Rohit Lal, MD
The vinca alkaloid vintafolide administered with docetaxel showed improvements in progression-free survival (PFS) and overall survival (OS) compared with single-agent docetaxel as second-line treatment in a randomized phase II study of patients with folate receptor–positive non-small cell lung cancer (NSCLC). The study (known as TARGET) failed, however, to achieve significance on the primary endpoint of at least a 50% improvement in PFS with the combination over docetaxel alone.
The combination worked especially well in a predefined subset of patients with adenocarcinoma, who had a near 50% improvement in OS compared with docetaxel alone, according to Rohit Lal, MD, at the 2014 ESMO Congress.
The data demonstrate that the folate receptor is a promising target in NSCLC, said Lal, consultant medical oncologist, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom.
Vintafolide is a small molecule conjugate with a folate receptor-specific targeting ligand, with a vinca alkaloid chemotherapy group, joined by a spacer linker system. “The folate conjugate binds the folate receptor and is internalized by endocytosis,” said Lal.” The vinca alkaloid chemotherapy is cleaved inside the endosome. The drug exits the endosome and exerts cytotoxic activity on the cell. The folate receptor recycles back to the cell surface.”
Tc-etarfolatide is a complementary imaging biomarker developed along with vintafolide. Tc-etarfolatide has the same folate receptor-specific targeting ligand but is joined with the tracer technetium 99, joined by a covalent bond.
In explaining the rationale for TARGET, Lal pointed to a phase II study of heavily pretreated folate receptor–positive patients with NSCLC, in which single-agent vintafolide was associated with a disease control rate of 57.1%, a median PFS of 7.1 months, and a median OS of 10.8 months.
TARGET was open to all subgroups of patients with NSCLC who had been treated with 1 prior therapy. All patients underwent a Tc-etarfolatide scan. The 199 patients in whom all target lesions were folate receptor–positive moved forward into randomization equally into 3 study arms.
Arm A received vintafolide, 2.5 mg intravenously on days 1, 4, 8, and 11 every 3 weeks
Arm B received vintafolide per arm A plus docetaxel, 75 mg/m2 intravenously on day 1 every 3 weeks.
Arm C received docetaxel alone per arm B.
Patients continued on treatment until disease progression or unacceptable toxicity. The primary endpoint was PFS, with a 75% power to detect a 50% improvement in PFS over docetaxel. Results were were stratified according to histologic subgroup—squamous or adenocarcinoma. Some 63% to 72% of patients in each arm had adenocarcinoma.
The median number of treatment cycles was 2 in the vintafolide monotherapy arm, 4 in the vintafolide plus docetaxel arm, and 4 in the docetaxel monotherapy arm. Some 81% in the combination arm had ≥1 dose omitted, mostly due to hematologic toxicity.
“The primary endpoint for the study was negative. The study failed to show a 50% improvement in PFS when compared to docetaxel,” said Lal. The median PFS was 1.6, 4.2, and 3.3 months in arms A, B, and C, respectively. The PFS hazard ratio (HR) for vintafolide alone compared with docetaxel alone was 1.35 (1-sided, P
= .9421) and for the vintafolide/docetaxel combination versus docetaxel alone it was 0.75 (1-sided, P
=.0696). Median OS was 8.4, 11.5, and 8.8 months in arms A, B, and C, respectively.
The HR for OS for vintafolide alone compared with docetaxel alone was 1.05 (1-sided, P
= .5818), and for the combination compared with docetaxel alone, the PFS HR was 0.88 (1-sided P
The disease control rates were 41.2% in the vintafolide monotherapy arm, 70.6% in the combination arm, and 60.3% in the docetaxel monotherapy arm.
The PFS endpoint was not significantly different between arms in the overall study population and in the subgroup with adenocarcinoma. Likewise, there was no significant difference in OS between the 3 arms in the overall study population. For the subgroup with adenocarcinoma, however, the HR for OS in the combination arm was 0.51 compared with the docetaxel arm (1-sided, P
The safety profile was as expected from the experience with the single agents. Peripheral neuropathy was nearly twice as common in the vintafolide/docetaxel arm compared with either monotherapy. Grade 3 peripheral neuropathy occurred in 9 patients randomized to combination therapy compared with 2 patients randomized to vintafolide alone and 0 randomized to docetaxel alone.