Lapatinib minimally effective for non-small-cell lung cancer
3 D0 ^& @( q; a' [, C: O% kMARCH 18, 2010
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+ i* F- A* ?5 P8 CNEW YORK (Reuters Health) - Although well tolerated, lapatinib is minimally effective as monotherapy for advanced or metastatic non-small-cell lung cancer (NSCLC), according to a report in the March 15th Clinical Cancer Research.
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Lapatinib (GlaxoSmithKline) is a tyrosine kinase inhibitor of both epidermal growth factor receptor (EGFR) and HER2, the authors explain, and thus has theoretical advantages over inhibition of either EGFR or HER2 alone.
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. U% R3 @/ ?9 R* ?! O6 VDr. Helen J. Ross, from Mayo Clinic, Scottsdale, Arizona, and colleagues evaluated the overall response rate to lapatinib in 131 patients with advanced or metastatic NSCLC. Sixty-five patients were randomized to lapatinib 1500 mg once daily and 66 to lapatinib 500 mg twice daily.
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4 ?& C6 D- Y- H" ~! PWhen the study began, patients with any type of advanced or metastatic NSCLC were recruited ("non-targeted" population). However, when data from other studies began to show that EGFR inhibitors are particularly effective in patients with bronchioloalveolar carcinoma and in never-smokers with any histology of NSCLC, recruitment began to "target" such patients.0 p$ g* |4 T2 j. V$ [ L; t( X
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The targeted population included 24 patients in the 1500 mg/day group and 32 in the 500 mg twice daily group. The corresponding numbers in the non-targeted population were 41 and 34.
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" m! o& P ]- z) V" D! G8 f& f8 s7 ZAt the interim analysis of the first 30 targeted patients to reach the initial response evaluation, the response rate was 0% in both treatment groups. In the non-targeted population, one patient in the 1500-mg group achieved a partial response. / T* c+ h0 w2 A5 ?+ L
& L0 }6 f' M+ H7 C1 P% fOverall, 31 of 131 patients (24%) had stable disease or better. 8 W% [% C, n- X$ l- [" q+ `/ X& x
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Based on these findings, the study was stopped for reasons of futility, the investigators state. % G! b( V' P4 L& ~9 u) u7 e, J# A
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Overall survival in the targeted population was 15.2 months for the 1500-mg once-daily group and 13.9 months for the 500-mg twice-daily group, and in the nontargeted population, overall survival was 11.4 months for the 1500-mg once-daily group and 8.1 months for the 500-mg twice-daily group. - z% c G6 f& N, z9 P$ c# l$ h8 k
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Median progression-free survival was 15.6 weeks (1500-mg once-daily) and 8.7 weeks (500-mg twice-daily) in the targeted population and 12.0 weeks (1500-mg once-daily) and 8.6 weeks (500-mg twice-daily) in the nontargeted population. 6 j7 k3 _. F5 f; o+ E* N
3 f! X9 j" R0 M& s$ t! kThe incidence of adverse events considered to be related to study medication was 89% for 1500 mg once daily and 83% for 500 mg twice daily, but only 8% of patients in each group experienced serious adverse events related to study medication.
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Among 92 patients with tumor tissue available, 2 had mutations in EGFR and 1 had mutations in both EGFR and KRAS. None had mutations in HER2. 0 R0 D: @7 E% ?3 |. [3 c" C' l& C
* _" n3 N: D7 \# |8 ~Of 77 patients with sufficient DNA for gene copy evaluation, 5 (8.8%) had increased EGFR copy number and 2 (3.5%) had increased HER2 gene copy number.
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None of the patients with EGFR mutations responded to lapatinib, and only 1 patient with HER2 amplification had an unconfirmed decrease of 51% in tumor measurement.
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5 Y$ A. ]0 }: W"Lapatinib as a single agent at the doses studied seems to have minimal single-agent activity, at least as measured by response rates," the authors conclude, "although progression-free survival in the 1500-mg once-daily group was in the range that would be expected with first-line chemotherapy." ; l0 f* D% x2 N
8 @7 u3 G% u* K; N! @: V; V1 C"Patients in this small study had a suggestion of disease stabilization with lapatinib," Dr. Ross said. "It would be of interest to examine it in the adjuvant setting after resection perhaps, after chemoradiotherapy perhaps or after up-front chemotherapy. It is possible that combination with other targeted agents, such as anti-angiogenic agents, might be useful."
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The study was sponsored by GlaxoSmithKline., X3 T* [6 U2 Q& B1 W9 H8 V
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