Erlotinib as first-line treatment of European non-small-cell lung cancer (NSCLC) patients (pts.)...

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Abstracts / Lung Ca

ethodology: All patients from an investigated group with clin-cally verified diagnosis of NSCLC were undergone tumor tissueampling and peripheral anticoagulated blood collection whichmmediately blood plasma was isolated from. The tissue samples

ere examined for mutations of EGFR and KRAS. Patients withetected mutation were also submitted methylation tests in tis-ue. The cfDNA was extracted from a plasma sample, and a test ofresence of the mutation in cfDNA (detection of a tumor compo-ent) was carried out. In the tumor cfDNA the methylation test ofpanel of 30 selected genes was performed.ll mutation analyses were carried out with a denaturing capillarylectrophoresis (DCE) on a standard DNA sequencer ABI3100 usingits Genoscan KRAS and Genoscan EGFR. Methylation tests wereerformed using MLPA.esults: A group of 107 patients in the study included 26 patientsith some of EGFR or KRAS mutations (14× EGFR, KRAS 12×).

he presence of the tumor cfDNA was detected in plasma ofpatients who were subsequently undergone the methylation

ests. Comparing the methylation profiles of primary tumors andumor cfDNA compliance in genes VHL (4/8, 50%), APC (3/8, 37%),TEN (3/8, 37%), CASP8 (3/8, 37%) and TIMP3 (3/8, 37%) wasetected. Each of observed patients showed hypermethylation

n a primary tumor in at least one of the affected genes andubsequently hypermethylation was demonstrated in the tumorfDNA.onclusion: Results of our pilot study have demonstrated theotential for free DNA in the peripheral blood not only for investiga-ion of the presence of EGFR and KRAS gene mutations, but also fornvestigation of methylation status of genes significant for biolog-cal manifestation of non-small cell carcinoma. In this study EGFRnd KRAS gene mutations were used as a marker of the presence ofhe tumor DNA in peripheral blood.

ttp://dx.doi.org/10.1016/j.lungcan.2012.05.041

rlotinib as first-line treatment of European non-small-cellung cancer (NSCLC) patients (pts.) with epidermal growthactor receptor (EGFR) activating mutations (mut+)

ubos Petruzelka. Department of Oncology and Institute foradiation Oncology, 1st Faculty of Medicine, Charles University,rague, Czech Republic

ackground: Mutation at the tyrosine kinase (TK) domain ofGFR results in its constitutive activation. Downstream EGFR sig-alling leads to increased proliferation, angiogenesis, metastasisnd decreased apoptosis. Nearly 90% of EGFR mutations representoint mutation L858R and exon 19 deletion. EGFR mut+ NSCLC isore common in East Asian pts. (∼30%), women, never smokers

nd adenocarcinoma. Phase II SLCG study detected EGFR mutationsn 16.6% of Spanish pt., although pts. were slightly pre-selected.URTAC was the first prospective phase III study assessing TKnhibitor, erlotinib vs chemotherapy (CT) in first line of NSCLC treat-

ent of EGFR mut+ European pts.ethods: 1227 Caucasian pts. were screened in EURTAC study for

GFR mutations. 174 patients were randomised to receive erlotinibr platinum-based CT. The primary endpoint was progression-freeurvival (PFS). Secondary endpoints included response, overall sur-ival and toxicity profiles.esults: PFS results from OPTIMAL study, assessing erlotinib vs CT

n Chinese pts. with EGFR mut+ NSCLC showed HR 0.16, with PFS3.1 months in favour of erlotinib vs 4.6 months in CT arm. Phase

I studies in Caucasian pts. showed PFS 14 months (SLCG), 14.1onths (CALBG30406) and 13.0 months (FIELT). At final data cut-off

26 January 2011) mPFS in EURTAC was 9.7 months in the erlotinibs 5.2 months in CT arm (HR0.37; p < 0.0001), response rate 58%

7 (2012) S21–S27 S25

in erlotinib vs 15% in CT arm (p < 0.0001).Main grade 3/4 toxicitieswere rash (13%), fatigue (6%) and diarrhoea (5%) in erlotinib, andneutropenia (22%), fatigue (20%), and thrombocytopenia (14%) inCT arm.Conclusion: Before deciding on first-line TKI it is essential to defineEGFR mutation status. Erlotinib as first-line treatment for CaucasianNSCLC pts. with EGFR mutations improves PFS, with acceptabletoxicity, compared to platinum-based chemotherapy. Most appro-priate treatment option should be given to patient to maximise itsclinical benefit.

http://dx.doi.org/10.1016/j.lungcan.2012.05.042

LUX-lung 3: A randomized, open-label, phase III study ofafatinib vs pemetrexed and cisplatin as first-line treatment forpatients with advanced adenocarcinoma of the lung harboringEGFR-activating mutations

Martin Schuler 1, James Chih-Hsin Yang 2, Nobuyuki Yamamoto 3,Ken O’Byrne 4, Vera Hirsh 5, Tony Mok 6, Dan Massey 7, VictoriaZazulina 7, Mehdi Shahidi 7, Lecia Sequist 8. 1 West German CancerCenter, University Duisburg-Essen, Essen, Germany, 2 NationalTaiwan University Hospital, Taipei, Taiwan, 3 Shizuoka CancerCenter, Shizuoka, Japan, 4 St. James’ Hospital, Dublin, Ireland, 5 McGillUniversity, Montreal, QC, Canada, 6 Prince of Wales Hospital, Shatin,Hong Kong, 7 Boehringer Ingelheim Limited, Bracknell, UK,8 Massachusetts General Hospital, Boston, MA, USA

Background: Afatinib is a selective, orally bioavailable, irreversibleErbB family blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4. Thisglobal study investigated the efficacy and safety of afatinib com-pared with pemetrexed/cisplatin in patients with EGFR mutationpositive advanced lung adenocarcinoma.Materials and methods: Following central testing for EGFR muta-tions (companion diagnostic TheraScreen EGFR RGQ PCR kit), 345patients (stage IIIB/IV, PS 0–1, chemo-naive) were randomized 2:1(afatinib: 230; pemetrexed/cisplatin: 115) to daily afatinib 40 mgor iv pemetrexed/cisplatin (500 mg/m2 + 75 mg/m2 q21 days up to6 cycles). Primary endpoint was progression-free survival (PFS) bycentral independent review; secondary endpoints included objec-tive response rate (ORR), time to deterioration in cancer-relatedsymptoms and safety.Results: Baseline characteristics were balanced in both arms:median age, 61 years; female, 65%; Asian, 72%; never-smoker, 68%;Del19, 49%; L858R, 40%; other mutations, 11%. Treatment with afa-tinib led to a significantly prolonged PFS vs pemetrexed/cisplatin(median 11.1 vs 6.9 months; HR 0.58 [0.43–0.78]; p = 0.0004).In 308 patients with common mutations (Del19/L858R), medianPFS was 13.6 vs 6.9 months, respectively (HR = 0.47 [0.34–0.65];p < 0.0001). ORR was significantly higher with afatinib (56% vs23%; p < 0.0001). Significant delay in time to deterioration ofcancer-related symptoms of cough (HR = 0.60, p = 0.0072) anddyspnea (HR = 0.68, p = 0.0145) was seen with afatinib vs peme-trexed/cisplatin. Most common drug-related adverse events (AEs)were diarrhea (95%), rash (62%) and paronychia (57%) with afa-tinib, and nausea (66%), decreased appetite (53%) and vomiting(42%) with pemetrexed/cisplatin. Drug-related AEs led to discon-tinuation in 8% (afatinib; 1% due to diarrhea) and 12% of patients(pemetrexed/cisplatin).Conclusions: LUX-Lung 3 is the largest prospective trial inEGFR mutation positive lung cancer and the first study usingpemetrexed/cisplatin as a comparator. Treatment with afatinib sig-