Tx-related Adverse Events Research Articles

814P - A Phase IB Clinical Trial of the Multitargeted Kinase Inhibitor Lenvatinib (E7080) in Combination with Everolimus for Treatment of Metastatic Renal Cell Carcinoma (RCC)

ABSTRACT Background Lenvatinib (L) is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR 1-4, RET, KIT, and PDGFβ. Everolimus (E) is an oral mTOR inhibitor approved for RCC. This Phase (Ph) 1b/2 study investigates the combination of L plus E in RCC patients (pts) (NCT01136733). The Ph 1b component reported here assessed safety, tolerability, and maximum tolerated dose (MTD). The 3-arm randomised Ph 2 comparing PFS of L plus E and L alone versus E alone is ongoing. Methods Pts with advanced unresectable or metastatic RCC, ECOG PS 0-1, age ≥18 y were eligible for Ph 1b. Pts received L plus E, daily, in 28-day cycles. A standard 3 + 3 dose-escalation design with expansion cohort was used to identify the MTD. Results 20 pts (M/F: 14/6; median age: 59 y [range 46-72]; median of 2 prior therapeutic regimens [range 0-5]; 17/20 pts [85%] had received prior anti-VEGF treatment (tx); 7/20 pts [35%] had also received prior mTOR-targeted tx) were treated at 3 dose levels of L (12 mg [n = 7]; 18 mg [n = 11]; 24 mg [n = 2]) in combination with E 5 mg. 4 DLTs were observed: G3 nausea and vomiting (1 pt) and G2 mucositis (1 pt) at 24 mg; G3 elevated CPK at 18 mg; G3 abdominal pain at 12 mg. The MTD was L 18 mg plus E 5 mg. Median duration of tx was 14.5 wk (range 1-68, 7/20 (35%) pts ongoing). The most common tx-related adverse events (AEs), all grades were fatigue 45% (G3, 5%); mucosal inflammation 40%; proteinuria 35% (G3, 10%); diarrhoea 30% (G3, 5%); rash 30%; hypertension 25%; nausea, vomiting each 25% (each G3 5%); constipation, decreased appetite, epistaxis each 20%. There was 1 G4 related AE of hypercholesterolemia. PR was observed in 6/18 (33%) pts in the MTD and lower dosing cohorts. Durable stable disease (≥23 wk) or PR were achieved in 8/16 (50%) pts with postbaseline tumor assessments (and 3 pts ongoing with SD Conclusions Lenvatinib 18 mg in combination with everolimus 5 mg appeared to be safe when administered to multiply pretreated patients with advanced RCC in this Ph 1b part. The PRs observed and response durability warrant further evaluation in this refractory population during the ongoing Ph 2 part of the study. Disclosure A.M. Molina: A. Molina discloses research funding from EISAI and Novartis. J. Larkin: J. Larkin has received honoraria from EISAI. A. Gold: A. Gold is an employee of Eisai, Inc. C. Andresen: C. Andresen is an employee of Eisai, Inc. K. Wood: K. Wood is an employee of EISAI, Ltd. R.J. Motzer: R. Motzer discloses research funding from EISAI and Novartis, both >$10,000. M.D. Michaelson: Dr. Michaelson discloses institutional research funding from: EISAI, Pfizer, Abbott, GlaxoSmithKline, Genentech Consultant or advisory role (UNCOMPENSATED): Pfizer, EISAI. All other authors have declared no conflicts of interest.

Randomized phase II multicenter study of the efficacy and safety of sunitinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma: Renal EFFECT Trial.

LBA308 Background: In a randomized phase III trial, sunitinib 50 mg/d on Schedule 4/2 (4 wk on treatment [Tx], 2 wk off) showed superior progression-free survival (primary endpoint) to IFN-α (11 vs. 5 mo; p<0.001) as first-line metastatic renal cell carcinoma (mRCC) therapy with a median overall survival (OS) of >2 yr (Motzer 2009). Continuous dosing of sunitinib 37.5 mg has demonstrated antitumor activity with a manageable safety profile in first- and second-line mRCC (Barrios; Escudier, 2009). Methods: This randomized phase II trial compared sunitinib 50 mg/d on Schedule 4/2 (Arm A) vs. 37.5 mg continuous once-daily dosing (Arm B) in first-line mRCC. Eligible patients (pts) had clear cell locally recurrent or mRCC; measurable disease; and Karnofsky performance status ≥70%. Randomization (1:1) was stratified by MSKCC risk groups. Sunitinib was continued until progression, unacceptable toxicity, or up to 2 yr. The primary endpoint was time to tumor progression (TTP) by Kaplan-Meier estimate. Secondary endpoints included objective response rate (ORR), OS, and adverse events (AEs). Results: Between January 2007 and June 2008, 292 pts were randomized. As of October 2010, 289 pts had received sunitinib, and all pts were off therapy. Median age was 62 yr. 65% were male. By MSKCC criteria, 28%, 61%, and 11% were favorable, intermediate, and poor risk, respectively. Pts received a median 4 and 5 Tx cycles in Arms A and B, respectively; median relative dose intensity was 90.8% and 77.5%. Dose delays, reductions, and interruptions occurred in 30% vs. 13%, 36% vs. 43%, and 65% vs. 62%, respectively; 11% and 15% discontinued due to Tx-related AEs. Median TTP was 9.9 vs. 7.1 mo in Arms A and B, respectively (HR=0.773, 95.1% CI, 0.572, 1.044; p=0.090). ORR was 32.2% vs. 28.1% (p=0.444). Median OS was 23.1 vs. 23.5 mo (p=0.615). The most common Tx-related AEs were fatigue (both 62%), nausea (56% vs. 49%), and diarrhea (56% vs. 64%). Conclusions: In this randomized phase II mRCC trial, there was a trend toward inferior TTP with continuous dosing. ORR, OS, and AE profiles were similar for the approved sunitinib 50 mg/d dose on Schedule 4/2 vs. 37.5 mg continuous dosing. [Table: see text]

Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC).

296 Background: SOR prolongs survival in patients (pts) with HCC. In preclinical studies, mammalian target of rapamycin (mTOR) inhibitors (I) impair HCC growth and angiogenesis. Adding mTOR-I to SOR augments antitumor effect. Phase I studies of mTOR-I plus SOR have shown tolerability but did not include cirrhotic pts. We developed a phase I trial of mTOR-I TEM plus SOR to determine safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) in pts with HCC. The study was approved and funded by the National Comprehensive Cancer Network (NCCN). Methods: Eligibility: Advanced HCC diagnosed histologically or clinically. No prior systemic therapy (Tx). Prior resection/local Tx permitted if ≥1 measurable site. ECOG score ≤2, Child-Pugh ≤7, bilirubin ≤2 mg/dL, platelets ≥75,000/mcL. Design: 3+3 escalation to MTD with dose-limiting toxicity (DLT) window 28 days; 6 pts at MTD for pharmacokinetics (PK). Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK. Results: 9 pts enrolled to date: 7 at DL1, 2 at DL-1. Toxicity: DL1: 1 DLT of Gr3 thrombocytopenia. 1 pt removed for hypertensive urgency, adjudicated not Tx-related. 1 pt not evaluable due to abscess. 1 pt removed for Gr3 hypersensitivity to TEM in cycle 2. All remaining pts required reduction and/or delay for adverse events (AE). Tx-related AE at DL1 include: fatigue 57%, Gr3 11%; weight loss 22%, all Gr1; anorexia 57%, all Gr1/2; diarrhea 71%, all Gr1/2; rash/hand-foot syndrome 71%, Gr3 11%; thrombocytopenia 57%, Gr3 11%; hypophosphatemia 77%, Gr3 57%, refractory 11%. Study de-escalated to DL-1 due to non-DLT cumulative AE. DL-1: 2 pts enrolled have not had DLT nor dose reduction to date. Response: 4 of 7 pts in DL1 were evaluable. 3 of 4 had stable disease as best response. Conclusions: Tx-limiting, class-related AE occurred at DL1 of this double-biologic regimen. MTD in pts with Child-Pugh Class A cirrhosis appears lower than in pts without liver disease. Tolerability and dose delivery must be achieved to determine efficacy. A phase II study with correlative endpoints is planned at RP2D. Updated accrual and results will be presented. [Table: see text] [Table: see text]

PF-00299804 (PF299) patient (pt)-reported outcomes (PROs) and efficacy in adenocarcinoma (adeno) and nonadeno non-small cell lung cancer (NSCLC): A phase (P) II trial in advanced NSCLC after failure of chemotherapy (CT) and erlotinib (E).

7596 Background: Treatment (tx) options are limited for pts with NSCLC after failure of CT and E. Cough, dyspnea, and pain (chest) are key pt-reported NSCLC symptoms (symp). PF299 is an oral, irreversible, small-molecule pan-human epidermal growth factor receptor (-1, -2, and -4) tyrosine kinase inhibitor. Methods: This open-label, single-stage, P2 trial evaluated PF299 efficacy in pts with KRAS wild-type advanced NSCLC after failure of ≥1 CT regimen and E. Pts (adeno and nonadeno) received 45 mg PF299 once daily (3-week [wk] cycles [C]). Endpoints included response (primary), safety/tolerability, and PROs assessed by the EORTC-QLQ-C30/LC13 on day (D) 1 of each C (improvement of > 5 points [p] indicates meaningful benefit). Results: 65 pts (37 female, 50 adeno) have enrolled. Of 62 evaluable pts, 3 had a partial response and 35 stable disease (SD) ≥ 6 wks. 28 pts remained on treatment (tx) at C4D1 and had complete PRO data. Common tx-related adverse events (TRAEs) included diarrhea (86%), fatigue (40%), rash (45%), and stomatitis/mucosal inflammation (23%); mainly grade 1/2 and manageable. Pts reported an increase in “diarrhea” and “sore mouth” symp after C1 then gradual improvement. Qualitatively, raw scores for these symp moved from “not at all” at baseline to “a little” at C4D1. Importantly, pts reported clinically meaningful improvements (CMIs; > 5 p) in NSCLC symp. Mean baseline QLQ-LC13 scores were: dyspnea (21.4 p), cough (28.6 p), chest pain (14.3 p), and arm/shoulder pain (20.2 p). Improvements were: dyspnea (wk 6, 8.5 p; wk 9, 5.1 p), cough (wk 3, 8.8 p; wk 6, 5.9 p), chest pain (wk 3, 6.0 p; wk 6, 5.3 p; wk 9, 10.7 p), and arm/shoulder pain (wk 6, 10 p; wk 9, 8.3 p). Conclusions: Pts with adeno or nonadeno refractory NSCLC receiving PF299 in this study experience clinical benefit despite prior erlotinib tx. Pts report relief of NSCLC symp, including CMIs in key symp of cough, dyspnea, and pain. TRAEs were manageable. PRO results suggest that diarrhea and mucositis, while present, were tolerable. These results support further evaluation; a P3 trial of PF299 in refractory NSCLC is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Gatekeeper Pharmaceuticals, Pfizer AVEO, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, MedImmune, Millennium, Novartis, OSI Pharmaceuticals, Pfizer, Roche, Schering-Plough, Syndax Pharmaceuticals Gatekeeper Pharmaceuticals, Pfizer Novartis, Pfizer Genzyme

Randomized, open-label, phase III study of panitumumab (pmab) with FOLFOX4 versus FOLFOX4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): Efficacy by skin toxicity (ST).

3528^ Background: Pmab is a fully human antiepidermal growth factor receptor (EGFR) monoclonal antibody approved as monotherapy for chemorefractory mCRC. ST is the most common anti-EGFR tx-related adverse event (AE). We evaluated the efficacy and safety of pmab+FOLFOX4 vs FOLFOX4 as first-line tx for mCRC; outcomes by tumor KRAS status and ST severity were evaluated. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg Q2W+FOLFOX4 vs FOLFOX4. Pts had metastatic adenocarcinoma of the colon or rectum, no prior chemotherapy for mCRC, no prior oxaliplatin, ECOG 0-2. The primary endpoint was progression-free survival (PFS); overall survival (OS) was secondary. Results: 1183 pts were randomized: 593 Pmab+FOLFOX4, 590 FOLFOX4. Demographics and disease characteristics were generally balanced. 1,096/1,183 pts (93%) had KRAS results: 656 (60%) wild-type (WT), 440 (40%) mutant (MT). Pmab significantly improved PFS (HR = 0.80; 95% CI: 0.66-0.97; p = 0.02; median 9.6 vs. 8.0 mo) in pts with WT KRAS. 97% of pts with WT KRAS and 95% with MT KRAS tumor status receiving pmab experienced any ST. Maximum grade (gr) ST was observed by day 28 in 50% of pts. Pts with ≥ gr 1 ST who were alive w/o progression at day 28 were included in the ST analysis. For WT KRAS pts with maximum ST gr 2-4 vs. gr 1, median PFS (n = 305) was 10.8 mos vs 6.0 mos (HR = 0.63; 95% CI: 0.42-0.93; p = 0.019), median OS (n = 308) was 28.3 mos vs. 11.5 mos (HR = 0.47; 95 CI: 0.32-0.71; p = 0.0002); in pts with MT KRAS, median PFS (n = 203) was 7.6 mos vs. 5.7 mos (HR = 0.65 [95% CI: 0.45, 0.94] p = 0.022) and median OS (n= 203) was 16.9 mos vs. 10.1 mos (HR = 0.60 [95% CI: 0.41, 0.88] p = 0.009). Except for ST and other known AEs associated with anti-EGFR tx, AEs were comparable across arms. Conclusions: Pmab+FOLFOX4 as first-line tx for mCRC significantly improved PFS in pts with WT KRAS and was well tolerated. ST gr 2-4 vs. 1 was associated with longer PFS and OS in pts with KRAS WT tumors. However, since the same association was seen in pts with MT KRAS who overall do not benefit from pmab, this finding may be confounded with prognostic factors which will be examined. Response rate and patient-reported outcome analyses by ST severity will also be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, Merck Serono, sanofiaventis Amgen Amgen, Merck Serono, sanofiaventis Amgen In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

Efficacy and safety of PF-00299804 (PF299), an oral, irreversible, pan-human epidermal growth factor receptor (pan-HER) tyrosine kinase inhibitor (TKI), as first-line treatment (tx) of selected patients (pts) with advanced (adv) non-small cell lung cancer (NSCLC).

7537 Background: Efficacy of gefitinib as first-line tx of adv NSCLC with epidermal growth factor receptor (EGFR) mutation (mu) has been shown in a phase (P) 3 trial. PF299 shows preclinical activity in EGFR-mutant NSCLC, including T790M (a secondary resistance mu arising in ∼50% of pts after EGFR TKI benefit). This open-label, single-stage P2 study evaluates efficacy and safety of first-line PF299 in a pt population with adv NSCLC, molecularly selected or clinically enriched for EGFR mu. Methods: Pts with adv adenocarcinoma of lung and no prior systemic tx for adv NSCLC are eligible if they are non/light smokers or known to have EGFR mu. Tissue is requested from all pts. Pts receive PF299 45 mg continuously once daily and are assessed every 28 days. Endpoints include: progression-free survival at 4 months (PFS4m; primary), tumor response, safety, serial pharmacokinetics, and tissue- and blood-based biomarkers, including T790M mu. Planned enrolment is ∼80 pts, including ≥ 30 each of Asian and of non-Asian ethnicity. Results: To date, 39 pts have enrolled (23 female; 23 Asian). Of 29 evaluable pts, 1 had a complete response, 6 a partial response, and 16 stable disease ≥ 6 weeks. Preliminary PFS rates at 3, 4, and 6 m were 90%, 79%, and 79%, respectively. Mu status was obtained in 31/39 pts. All evaluable pts with known EGFR mutant NSCLC (n = 14) showed tumor shrinkage. Common tx-related adverse event (AEs) were diarrhea (79%; grade 3; 9%), dermatitis acneiform (49%; 9%), stomatitis (42%; 6%), acne (24%; 0%), rash (21%; 0%), and anorexia (18%; 0%). One pt discontinued due to AE; 10 required dose reduction while remaining on study. Conclusions: Preliminary data suggest PF299 demonstrates encouraging efficacy as first-line tx of selected Asian and non-Asian pts with NSCLC, as reflected by PFS rates. Of note, tumor shrinkage was seen in all evaluable pts with EGFR mutant disease. AEs were mostly grade 1/2 and manageable; however, to ensure long term tolerability, a lower starting dose is being considered. Clinical follow-up and biomarker data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer AstraZeneca, AVEO, Boehringer Ingelheim, Eisai, Genentech, Lilly, Merck Serono, OSI Pharmaceuticals, Pfizer, Roche, Syndax Pharmaceuticals Gatekeeper Pharmaceuticals, Pfizer AstraZeneca, Genentech, Lilly, Pfizer, Roche, sanofi-aventis Abraxis BioScience, Celgene, Genentech, Lilly, Pfizer Genzyme

Randomized, open-label, phase III study of panitumumab (pmab) with FOLFIRI versus FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy by skin toxicity (ST).

3529^ Background: Pmab is a fully human anti-epidermal growth factor receptor (EGFR) mAb approved as monotherapy for pts with chemorefractory mCRC. ST is the most common tx-related adverse event (AE). This study evaluated the efficacy and safety of pmab + FOLFIRI vs. FOLFIRI as second-line tx for mCRC by KRAS status; outcomes by ST severity were also evaluated. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg Q2W + FOLFIRI or FOLFIRI. Pts had metastatic adenocarcinoma of the colon or rectum, 1 prior chemotherapy tx for mCRC, ECOG 0-2. Independently tested co-primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: 1,186 pts were randomized: 591 pmab + FOLFIRI, 595 FOLFIRI. Demographics and baseline characteristics were generally balanced. 1,083 (91%) pts had KRAS results: 597 (55%) wild-type (WT), 486 (45%) mutant (MT). Pmab+FOLFIRI significantly improved PFS in pts with WT KRAS (HR = 0.73; 95% CI:0.59-0.90, p = 0.004; median PFS 5.9 vs 3.9 mos). 93% of pts with WT KRAS and 91% with MT KRAS receiving pmab experienced any ST. Maximum grade (gr) ST was observed by day 28 in > 50% of pts. Pts with at least gr 1 ST who were alive w/o progression at day 28 were included in the ST analysis. In pts with WT KRAS with ST gr 2-4 vs. gr 1, median PFS was 7.4 mos vs. 5.2 mos (HR = 0.67; 95% CI: 0.49-0.90, p = 0.009); median OS was 16.5 mos vs. 10.3 mos (HR = 0.46; 95 CI: 0.33-0.65; p < 0.0001). In pts with MT KRAS, higher ST severity (gr 2-4) was also associated with longer PFS (HR = 0.575; 95% CI: 0.410, 0.805; p = 0.001) and OS (HR = 0.488; 95% CI: 0.340, 0.701, p = 0.0001). AE rates were comparable across arms with the exception of ST and known toxicities associated with anti-EGFR therapy. Conclusions: Pmab + FOLFIRI as second-line tx for mCRC significantly improved PFS in pts with WT KRAS and was well tolerated. In pts with KRAS WT tumors, ST gr 2-4 was associated with longer PFS and OS. Although pts with MT KRAS tumors do not benefit from pmab, a similar association between PFS, OS and ST was seen in these pts. The possible confounding effect of prognosis will be examined. Response rate and patient-reported outcome analyses by ST severity will also be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, AstraZeneca, Bayer, Lilly, Merck, Merck Serono, Onyx, Pfizer, Roche, sanofi-aventis Amgen Amgen, AstraZeneca, Bayer, Lilly, Merck, Merck Serono, Onyx, Pfizer, Roche, sanofi-aventis Amgen Amgen Amgen, Lilly, Merck, sanofiaventis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

A phase Ib/II trial of AMG 655 and panitumumab (pmab) for the treatment (tx) of metastatic colorectal cancer (mCRC): Safety results

4130^ Introduction: Pmab is a fully human antibody targeting the epidermal growth factor receptor that is approved as monotherapy for mCRC in the US, EU, and Canada. AMG 655 is an investigational, fully human agonistic antibody against death receptor 5. This is the first study to evaluate the safety, tolerability, and efficacy of AMG 655 and pmab for the tx of mCRC. Methods: Eligible patients (pts) were ≥ 18 years old, had ECOG status 0–1, radiographic disease progression (PD) during or after tx with fluoropyrimidine, irinotecan, and/or oxaliplatin chemotherapy for mCRC. This is a 2-part study: in part 1 (n∼6–27 pts), the primary endpoint is the incidence of dose-limiting toxicities (DLTs); in part 2 (n∼38–41 pts), the primary endpoint is objective response rate per modified RECIST. Secondary endpoints for both parts include efficacy, pharmacokinetics (PK), and antibody formation. In part 1, pts received pmab 6 mg/kg Q2W plus AMG 655 at a starting dose of 10 mg/kg (evaluation of subsequent doses of 3 mg/kg or 1 mg/kg if needed; 6–9 pts at each dose) by sequential intravenous infusion at week 1 and Q2W thereafter until PD or intolerability. The tolerable dose in part 1 was selected for part 2. Results: We describe here the safety of the first 15 pts (n=5 part 1; n=10 part 2) after ≥ 8 weeks on study. Eight (53%) pts were women, 14 (93%) pts were white, and 9 (60%) pts had ECOG 1. Median (range) age was 61 (38–77) years. All pts received pmab 6 mg/kg and AMG 655 10 mg/kg Q2W. Median (range) follow-up time was 15.4 (9–31) weeks. There were no DLTs in part 1, thus AMG 655 10 mg/kg Q2W was selected for part 2. One (7%) pt had a tx-related adverse event (AE) ≥ grade (gr) 3: gr 3 hypomagnesemia. Tx-emergent Aes ≥ 25% are shown ( Table ). Laboratory values ≥ gr 3: one gr 3 AST and ALT; one gr 3 lipase. From intensive PK samples from the first 6 pts, pmab had no apparent impact on the PK of AMG 655. Conclusions: AMG 655 and pmab can be safely combined in later lines of tx for mCRC. The study is ongoing. Safety results for additional pts will be presented. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

Long-term safety of sorafenib (SOR) for the treatment (tx) of advanced clear-cell renal-cell carcinoma (RCC): Data analysis from patients (pts) treated for over 1 year in the phase III TARGET study

e16057 Background: Results of the phase III multicenter TARGET study, a randomized, double-blind, placebo (PBO)- controlled study of tx with SOR in pts with clear-cell RCC in whom 1 prior systemic therapy had failed, indicated that SOR is effective (PFS 5.5 vs 2.8 mo, HR=0.44, P&lt;0.000001, and 39% increase in survival for SOR vs PBO, HR=0.71, P=0.015) and safe in pts with advanced RCC (Escudier et al. N Engl J Med. 2007). With a database cut-off of Sept 8, 2006, we analyzed the safety of long-term use of SOR in pts in TARGET (study start Nov 2003). Methods: Pts (N=903) with advanced metastatic clear-cell RCC that had progressed after 1 systemic tx, ECOG PS 0–2, and low- or intermediate-risk MSKCC score were randomized 1:1 to SOR 400 mg BID or PBO. End points included OS, PFS, and safety. A single planned analysis of PFS showed a significant benefit of SOR over PBO; consequently, pts assigned to PBO were offered SOR. Descriptive analysis of safety and efficacy of pts treated &gt;1 year (y) was conducted. Results: 169/903 pts were randomized to SOR and treated &gt;1 y and 27 pts treated &gt;2 y. Due to crossover of PBO to SOR, only 6 pts randomized to PBO were treated with SOR &gt;1 y. Pts treated with SOR &gt;1 y had median PFS of 10.9 months and a response rate of 22.5%. Median tx duration was 20 months. Drug-related adverse events (AEs) were mainly grades 1 and 2 and occurred early during tx (see Table ); 31% and 22% of pts required dose interruption and reduction, respectively, because of AEs. Conclusions: Long-term tx with SOR did not result in new toxicities or an increase in overall incidence of tx-related AEs. Toxicity was not cumulative and no increase in grades 3/4 AEs was observed. Pts with preexisting cardiac disease or hypertension tolerated long-term tx with SOR; no dose reduction was required. No increase in cardiovascular toxicity was observed in this pt population. Long-term tx of pts with advanced RCC with SOR is medically manageable, with a predictable AE profile. [Table: see text] [Table: see text]

Sunitinib in metastatic renal cell carcinoma (mRCC) patients (pts) with brain metastases (mets): data from an expanded access trial

5094 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs that has demonstrated substantial antitumor activity in first- and second-line mRCC (JAMA 2006;295:2516; NEJM 2007;356:115). Brain mets are common from RCC and result in significant mortality (Curr Treat Options Oncol 2003;4:385; Med Oncol 2000;17:279). Safety and efficacy data for mRCC pts with brain mets on sunitinib in an ongoing, international, open-label expanded access trial are presented. Methods: The purpose was to provide sunitinib prior to regulatory approval to mRCC pts without access to study drug due to trial ineligibility or other reasons; as such, eligibility criteria were minimized to broaden enrollment, including allowance of pts with asymptomatic brain mets and any ECOG PS. Pts ≥18 yrs with histologically-confirmed mRCC received sunitinib 50 mg orally, once-daily in 6-wk cycles (4 wks on treatment [Tx], 2 wks off). Results: As of December 2007, 4,616 pts had been enrolled, with data available for 3,997 pts of whom 298 pts (7%) had baseline brain mets. Within this subgroup, 75% were male, median age was 58 yrs (range: 23–81), and prior Tx included nephrectomy (89%), cytokines (77%), and anti-angiogenic agents (7%). Median Tx duration was 4.3 mo. Dosing reductions (for any cause) occurred in 102 pts (34%); 196 pts (66%) discontinued, 81 pts (27%) due to lack of efficacy and 19 pts (6%) adverse events (AEs), rates similar to those for all clinical trial mRCC pts treated with sunitinib. The most common grade 3/4 Tx-related AEs were fatigue (6%), asthenia (5%), and vomiting, hypertension, thrombocytopenia, neutropenia, and anemia (all 3%). One pt experienced grade 1/2 Tx-related cerebral hemorrhage. Of 192 brain mets pts with efficacy data, 22 (11%) had a partial response and 98 (51%) had stable disease ≥3 mo. For brain mets pts with (n=217) and without (n=58) prior cytokine Tx, median progression-free survival was 5.6 and 5.3 months, respectively. Median overall survival had not yet been reached. Conclusions: The safety of sunitinib in mRCC pts with brain mets mirrored that for the overall trial population, as previously reported. Sunitinib showed antitumor activity in this subgroup of pts with limited treatment options. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Bayer, GlaxoSmithKline, Pfizer, Roche, Schering-Plough, Wyeth Pfizer Pfizer Bayer, Pfizer Pfizer

A phase II, open-label trial of skin toxicity (ST) evaluation (STEPP) in metastatic colorectal cancer (mCRC) patients (pts) receiving panitumumab (pmab) + FOLFIRI or irinotecan-only chemotherapy (CT) as 2nd-line treatment (tx): Interim analysis

15007 Background: Pmab, a fully human monoclonal antibody against the epidermal growth factor receptor, is approved in the US for the tx of pts with refractory mCRC. This randomized study examined differences between pre-emptive and reactive skin tx for ST associated with pmab therapy. Methods: Pts with unresectable mCRC and disease progression whose 1st-line tx with CT± bevacizumab failed were enrolled. Pts received Q2W FOLFIRI+pmab (6.0mg/kg) or Q3W irinotecan+pmab (9.0mg/kg). Within cohorts, pts were randomized 1:1 to pre-emptive ST tx (24 hrs prior to 1st pmab dose, daily through wk 6) or reactive tx (after ST developed). ST tx included use of skin moisturizers, sunscreen, topical corticosteroids, and oral doxycycline. The primary endpoint was incidence of specific ≥ grade (gr) 2 ST during the 6-wk skin tx period. This early analysis assessed pooled safety (data cutoff 06/07). Results: Of 58 pts with available data, 32 pts and 26 pts received the Q2W and Q3W regimens, respectively. Pts received a median of 7.5 (Q2W cohort) and 4.0 (Q3W cohort) doses of pmab and CT. Tx-related adverse events (AEs) were seen in 95% of pts; 62% had gr 3/4. AEs of interest are shown (table). Pmab dose reductions occurred in 6 pts (10%) due to ST; 19 pts had serious AEs; 2 pts ended the study because of an AE. Ten pts (31%) in the Q2W cohort and 1 pt (4%) in the Q3W cohort had an objective response to pmab. Planned enrollment of 95 pts has been completed; efficacy outcomes (pre-emptive vs reactive ST tx and objective response) by KRAS status for all pts will be presented. Conclusions: No safety issues were identified in this early analysis of pts receiving pmab + irinotecan-based CT. Pooled Analysis of Adverse Events (n = 58) AE Any grade, n (%) ≥ Grade 3, n (%) Skin Toxicity 51 (88) 13 (22) Infections * 42 (72) 13 (22) Diarrhea 40 (69) 8 (14) Nausea 31 (53) 4 (7) Neutropenia 16 (28) 9 (16) Dehydration 13 (22) 7 (12) Hypomagnesemia 10 (17) 3 (5) Deep venous thrombosis 2 (3) 2 (3) Pulmonary embolism 0 (0) 0 (0) Per MedDRA; grading based on CTCAEv3, modified for ST. * Includes rash pustular and paronychia No significant financial relationships to disclose.

Safety of erlotinib in TRUST, a phase IV trial in patients with advanced non-small cell lung cancer (NSCLC): Initial results from the East/South East (E/SE) Asian subgroup

18018 Background: Erlotinib significantly improved survival versus placebo and was well tolerated in patients (pts) with previously treated advanced NSCLC in the phase III BR.21 study (Shepherd et al. N Engl J Med 2005;353;123–32). TRUST, an open-label, multicenter study was initiated to provide erlotinib access to pts with advanced NSCLC. Here we report data for E/SE Asian pts. Methods: Eligible pts had failed 1–2 prior standard chemotherapy (CT) regimens, or were unsuitable for CT. Erlotinib 150 mg/day p.o. was given until disease progression/unacceptable toxicity. NCI CTC v3.0 was used to grade toxicities. Results: At data cut-off of 20/11/06, 885 pts were included in the analysis: n= Taiwan 297, mainland China 248, Hong Kong 160, South Korea 146, Thailand 30, Indonesia 2, Malaysia 2. Median age was 61yrs (range 22–95). Pt characteristics (%): male/female 55/45, ECOG PS 0/1/2/3 15/67/14/4, stage IIIb/IV 20/79, adenocarcinoma/other 68/32, erlotinib as 1st/2nd/3rd/other line therapy 11/55/33/&lt;1, never/ever smoker 52/47 (no data &lt;1). 83% pts experienced rash, of which 9% was grade (gr)3/4. Safety data forms were available for 598 pts; 54% had at least one adverse event (AE).104 pts (17%) had a treatment (tx)-related unexpected adverse event (AE) but no single AE occurred in &gt;3% pts and only 3% were ≥gr3. Serious tx-related AEs were experienced by 19 pts (3%); 17 were gr3/4, most commonly gastrointestinal (n=6). One pt had suspected tx-related interstitial lung disease (gr2); the patient continued tx. 18 pts (3%) withdrew due to a tx-related event; 11 were gr3/4, most commonly gastrointestinal (n=4) and respiratory (idiopathic pulmonary fibrosis n=1, pneumonitis n=2). 76 pts (13%) required dose reduction due to a tx-related event (13%), mainly due to rash (n=57). 83% pts received erlotinib for &gt;4 weeks. Efficacy will be presented. Conclusions: The results reported here for E/SE Asian pts in the TRUST study confirm in a community setting the good tolerability observed with erlotinib in clinical trials. Importantly, erlotinib was generally well tolerated and so could be administered at full tx dose to most pts. [Table: see text]