Sifting through puddles from the firehose of last week’s American Society of Clinical Oncology annual meeting brought to my attention some promising news from the world of ovarian cancer. This early efficacy study with a synthetic drug based on a naturally-occurring molecule also demonstrates the continued value of prospecting the planet to harvest chemical diversity for the relief of human suffering.
PharmaMar, a Madrid-based marine natural products pharmaceutical company and division of Zeltia, conducts what I call “ocean-to-bedside” drug development. Their first marine-derived drug for cancer, Yondelis® (trabectedin, ET-743), is approved in the European Union and Japan.
The current study builds on this work with the semi-synthetic analogue, lurbinectedin (PM01183; brand name pending).
Lurbinectedin is a second-generation analogue of trabectedin (Yondelis). Known previously as ecteinascidin-743, or ET-743, trabectedin is derived from the Caribbean sea squirt, Ecteinascidia turbinata. Credit: PharmaMar.
Andres Poveda, MD, a gynecological oncologist at Instituto Valencieno de Oncologia, presented the results on behalf of a team of European Union investigators who assessed the anticancer activity of lurbinectedin in women with ovarian cancer that had become resistant or refractory to platinum-containing drugs, such as carboplatin or cisplatin (formerly BMS drugs, now available as generics).
An aside: I had always thought that “resistant” and “refractory” were synonyms when used to describe cancer responsiveness to drugs. But not so in the case of patients whose cancer no longer responds to platinum drugs. Patients with platinum-refractory cancer are those whose disease continues to grow while receiving a platinum drug. Patients with platinum-resistant cancer are those whose disease progresses within 6 months of cessation of platinum therapy. Therefore, platinum-refractory patients are considered to have more aggressive disease. This distinction is essential in appreciating the results of the trial.
This two-part, 81-patient Phase II study first established the anticancer activity of lurbinectedin in a cohort of 22 ovarian cancer patients. Those data were presented on their own at the European Society of Medical Oncology in 2012. The newly-reported data at the 2014 ASCO meeting come from another group of 59 patients randomized 1:1 to receive either lurbinectedin or topotecan (Hycamtin®; GlaxoSmithKline).
Lurbinectedin superior to topotecan in platinum-resistant ovarian cancer .
Overall response rate (ORR), the primary endpoint together with safety, was 22% with lurbinectedin and 0% with topotecan. Lurbinectedin was more effective in platinum-resistant patients (30%) than in patients with the more challenging platinum-refractory cancer (6%).
Lurbinectedin was also statistically superior with regard to median progression-free survival: 3.9 months for lurbinectedin versus 2.0 months for topotecan. When subclassified by previous platinum sensitivity, those patients with platinum-resistant disease fared even better: 7.1 months for lurbinectedin versus 1.7 months for topotecan. Unfortunately, patients with platinum-refractory cancer showed no statistical difference in progression-free survival between the two drugs.
Another secondary endpoint, and perhaps the one most important to patients and their loved ones, was overall survival. Lurbinectedin won out with overall median survival of 10.6 months relative to 5.7 months for topotecan. Again, patients with platinum-resistant disease fared best. In this subset, topotecan’s median overall survival was 7.0 months but it could not yet be calculated for lurbinectedin because more than 50% of these patients were still alive when the data were compiled. That’s an impressive result in this patient population.
Lurbinectedin was, of course, not without side effects. A total of 85% of patients receiving lurbinectedin experienced severe drops in white blood cell counts (grade 3-4 neutropenia) but this was predictable and reversible. The study authors recommended that the neutropenia could be prevented with the blood stimulating factor, G-CSF.
Other adverse events included febrile neutropenia (23%), thrombocytopenia (Grade 3-4, 29%), nausea & vomiting (Grade 3-4, 16%), and fatigue (Grade 3, 37%).
Remember that while we’re talking in terms of months of increased survival, the drugs were being tested after the patients’ disease no longer responded to platinum drugs. We don’t know how lurbinectedin would perform if given to women with ovarian cancer as a first-line treatment, alone or with a platinum drug.
Limitations
At this point, the results should be considered preliminary since the study has not been peer-reviewed and accepted for publication.
I still have some questions about how the data were compiled for lurbinectedin. Sometimes the results were given for the combination of the two parts of the lurbinectedin study arms (51 total patients) and other times it was separated out (22 patients first, then 29 patients in the part where compared with another 29 patients on topotecan).
The study design also allowed for patients whose disease progressed on topotecan to be given the choice to then receive lurbinectedin. However, it’s not clear how this factor was accounted for in the overall topotecan survival data.
Nevertheless, the continued survival of many patients receiving lurbinectedin is highly promising and bodes well continuing the path to approval in the EU and elsewhere.
PharmaMar now plans a Phase III trial in patients with platinum-resistant ovarian cancer.