At its latest meeting the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA) recommended a conditional marketing authorization for rucaparib for the treatment of relapsed or progressive ovarian cancer with a BRCA mutation.
Rucaparib was approved in the United States for this indication in December 2016.
The CHMP lists "the benefits" of rucaparib as its antitumor activity, as measured by objective response rate and response duration, as well its safety profile.
The most common side effects are fatigue, nausea, creatinine elevations, liver enzyme elevations, vomiting, anemia, decreased appetite, dysgeusia, diarrhea, and thrombocytopenia.
The full indication is "monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy."
At the same meeting, the CHMP also recommended approval of an extension of indication for cabozantinib (Cabometyx, Ipsen Pharma).
Cabozantinib is now indicated for the first-line treatment of adults with intermediate- or poor-risk advanced renal cell carcinoma. This recommendation was based on the CABOSUN trial, which demonstrated that cabozantinib prolongs progression-free survival in treatment-naive patients with advanced renal cell carcinoma with intermediate or poor risk, says the company. The indication will be updated if approved by the European Commission.
The drug was already approved for second-line use in kidney cancer, for use after prior vascular endothelial growth factor–targeted therapy.
Also recommended was an extension of the indication for fosaprepitant (Emend, Merck Sharp & Dohme). The new indication is for prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adult and pediatric patients (age 6 months and older).
New Biosimilar and Generic
The CHMP also recommended for approval a biosimilar trastuzumab product, Kanjinti (from Amgen), for treatment of breast and gastric cancer, and also a generic version of pemetrexed, Pemetrexed Krka (from Krka), for the treatment of malignant pleural mesothelioma and non-small cell lung cancer.
Negative Opinion Confirmed
The CHMP also confirmed its previous negative opinion (made in December 2017) to refuse the granting of a marketing authorization for plitidepsin (Aplidin, Pharma Mar), which was expected to be used to treat adults with multiple myeloma.
The committee had been asked to re-examine its negative opinion by the manufacturer but came to the same conclusion the second time around.
The CHMP says it was concerned that the data from the main study showed only a modest increase in progression-free survival of around 1 month with the combination of plitidepsin and dexamethasone, compared with those treated with dexamethasone alone. In addition, improvement in overall survival was not sufficiently demonstrated. Regarding safety, severe side effects were reported more frequently with the combination than with dexamethasone alone. Based on the above, the CHMP was of the opinion that the benefits of plitidepsin did not outweigh its risks and therefore issued the negative opinion to recommended refusal of approval.
Re-examining Recent Negative Opinions
The CHMP noted that it is re-examining two negative opinions that it issued at its last meeting, in February 2018, as the request of the manufacturers.
The first is a re-examination of the negative opinion on neratinib (Nerlynx, Puma Biotechnology), which was not recommended for approval.
Neratinib is a HER-targeted therapy intended for use in the treatment of early breast cancer that is HER2 positive, in women who have already undergone treatment with the targeted therapy trastuzumab.
As previously reported by Medscape Medical News, the negative opinion from the EMA was a surprise because it was based on the same clinical data that had been submitted in the United States; the US Food and Drug Administration approved neratinib in July 2017.
The clinical data come from the pivotal ExteNET phase 3 trial, which was conducted in 2840 women with early breast cancer with high levels of HER2. These women had already received treatment that included trastuzumab. They were randomly assigned to a year of daily treatment with neratinib or placebo.
The CHMP notes that the main measure of effectiveness was the proportion of women who had lived without having their cancer return by the end of the 2-year study (the endpoint was invasive disease free–survival). This target was met in 94% of patients who received neratinib and in 92% of patients who received placebo.
"It is uncertain that this difference in benefit would be seen in clinical practice," the CHMP stated
"Furthermore, neratinib causes side effects in the digestive system, particularly diarrhoea, which affected most patients and might be difficult to manage," the CHMP noted. It "therefore concluded that the benefits were not enough to outweigh the risk of side effects" and issued the negative opinion.
The other negative opinion to be re-examined concerns the extension of an indication for sunitinib (Sutent, Pfizer), specifically its refusal to recommend approval for use of the drug in the adjuvant treatment of kidney cancer.
The CHMP said that the application for this extra indication was based on a main study comparing sunitinib with placebo in 615 patients at high risk for relapse of kidney cancer after surgery. Patients were treated for around a year, and the study looked at how long it took for the cancer to come back (disease-free survival).
As previously reported by Medscape Medical News, this is the S-TRAC study, published in 2016 in The New England Journal of Medicine. It found that the median duration of disease-free survival was 6.8 years in the sunitinib group and 5.6 years in the placebo group (hazard ratio, 0.76; P = .03). At the time, the lead author, Alain Ravaud, MD, PhD, head of medical oncology at the University Hospital of Bordeaux, France, said, "If you ask me, does this become the standard, the answer is 'no.'" Instead, he feels that sunitinib is "an option to be discussed with patients," with the potential gains to be balanced against the risk for adverse events and their impact on quality of life, as reported at the time by Medscape Medical News.
The CHMP said that it felt the evidence for sunitinib's delaying cancer relapse was "not convincing." Even when only the patients who were at highest risk for relapse were looked at separately, the benefits "were still not convincing."
"Given the known side effects of the medicine," the Committee concluded that the benefits did not outweigh the risks and recommended that this change to the marketing authorization be refused.
Sunitinib is already approved in Europe for use in metastatic kidney cancer, as well as for gastrointestinal stromal tumors and pancreatic neuroendocrine tumors.
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Cite this: Rucaparib for Ovarian Cancer OK'd for Approval in Europe - Medscape - Mar 23, 2018.