June 2014 Edition Vol.8, Issue 6

Targeted Therapies Stay in the Spotlight: Late Breaking Studies in NSCLC, Thyroid, and Ovarian Cancers

Targeted Therapies Stay in the Spotlight: Late Breaking Studies in NSCLC, Thyroid, and Ovarian Cancers

By Lynne Lederman, PhD

Ramucirumab in NSCLC: Results from the REVEL Trial

Maurice Pérol, MD, Léon-Bérard Cancer Centre, Lyon, France, presented REVEL: a randomized, double-blind, phase 3 study of docetaxel and ramucirumab (RAM; IMC-1121B) versus docetaxel and placebo in the second-line treatment of stage IV NSCLC following disease progression after one prior platinum-based therapy.1 This trial (NCT01168973) was sponsored by ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company. Results were published in conjunction with the meeting.2

Most patients with NSCLC will not have an identifiable biomarker that can be targeted and will experience disease progression; many will require second-line therapy, in which progress has been limited. The median overall survival (OS) for the approved agents in this setting (docetaxel, pemetrexed, and erlotinib) is 7 to 8 months.

Ramucirumab, a human IgG1 monoclonal antibody, specifically binds to the extra-cellular domain of vascular endothelia growth factor receptor (VEGFR)-2. It was FDA approved for second-line therapy of advanced gastric cancer or gastro-esophageal junction adenocarcinoma cancer in April.3

The REVEL trial randomly assigned patients with stage IV NSCLC after one platinum-based chemotherapy regimen to either ramucirumab plus docetaxel (n=628) or to placebo plus docetaxel (n=625). Prior therapy could include bevacizumab but not docetaxel or monotherapy with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The planned enrollment was needed to show an OS benefit.

ORR (overall response rate) [complete response (CR) + partial response (PR)] was 22.9% in the ramucirumab plus docetaxel arm vs. 13.6% in the docetaxel alone arm (P<.001). The disease control rate [CR+PR+SD (stable disease)] was 64.0% vs. 53.6% respectively (P<.001). Median OS was 10.5 months vs. 9.1 month (P=.0235) and median progression-free survival (PFS) was 4.5 months vs. 3.0 months, respectively (P<.0001).

Subgroup analyses favored the ramucirumab arm for PFS and OS in most subgroups, including smoking history, prior taxanes, prior bevacizumab, and tumor histology. Treatment-emergent adverse events (TEAE) occurred in most patients in both arms and were as expected: neutropenia, febrile neutropenia, thrombocytopenia, stomatitis, mucosal inflammation peripheral edema, and increased lacrimation occurred more often in the ramucirumab group, as did Grade 1 and 2, but not higher grade bleeding/hemorrhage and epistaxis.

REVEL is the first study to show that adding a novel targeted agent to standard chemotherapy improves survival in stage IV NSCLC with disease progression after platinum-based therapy, and the first to show some efficacy using an anti-angiogenic monoclonal antibody in this setting. Although the benefit for ramucirumab was only a 1.4 month increase in median OS and 1.5 month increase in PFS, Gregory A. Masters, MD, Helen F. Graham Cancer Center, Newark, Delaware and a member of ASCO’s Cancer Communication Committee, commented that the steps in improving survival in lung cancer are “small, but encouraging.” However, there is no predictive biomarker for the use of ramucirumab.

It is not yet clear what the cost of ramucirumab for treating NSCLC will be, although it is not unreasonable to assume the drug will be in the range of other monoclonal antibodies, so a cost-benefit analysis will need to take into account the small increases in OS and PFS and the side-effect profile.

Radioiodine-Resistant Thyroid Cancer Responds to Lenvatinib

Martin Schlumberger, MD, Gustave Roussy and University Paris-Sud, Villejuif, France, presented a phase 3, multicenter, double-blind, placebo-controlled SELECT trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer.4 As with stage IV NSCLC, treatment options are limited for patients with radioiodine-resistant differentiated thyroid cancer (RR-DTC). Although VEGF-signaling pathways appear to drive angiogenesis in thyroid cancer, other pathways are involved in the pathogenesis of this disease.

Lenvatinib is an oral multi-tyrosine kinase inhibitor with activity against VEGF-1, -2, -3, FGFR-1, -2, -3, -4, PDGFR (platelet-derived growth factor receptor), RET, and KIT, and showed activity in a phase 2 study in RR-DTC. In the SELECT trial (NCT01321554, sponsored by Eisai Inc., patients with 131I-refractory DTC previously treated with up to 1 prior VEGF or VEGFR-targeted therapy were randomly assigned 2:1 to lenvatinib (n=261) or placebo (n=131). Most patients had not received prior VEGF-targeted therapy.

Patients receiving lenvatinib had a median PFS (the primary endpoint) of 18.3 months vs. 3.6 months for placebo (P<.0001). For patients with no prior VEGF-targeted therapy the median PFS was 18.7 months vs. 3.6 months; for patients with prior VEGF-targeted therapy the median PFS was 15.1 months vs. 3.6 months (P<.0001 for both analyses). Lenvatinib was favored in a PFS subgroup analyses for all subgroups. ORR was 65% for lenvatinib (63% PR) vs. 2% for placebo (P<.0001). Median time to objective response was 2.0 months and the duration of response was not reached for the lenvatinib arm; 75% of responders had an objective response for over 9.4 months. Median OS was not reached for either arm and no significant difference was observed in the rank-preserving structural failure time-adjusted OS, which was used to correct for any cross-over effect in the placebo arm (allowed for progressive disease).


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