Second-line lenvatinib in patients with recurrent endometrial cancer.

OBJECTIVE: This study assessed the efficacy of lenvatinib, a multitargeted tyrosine kinase inhibitor, as second-line therapy in patients with unresectable endometrial cancer. The primary end point was the objective response rate (ORR) as assessed by independent radiologic review (IRR). Secondary end points included median progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Exploratory end points examined the association of baseline levels of plasma biomarkers (50 circulating cytokine and/or angiogenic factors measured by immunoassays) with efficacy outcomes. METHODS: An international, open-label, single-arm, multicenter, phase 2 trial was conducted. Eligible patients had histologically confirmed unresectable endometrial cancer that relapsed after 1 prior systemic platinum-based chemotherapy. Patients received once-daily oral lenvatinib 24 mg in a 28-day dosing cycle. RESULTS: There were 133 patients in the study. By IRR, 19 patients had a confirmed objective response for an ORR of 14.3% (95% CI: 8.8-21.4). Durable stable disease (≥23 weeks) was observed in 31 patients (23.3%) and the clinical benefit rate was 37.6% (95% CI: 29.3-46.4). Median PFS was 5.6 months (95% CI: 3.7-6.3), and median OS was 10.6 months (95% CI: 8.9-14.9). The most common (any grade) treatment-related adverse events were fatigue/asthenia (48%), hypertension (49%), nausea/vomiting (32%), decreased appetite (32%), and diarrhea (31%). Lower baseline levels of angiopoietin-2 were associated with longer PFS, OS, and a higher ORR. CONCLUSIONS: Patients with recurrent endometrial cancer treated with second-line lenvatinib experienced modest antitumor activity and treatment was generally well tolerated, with a safety profile consistent with previous studies.

PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer.

PURPOSE: Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined. PATIENTS AND METHODS: Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups. RESULTS: The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806). CONCLUSION: Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.

OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.

PURPOSE: This randomized, multicenter, blinded, placebo-controlled phase III trial tested the efficacy and safety of bevacizumab (BV) with gemcitabine and carboplatin (GC) compared with GC in platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer (ROC). PATIENTS AND METHODS: Patients with platinum-sensitive ROC (recurrence ≥ 6 months after front-line platinum-based therapy) and measurable disease were randomly assigned to GC plus either BV or placebo (PL) for six to 10 cycles. BV or PL, respectively, was then continued until disease progression. The primary end point was progression-free survival (PFS) by RECIST; secondary end points were objective response rate, duration of response (DOR), overall survival, and safety. RESULTS: Overall, 484 patients were randomly assigned. PFS for the BV arm was superior to that for the PL arm (hazard ratio [HR], 0.484; 95% CI, 0.388 to 0.605; log-rank P < .0001); median PFS was 12.4 v 8.4 months, respectively. The objective response rate (78.5% v 57.4%; P < .0001) and DOR (10.4 v 7.4 months; HR, 0.534; 95% CI, 0.408 to 0.698) were significantly improved with the addition of BV. No new safety concerns were noted. Grade 3 or higher hypertension (17.4% v < 1%) and proteinuria (8.5% v < 1%) occurred more frequently in the BV arm. The rates of neutropenia and febrile neutropenia were similar in both arms. Two patients in the BV arm experienced GI perforation after study treatment discontinuation. CONCLUSION: GC plus BV followed by BV until progression resulted in a statistically significant improvement in PFS compared with GC plus PL in platinum-sensitive ROC.

Phase II evaluation of nanoparticle albumin-bound paclitaxel in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer.

PURPOSE: Patients with recurrent ovarian, peritoneal, or fallopian tube cancer have limited therapeutic options. There are no reports of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with recurrent platinum-sensitive disease. We report efficacy and toxicity with nab-paclitaxel in this group. PATIENTS AND METHODS: Forty-seven patients enrolled (44 assessable patients). Main inclusion criteria were histologically or cytologically confirmed epithelial cancer of the ovary, fallopian tube, or peritoneum (any stage, grade 2 to 3 if stage I) and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) or elevated CA-125 (> 70 U/mL) in patients without measurable disease. Patients received nab-paclitaxel 260 mg/m(2) administered intravenously for 30 minutes on day 1 of a 21-day cycle for six cycles or until disease progression. RESULTS: Median age was 65.5 years; 76% of patients had stage IIIC or IV disease, 81% had Eastern Cooperative Oncology Group performance status of 0, and 94% had prior surgery. For assessable patients, the objective response rate (ORR) was 64% (15 complete responses [CR] and 13 partial responses [PR] among 44 assessable patients). In patients evaluated with RECIST only, the ORR was 45% (one CR and four PR of 11 patients). In patients with only elevated CA-125, ORR was 82% (seven CRs and two PRs of 11 patients). In patients meeting both RECIST and CA-125 criteria, the ORR was 64% (seven CRs and seven PRs of 22 patients). Median time to response was 1.3 months (range, 0.5 to 4.8 months). Estimated median progression-free survival was 8.5 months. The most frequent grade 3 to 4 treatment-related toxicities were neutropenia (24%) and neuropathy (9%). CONCLUSION: Nab-paclitaxel is active in this group of patients with recurrent ovarian, peritoneal, or fallopian tube cancer. The ORR was 64%. Toxicities were manageable. Further studies of nab-paclitaxel in combination with platinum are warranted.

Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer.

PURPOSE: Ovarian cancer (OC) patients experiencing progressive disease (PD) within 6 months of platinum-based therapy in the primary setting are considered platinum resistant (Pt-R). Currently, pegylated liposomal doxorubicin (PLD) is a standard of care for treatment of recurrent Pt-R disease. On the basis of promising phase II results, gemcitabine was compared with PLD for efficacy and safety in taxane-pretreated Pt-R OC patients. PATIENTS AND METHODS: Patients (n = 195) with Pt-R OC were randomly assigned to either gemcitabine 1,000 mg/m2 (days 1 and 8; every 21 days) or PLD 50 mg/m2 (day 1; every 28 days) until PD or undue toxicity. Optional cross-over therapy was allowed at PD or at withdrawal because of toxicity. Primary end point was progression-free survival (PFS). Additional end points included tumor response, time to treatment failure, survival, and quality of life. RESULTS: In the gemcitabine and PLD groups, median PFS was 3.6 v 3.1 months; median overall survival was 12.7 v 13.5 months; overall response rate (ORR) was 6.1% v 8.3%; and in the subset of patients with measurable disease, ORR was 9.2% v 11.7%, respectively. None of the efficacy end points showed a statistically significant difference between treatment groups. The PLD group experienced significantly more hand-foot syndrome and mucositis; the gemcitabine group experienced significantly more constipation, nausea/vomiting, fatigue, and neutropenia but not febrile neutropenia. CONCLUSION: Although this was not designed as an equivalency study, gemcitabine and PLD seem to have a comparable therapeutic index in this population of Pt-R taxane-pretreated OC patients. Single-agent gemcitabine may be an acceptable alternative to PLD for patients with Pt-R OC.