Patients with platinum-resistant ovarian cancer had a twofold increase in progression-free survival (PFS) when treated with an investigational folate conjugate, a phase II randomized trial showed.
Median PFS increased from 2.7 months with pegylated liposomal doxorubicin (PLD) to 5.0 months when vintafolide was added to PLD.
The between-group difference increased to 4 months in the subgroup of patients whose lesions had imaging-confirmed folate-receptor expression.
Overall survival did not differ between the groups, due in part to an unusually prolonged survival in the control arm, R. Wendel Naumann, MD, said here at the Society of Gynecologic Oncology meeting.
“This is the first clinical trial that has shown a benefit in progression-free survival over standardized therapy in a randomized trial in patients with platinum-resistant ovarian cancer, and we think it’s pretty exciting,” said Naumann, of Carolinas Medical Center in Charlotte, N.C.
“We know that EC20 scanning identifies patients who will benefit most from the combination of pegylated liposomal doxorubicin and vintafolide, as well as those who will not benefit. It appears that patients in whom all lesions are folate-receptor positive benefit the most from this combination.”
Two-Drug Combination Fights Resistant Ovarian Cancer Cells
Ovarian cancer is one of the most common malignancies among women all over the globe. Various studies have been initiated to explore options with regard to effective treatments for this pathology. In a recent research published online in Gynecologic Oncology, two drugs never previously used together were said to kill 70% of ovarian cancer cells resistant to usual chemotherapeutic agents. The Lead Author Dr. Prakash Vishnu, of the May Clinic in Jacksonville, Florida, and her team have high hopes that the combo of ixabepilone and sunitinib will become effective medical intervention for patients with this cancer.
According to Dr. Gerardo Colon-Otero, a hematologist-oncologist and co-author, the combination of chemotherapy compounds is crucial in saving lives, since the late stage of ovarian cancer becomes fatal due to its resistance to commonly used chemotherapeutic drugs. Furthermore, the “proof of principle” study revealed that RhoB, a cellular protein that is activated by the 2-drug combo, has a vital role in ovarian cancer. RhoB serves as a molecular switch that gives signals in cellular processes like gene expression, cell proliferation and cell suicide (apoptosis).
In addition, Dr. John Coplan, a senior author and cancer biologist, said that RhoB is a key modulator in aiding drugs to fight other kinds of tumor, although this is the first time for it to be linked to ovarian cancer. He added that RhoB becomes elevated and cell death occurs with this new drug combination. Moreover, he believed that this protein may be a possible marker that can assist in determining which ovarian cancer patients benefit from this chemotherapeutic combination.
A phase III randomized trial of PLD plus vintafolide has already begun, he added.
About 80% of epithelial ovarian cancers express folate receptor. Upon binding the receptor, folate enters cells by means of endocytosis, a process that can be exploited for targeted drug delivery, said Naumann.
Vintafolide (EC145) is a conjugate consisting of folic acid and the vinca alkaloid desacetylvinblastine hydrazide. Preclinical studies confirmed that the compound binds folate receptor on the surface of ovarian cancer cells and is internalized and cleaved, releasing the cytotoxic component of the conjugate.
Vintafolide was evaluated in an international randomized, open-label phase II trial involving patients with platinum-resistant ovarian cancer. About two-thirds of the patients had primary platinum resistance and a median platinum-free interval of less than 5 months.
Patients were randomized 2:1 to PLD plus vintafolide or PLD alone. The primary endpoint was PFS.
The final analysis comprised 149 patients, who had a median age of about 60. The PFS advantage in the vintafolide arm translated into a 37% reduction in the hazard for progression (P=0.031).
Prior to randomization, a subgroup of 94 patients underwent scanning with technetium-labeled folate (EC20, etarfolatide) to determine their folate receptor status. Imaging results showed that 20% of scanned patients had folate receptor-negative tumors, and 80% had at least one lesion that expressed folate receptor. In half of the receptor-positive patients, all lesions expressed folate receptor.
Naumann reported that receptor-negative patients randomized to the conjugate plus PLD did worse than those treated with PLD alone (median PFS 3.8 months versus 5.4 months).
Patients with one receptor-positive lesion had a median PFS of 5.7 months with vintafolide and 1.7 months with PLD alone (HR 0.55, P=0.041). A similar advantage was observed in patients who had only receptor-positive lesions (median PFS 5.5 months versus 1.5 months, HR 0.38, P=0.013).
Overall survival did not differ between treatment groups, and Naumann pointed out that the trial lacked statistical power to evaluate survival. He also noted that the patients who received only PLD had a median overall survival of 17 to 18 months, whereas historical patients from previous studies of single-agent PLD had a median survival of less than 13 months.
Treatment-emergent adverse events occurred more often in the vintafolide arm, particularly anemia (40.2% versus 26%), neutropenia (41.1% versus 24%), fatigue (48.6% versus 34%), constipation (32.7% versus 14%), peripheral neuropathy (25.2% versus 6%), stomatitis (43.9% versus 40%), and hand-foot syndrome (40.2% versus 40%).
Grade 3-4 adverse events were infrequent in both treatment arms. No patient developed febrile neutropenia, and the frequency of serious adverse events did not differ between groups.
If borne out in the ongoing phase III trial, the results would constitute a significant advance in the treatment of ovarian cancer, according to another investigator in the trial.
“It’s important to realize that all of these patients were treatment-resistant, and traditionally it has been very difficult to show a benefit in this subgroup of patients with ovarian cancer,” Robert L. Coleman, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today.
“In fact, no phase III study has ever shown an improvement in progression-free survival in platinum-resistant patients, beyond the standard therapies that we use.”
The study was supported by Endocyte.
Naumann had no disclosures. Coleman disclosed relationships with Regeneron, sanofi-aventis, Novartis, Morphotek, Merck, GlaxoSmithKline, Esperance, Genentech/Roche, AstraZeneca, Centocor, Boehringer-Ingelheim, Nektar, Janssen, and Endocyte.
Primary source: Society of Gynecologic Oncology
Source reference: Naumann RW, et al “A randomized phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, versus PLD alone, in subjects with platinum-resistant ovarian cancer” SGO 2012; Seminal Abstract.
By Charles Bankhead