Best response rate by dose level.

<p>Best response rate by dose level.</p

Adverse events in all cycles of treatment for all patients receiving at least one cycle of treatment in the CSV and MSV groups.

<p>Adverse events in all cycles of treatment for all patients receiving at least one cycle of treatment in the CSV and MSV groups.</p

CONSORT Flow diagram.

<p>CONSORT Flow diagram.</p

Dose Escalation Schedule for the CSV and MSV arms.

<p>Dose Escalation Schedule for the CSV and MSV arms.</p

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules - Fig 3

<p>Mean plasma concentration-time curves of erlotinib (A) on Day 3 after initial oral dose with CSV dosing regimen of vinorelbine, (B) on Day 10 at the steady state after oral dose with CSV dosing regimen of vinorelbine, (C) on Day 3 after initial oral dose with MSV dosing regimen of vinorelbine and (D) on Day 10 at the steady state after oral dose with MSV dosing regimen of vinorelbine.</p

Patient demographics and baseline characteristics.

<p>Patient demographics and baseline characteristics.</p

Survival curves.

<p>(A) Patients grouped according to the <i>ABCB1 3435C/T</i>, <i>1236C/T</i>, <i>2677G/T</i> haplotype; median PFS was 2.4 months for homozygous carriers of the <i>TTT</i> haplotype and 8.4 months for other cases (<i>P</i> = 0.001). (B) Patients grouped according to the <i>ABCB1 3435C/T</i>, <i>1236C/T</i>, <i>2677G/TA</i> haplotype; median OS was 4.6 months for homozygous carriers of the <i>TTT</i> haplotype and 19.6 months for other cases (<i>P</i> = 0.005).</p

Polymorphisms genotyped and allele frequencies.

<p>^a Patients successfully genotyped.</p><p>^b Includes 34 <i>GT</i> and 10 <i>AG</i> individuals.</p><p>^c Includes 2 <i>AA</i>, 12 <i>AT</i> and 13 <i>TT</i> individuals.</p><p>^d A 2,903-bp deletion polymorphism in intron 2 of <i>BIM</i> previously associated with resistance to tyrosine kinase inhibitors [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134102#pone.0134102.ref028" target="_blank">28</a>]. As we were unable to genotype formalin-fixed tissues with the current method, only 45 patients were typed.</p><p>^e Variant allele frequencies.</p><p>Polymorphisms genotyped and allele frequencies.</p

Association of <i>ABCB1</i> and <i>FLT3</i> Polymorphisms with Toxicities and Survival in Asian Patients Receiving Sunitinib for Renal Cell Carcinoma

<div><p>Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corresponding biomarkers of efficacy and toxicity has been hitherto conducted in Caucasian populations, and few of the reported associations have been externally validated. Our work thus aims to investigate candidate biomarkers in Asian patients receiving sunitinib, comparing the observed genotype effects with those reported in Caucasian populations. Using data from 97 Asian mRCC patients treated with sunitinib, we correlated 7 polymorphisms in <i>FLT3</i>, <i>ABCB1</i>, <i>VEGFR2</i>, <i>ABCG2</i> and <i>BIM</i> with patient toxicities, response, and survival. We observed a stronger association of <i>FLT3 738T</i> genotype with leucopenia in our Asian dataset than that previously reported in Caucasian mRCC patients (odds ratio [OR]=8.0; <i>P</i>=0.03). We observed significant associations of <i>FLT3 738T</i> (OR=2.7), <i>ABCB1 1236T</i> (OR=0.3), <i>ABCB1 3435T</i> (OR=0.1), <i>ABCB1 2677T</i> (OR=0.4), <i>ABCG2 421A</i> (OR=0.3) alleles and <i>ABCB1 3435</i>, <i>1236</i>, <i>2677 TTT</i> haplotype (OR=0.1) on neutropenia. Primary resistance (OR=0.1, <i>P</i>=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, <i>P</i>=0.001; overall: HR=5.0, <i>P</i>=0.005) were associated with the <i>ABCB1 3435</i>, <i>1236</i>, <i>2677 TTT</i> haplotype. In conclusion, <i>ABCB1</i> and <i>FLT3</i> polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients. We have also validated the association between <i>FLT3 738T</i> and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.</p></div

Patient demographics and baseline characteristics (n = 97).

<p>Patient demographics and baseline characteristics (n = 97).</p