherapy. A prior line of immunotherapy was also allowed.
"The minimum interval between any previous treatment and study commencement had to be 3 weeks for chemotherapy, 4 weeks for immunotherapy or radiotherapy, and 2 weeks for any investigational or palliative therapy," the authors explained.
Participants could also have had only grade 1 or lower toxicity from their first-line treatment with the exception of alopecia and peripheral neuropathy, for which grade 2 toxicity was allowed.
Lurbinectedin was given at a dose of 3.2 mg/m2 in a one-hour intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.
In their pre-planned analysis of overall response by chemotherapy-free interval, 60 patients had a chemotherapy-free interval of 90 days or longer.
In this group of patients with chemotherapy-sensitive disease, 45% (95% CI, 32.1-58.4%) had an overall response with a median duration of 6.2 months (95% CI, 3.5-7.3 months). Another 45 patients had a chemotherapy-free interval of less than 90 days, and in this group with chemotherapy-resistant disease, only 22.2% (95% CI, 11.2-37.1%) had an overall response at a median duration of 4.7 months (95% CI, 2.6-5.6 months), Trigo and colleagues noted.
Ninety-three percent of the group was also assessed by an independent review committee. In this slightly smaller subgroup of 98 patients, an overall response was seen in almost one-third of them at 32.7% (95% CI, 23.4-42.9%), with a median duration of response of 5.1 months (95% CI, 4.9-6.4 months). Here again, however, overall response was higher in patients with chemotherapy-sensitive disease at 44.8% (95% CI, 31.7-58.5%) and a median duration of response of 5.3 months (95% CI, 4.9-7.0 months).
In contrast, overall response at only 15% (95% CI, 5.7-29.8%) was much lower among patients with chemotherapy-resistant disease at a median duration of 4.8 months (95% CI, 2.4-5.3 months), the authors reported.
Looking at median progression-free survival (PFS) and median overall survival (OS) rates:
- PFS in the overall cohort was 3.5 months (95% CI, 2.6-4.3 months).
- PFS in patients with chemotherapy-sensitive disease was 4.6 months (95% CI, 2.8-6.5 months).
- PFS in patients with chemotherapy-resistant disease was 2.6 months (95% CI, 1.30-3.9 months).
- OS in the overall cohort was 9.3 months (95% CI, 6.3-11.8 months).
- OS in patients with chemotherapy-sensitive disease was 11.9 months (95% CI, 9.7-16.2 months).
- OS in patients with chemotherapy-resistant disease was 5.0 months (95% CI, 4.1-6.3 months).
Adverse Events
All 105 patients were included in the safety analysis.
Grade 3 and 4 adverse events (AEs) were most commonly hematologic in nature including neutropenia in 46%, leucopenia in 29%, anemia in 9%, thrombocytopenia in 7% and febrile neutropenia in 5%.
"Notably, no cases of drug-induced liver injury were reported," Trigo and colleagues pointed out.
Slightly fewer than one-quarter of patients at 22% received G-CSF secondary prophylaxis or as treatment for neutropenia. However, only 10% of patients developed serious treatment-related AEs, neutropenia and febrile neutropenia being the most common of these events at 5% each.
These rates suggest that the incidence of febrile neutropenia in the study was low, even without the primary use of G-CSF.
"The lurbinectedin treatment regimen that we used had an acceptable and manageable safety profile, with the main toxicity being reversible myelosuppression," the authors underscored.
Moreover, in contrast with topotecan, there were no treatment-related deaths from lurbinectedin in this study. The incidence of treatment-related death rate from topotecan can be as high as 11%, as investigators pointed out.
"These data outperform all previous results achieved with topotecan and other less established treatment schemes, including cyclophosphamide, doxorubicin, and vincristine or platinum re-challenge in this setting," Arrieta and colleagues emphasized.
"Overall, the study by Trigo and colleagues presents novel data for a very challenging disease for which few treatment options exist," they re-iterated.
Limitations to the study include the absence of a control group, the single-arm design of the trial and the exclusion of patients with brain metastases.
Disclosures:
Trigo reported receiving personal fees for scientific advice and speaker roles from AstraZeneca, Bristol-Myers Squibb, Merck Serono, Pfizer, and Roche as well as advisory board fees from Boehringer Ingelheim and Takeda. He has also received travel grants from Bristol-Myers Squibb and MSD.
Arrieta reported receiving personal fees from Pfizer, Lilly, Merck, and Bristol-Myers Squibb as well as grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Roche.
