Lurbinectedin Does Not Improve PFS in Platinum-Resistant Ovarian Cancer

Stephanie Gaillard, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Stephanie Gaillard, MD

Results of the phase III CORAIL trial demonstrated that the marine-derived treatment lurbinectedin did not improve progression-free survival (PFS) compared with pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer.¹

“The primary endpoint, an improvement in PFS with lurbinectedin, was not met,” said lead investigator Stephanie Gaillard, MD, during a presentation at the 2018 ESMO Congress. “Other efficacy measures, such as response rate and overall survival (OS), were not improved with lurbinectedin.”

Lurbinectedin blocks transcriptional transactivation. Its mechanism involves the specific degradation of RNA polymerase II by the ubiquitin-proteasome machinery and the subsequent accumulation of DNA breaks and apoptosis as downstream events.

“Lurbinectedin also reduces the level of tumor-associated macrophages and the inflammatory tumor microenvironment,” said Gaillard, assistant professor of oncology, Johns Hopkins University. “Preclinical data have shown strong single-agent lurbinectedin antitumor activity in cisplatin-resistant epithelial ovarian cancer models.”²

In a phase II trial of lurbinectedin in platinum-resistant/refractory ovarian cancer, the objective response rate with lurbinectedin per RECIST or GCIG criteria was 30% and the median PFS was 5.0 months in the subgroup of patients with platinum resistance.³ The results in the platinum-resistant cohort were the basis of the CORAIL study.

The data presented at the 2018 ESMO Congress were from a study of 442 patients with platinum-resistant ovarian, fallopian, or primary peritoneal cancer. Eligible patients had an ECOG performance score of 0 to 2 and received treatment with ≤3 lines of prior chemotherapy. They were randomized 1:1 to lurbinectedin at 3.2 mg/m² every 3 weeks (arm A) or investigator choice of PLD at 50 mg/m² every 4 weeks or topotecan at 1.5 mg/m² on days 1 to 5 every 3 weeks (arm B) until progression or discontinuation due to toxicity.

The primary endpoint was a 30% reduction in the relative risk of progression or death.

Baseline characteristics were well balanced. Median age was 63 years in arm A and 59 years in arm B. The primary cancer site was ovarian in 89% and 88%, respectively, and histology type was serous/papillary in 82% and 90%. Six patients in arm A and 5 in arm B had a germline BRCA mutation. The median number of prior lines of chemotherapy was 2 in each arm; 41% in arm A and 46% in arm B received prior bevacizumab (Avastin). The median platinum-free interval was 3.9 and 3.6 months in arms A and B, respectively.

The median PFS according to independent review committee (IRC) was 3.5 months in the lurbinectedin recipients and 3.6 months in arm B, corresponding to a hazard ratio of 1.043 (95% CI, 0.842-1.293; P = .6951), failing to meet the primary endpoint. Median PFS in arm was 3.6 months each in patients who received PLD or topotecan. PFS according to investigator assessment was 3.7 months in both arm A and arm B.

Median OS, which was a secondary endpoint, was likewise not different between the 2 arms at the time of data cutoff in October 2017. Median OS was 11.2 months in patients randomized to lurbinectedin compared with 11.1 months in those randomized to either PLD or topotecan (HR, 0.97; P = .8038). Separated by investigator choice, the median OS was 11.3 months and 10.2 months in the PLD and topotecan arms, respectively.

The ORR was 14.0% in arm A, which consisted of 3 complete responses (CRs), 28 partial responses (PRs), and 91 cases of stable disease (SD). In arm B, there were 3 CRs and 24 PRs, for an ORR of 12.2%, and 98 patients had SD. The median duration of response was 4.4 months in the lurbinectedin arm versus 3.7 months in the PLD/topotecan arm.

In patients with primary platinum resistance, the ORRs by IRC were 13.5% in arm A and 11.1% in arm B (P = .6874). In patients with secondary platinum resistance, the ORRs were 14.5% and 13.5% (P = .8463), respectively. The PFS was 3.1 months and 3.5 months in arm A and arm B (P = .3223), respectively, in patients with primary platinum resistance, and 3.7 months in each arm (P = .6820) in patients with secondary platinum resistance. Median OS was 9.2 months for arm A and 8.8 months for arm B in those with primary resistance; in those with secondary resistance, the median OS in arms A and B were 14.5 and 11.8 months.

Treatment-related grade 3/4 adverse events (TRAEs) were reported in 48% of patients in arm A and 64% in arm B (P = .001), and serious grade 3/4 TRAEs were reported by 18% and 20%, respectively. In arm B, topotecan accounted for a higher percentage of AEs than PLD. Treatment-related dose reductions (P < .0001) and delays (P = .017) were more frequent in arm B. Grade 3/4 anemia (26% vs 16%) and neutropenia (39% vs 30%) were also more frequent in arm B. There was higher use growth factors and red blood cell transfusions in arm B. Global quality-of-life scores were not different between arms, although the incidence of nausea and vomiting was slightly higher with lurbinectedin and skin problems, while alopecia were more prevalent in the control arm.

A panel of 206 DNA repair and cancer-related genes were sequenced in primary tumors from 184 patients. In those with an ARID1A mutation, 0 of 18 in the lurbinectedin group had a response compared with 3 of 13 in the control group. Median PFS was 2 months in the lurbinectedin group with ARID1A mutations versus 5.3 months in the control group.

“The presence of an ARID1A mutation may be a negative predictive biomarker for lurbinectedin,” said Gaillard. “Given ARID1A’s role in regulating transcriptional activity, this is intriguing but needs to be validated in other patient cohorts and studied further.”

References

1. Gaillard S, Oaknin A, Ray-Coquard IL, et al. Phase III trial of lurbinectedin versus PLD or topotecan in platinum-resistant ovarian cancer patients: results of CORAIL trial. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 932O.
2. Vidal A, Muñoz C, Guillén MJ, et al. Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer. Clin Cancer Res. 2012;18(19):5399-5411. doi: 10.1158/1078-0432.CCR-12-1513.
3. Poveda A, Del Campo JM, Ray-Coquard I, et al. Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer. Ann Oncol. 2017;28(6):1280-7. doi: 10.1093/annonc/mdx111.