Safety Of Neratinib Research Articles

P90-6 Efficacy and safety of neratinib and capecitabine in HER2-positive metastatic breast cancer: a systematic review

P90-6 Efficacy and safety of neratinib and capecitabine in HER2-positive metastatic breast cancer: a systematic review

Is early inclusion of neratinib with HER blockers possible in the treatment of stage 4 HER2 positive cancer?

e13019 Background: The management of the patients with breast cancer and choosing the most effective therapy still remains a challenge, but an achievable goal. 30-50% of the patients with stage IV HER2-positive breast cancer have an increased risk of developing brain metastases. In most patients, effective therapy for Her2+ BC does not reach the CNS due to the blood-brain barrier, which, in turn, can lead to cancer metastasis to the brain. Trastuzumab, Pertuzumab poorly penetrates the BBB, however the treatment regimens with the inclusion of trastuzumab increase life expectancy in patients with HER2+ BC with CNS metastases, mainly due to controlling of extracranial lesions. In contrast, neratinib penetrates the BBB well, and its combination with capecitabine produces responses in intensively pretreated patients, especially in cases where the only site of disease progression is the CNS. Our study was to directly compare the efficacy and safety of Neratinib plus Trastuzumab and Docetaxel(N+TDtx) and Pertuzumab plus Trastuzumab. Methods: This study involved 43 patients, among which 28 received (N+TDtx) -1st group and 15 received (N+TDtx) - 2nd group. A median number of 6 cycles were delivered in the two treatment arms, followed by Trastuzumab. Results: The primary endpoint was RFS and EFS. The median RFS was not reached in 2nd group at a median follow-up of 18.7 months, because of brain metastasis, disease progression and death of 23 (82%) patients. However, the 12-month RFS rate was significantly higher in the 1st group than in the 2nd 98% and 65%, respectively (hazard ratio [HR], 0.72; 95% CI, 0.56-0.93; P =.012). With median follow up of 36.4 months, neoadjuvant N+TDtx reduced the risk of disease recurrence, brain metastasis, progression or death by 98%, demonstrating a landmark three-year event-free survival (EFS) rate of 57% with N+TDtx, followed by trastuzumab compared to 17% with TDtx, followed by trastuzumab (Hazard Ratio [HR], 0.68; 95% Confidence Interval [CI], 0.49 to 0.93). The most frequent adverse event in the Neratinib arm was diarrhea, which was manageable with prophylactic treatment with loperamide. Conclusions: Neratinib, has shown that it was able to prevent brain metastases and demonstrated benefit in recurrence - free survival and event-survival in combination with Trastuzumab and Docetaxel over (PT+Dtx) for patients without brain metastases.

A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation

PurposeAberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.MethodsPatients with actionable somatic mutations or amplifications in ERBB genes or actionable KRAS mutations were enrolled to receive neratinib and trametinib in this phase I dose escalation trial. The primary endpoint was determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary endpoints included pharmacokinetic analysis and preliminary anti-tumor efficacy.ResultsTwenty patients were enrolled with a median age of 50.5 years and a median of 3 lines of prior therapy. Grade 3 treatment-related toxicities included: diarrhea (25%), vomiting (10%), nausea (5%), fatigue (5%) and malaise (5%). The MTD was dose level (DL) minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160 mg daily with trametinib 1 mg daily). The treatment-related toxicities of DL1 included: diarrhea (100%), nausea (55.6%) and rash (55.6%). Pharmacokinetic data showed trametinib clearance was significantly reduced leading to high drug exposures of trametinib. Two patients achieved stable disease (SD) ≥ 4 months.ConclusionNeratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug–drug interactions.Trial registration ID: NCT03065387.

98P Real-world effectiveness and safety of neratinib in the extended adjuvant treatment of patients with HER2+ early breast cancer (eBC) in the United States community oncology setting

98P Real-world effectiveness and safety of neratinib in the extended adjuvant treatment of patients with HER2+ early breast cancer (eBC) in the United States community oncology setting

228 (PB108) - Neratinib efficacy in patients with EGFR exon 18-mutant non-small-cell lung cancer: findings from the SUMMIT basket trial

Background: The phase 2 SUMMIT basket trial (NCT01953926) demonstrated efficacy of neratinib in patients with EGFR exon 18-mutant non-small-cell lung cancer (NSCLC). Here we report the efficacy and safety of neratinib in an expanded subgroup of patients with EGFR exon 18-mutant NSCLC in SUMMIT according to prior EGFR tyrosine kinase inhibitor (TKI) treatment.

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens

PurposeNeratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein.Methods621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1–14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1–14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety.Results104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity.ConclusionConsistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted.Clinical trial registrationNCT01808573

The Clinical Efficacy and Safety of Neratinib in Combination with Capecitabine for the Treatment of Adult Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) positive cancers account for 15–20% of all breast tumors. Several drugs have been approved in the metastatic setting, including monoclonal antibodies, tyrosine kinase inhibitors (TKI) and, more recently, antibody-drug conjugates. Neratinib is a pan-HER, irreversible TKI with potent preclinical activity against trastuzumab-resistant breast cancer models. Based on Phase I and II clinical trials, the combination of neratinib plus capecitabine was compared to lapatinib and capecitabine, an established regimen for trastuzumab-resistant disease, in the randomized, Phase III NALA trial. In this trial, neratinib yielded increased progression-free survival, response duration and a benefit in time to intervention for CNS progression. However, there was no overall survival benefit, no increase in overall response rate and no improvement in QoL. The most frequent adverse event in the neratinib arm was diarrhea, which was manageable with prophylactic treatment with loperamide. Conclusion: Neratinib is a valuable addition to the therapeutic armamentarium to treat metastatic, HER2-positive breast cancer. The current positioning of the combination of neratinib and capecitabine based on the results of the NALA trial needs to consider the rapidly evolving scenario due to the recent introduction of new drugs, like the pure-HER2 TKI tucatinib and the antibody drug-conjugate trastuzumab-deruxtecan.

Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial

ObjectiveSomatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors. MethodsPatients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety. ResultsSixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5–57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1–78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7–18.3 months); median OS was 16.8 months (95%CI 4.1–NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations. ConclusionsNeratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population.Trial registration number.NCT01953926 (ClinicalTrials.gov), 2013–002872-42 (EudraCT).

Tolerability of neratinib in older adults with HER2 positive or HER2 mutated metastatic breast cancer.

e13018 Background: The tolerability and efficacy of targeted therapy in older adults with cancer have not been adequately studied. Neratinib is an oral pan-HER1, HER2, and HER4 tyrosine kinase inhibitor that has been FDA approved for early stage HER 2+ breast cancer. This phase II trial is designed to evaluate the safety of neratinib in older adults (≥60 years) who have HER2 amplified or HER2 mutated metastatic breast cancer (MBC). Methods: Older adults with HER2+ or HER2 mutated MBC with any number of previous lines of therapy received neratinib at 240 mg daily in 28-day cycles. Loperamide was used for diarrhea prophylaxis: 4mg tid x 14 days followed by 4mg bid for days 15-28, and as needed after first cycle. Participants completed a pre-treatment geriatric assessment (GA) including measures of function, comorbidity, cognition, nutrition, and psychosocial status at cycle 1, cycle 4, and end of the study. Relationships between tolerability (dose reductions and number of completed courses) and log2 risk score were assessed using t-test and linear regression. Response rate (RR), progression free survival (PFS) and overall survival (OS) were evaluated. Results: Twenty-five patients (mean age 68 [60-79]) were enrolled from 12/2016 to 03/2019, and 36% of patients (pts) were &gt;70 years old. Median number of cycles completed was 3 (0-13): 1/25 (4%) pts had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not evaluable for response. PFS was 2.6 months (95% CI [2.56-5.26]). The median OS was 17.4 months (95% CI [10.3, NA]). A total of 9/25 pts (36%) had dose modification. Of these, 3/9 had at least one dose hold, and all 9 had at least one dose reduction (diarrhea, n = 6). 20/25 participants (80%, 95% CI [59%, 93%]) had grade ≥2 toxicities, and 9/25 pts (36%, 95% CI [18%, 57%]) had grade 3 toxicities that were attributable to treatment: diarrhea (n = 5), abdominal pain (n = 2), and vomiting (n = 2). There were no grade 4 or 5 toxicities. Two pts (8%) were hospitalized due to neratinib toxicity, and two pts went off treatment due to toxicity attributed to neratinib (diarrhea and nausea). There was a trend in the difference in toxicity risk scores by whether a participant had a dose reduction (t-test: p-value = 0.054) with participants with higher risk scores being more likely to require a dose reduction; however, toxicity risk score did not predict number of cycles completed based on linear regression (slope = -1.29, se = 1.44, p = .39). Conclusions: Neratinib is safe in older adults with HER2 positive or HER2 mutated MBC. Clinical trial information: NCT02673398 .

Neratinib After Trastuzumab-Based Adjuvant Therapy in Patients from Asia with Early Stage HER2-Positive Breast Cancer

Aim: To evaluate the efficacy and safety of neratinib as extended adjuvant therapy in patients from Asia based on exploratory analyses of the Phase III ExteNET trial. Patients & methods: A total of 2840 women with early stage HER2-positive breast cancer were randomly assigned to neratinib 240mg/day or placebo for 1year after trastuzumab-based adjuvant therapy. Results: A total of 341 patients were from Asia (neratinib, n=165; placebo, n=176). 2-year invasive disease-free survival rates were 92.8 and 90.8% with neratinib and placebo, respectively (HR: 0.70; 95% CI: 0.31-1.55), and 5-year rates were 91.9 and 87.2%, respectively (HR: 0.57; 95% CI: 0.27-1.13). Diarrhea was the most common adverse event with neratinib. Conclusion: Extended adjuvant therapy with neratinib reduces disease recurrences in Asian women with HER2-positive breast cancer. Trial registration: Clinicaltrials.gov NCT00878709.

Efficacy and CNS progression analysis from the randomized phase 2 trial of neratinib + paclitaxel vs trastuzumab + paclitaxel as first-line treatment for HER2+ metastatic breast cancer (NEfERTT).

610 Background: This large randomized open-label phase 2 trial compared the efficacy and safety of Neratinib (N), the irreversible pan-HER tyrosine kinase inhibitor, + Paclitaxel (P) vs Trastuzumab...

5066 POSTER A Clinical Study to Assess Pharmacokinetics and Safety of Neratinib in Subjects With Chronic Hepatic Impairment and Matched Healthy Subjects

5066 POSTER A Clinical Study to Assess Pharmacokinetics and Safety of Neratinib in Subjects With Chronic Hepatic Impairment and Matched Healthy Subjects

A phase III trial of adjuvant neratinib (NER) after trastuzumab (TRAS) in women with early-stage HER2+ breast cancer (BC).

TPS137 Background: The human epidermal growth factor receptors (HER1-4) are frequently overexpressed in human tumors. Increased HER receptor signaling is associated with increased resistance to standard therapies and poor prognosis. TRAS, an anti-HER2 monoclonal antibody, reduces recurrences and improves disease-free survival (DFS) in patients (pts) with HER2+ early BC. However, 15% to 25% of TRAS-treated pts still experience relapsed disease at 5 yrs. NER is a small molecule, irreversible tyrosine kinase inhibitor of HER2 as well as HER1 and HER4. In a phase II study, orally administered NER 240 mg/d was well tolerated with significant antitumor activity in pts with HER2+ BC, with or without prior TRAS (objective response rates of 24% and 56%; median progression-free survival of 22 wks and 40 wks, respectively). The current study will evaluate the efficacy and safety of NER in pts with early-stage HER2+ BC after adjuvant TRAS. Methods: This double-blind, placebo-controlled, multicenter, phase III study will include approximately 3,300 women with early-stage HER2-overexpressing/amplified, node-positive BC (or no pathologic complete response after neoadjuvant therapy) at high risk for recurrence. Pts will be randomized within 1 yr of prior adjuvant TRAS to oral NER 240 mg or placebo daily for 1 yr. Pts will be followed for up to 5 yrs post-randomization for recurrence and/or survival. Primary endpoint is DFS (time to disease recurrence or death), using a 1-sided log-rank test to compare treatment arms and a Cox proportional hazards regression model for hazard ratio estimation. Other efficacy endpoints include DFS including ductal carcinoma in situ, time to distant recurrence, distant DFS, incidence of central nervous system recurrence, and overall survival. Safety will be monitored, with particular attention to diarrhea. Biomarker analyses (including HER2 confirmation from archived samples) and health-related quality of life (FACT-B and EQ-5D) will also be assessed. Results: As of Jan 25, 2011, a total of 2,050 pts have been randomized, including 934 high-risk pts. Conclusions: Recruitment is planned to continue until late 2013. As of Nov 3, 2010, the IDMC recommended the trial to continue.

Abstract P3-14-04: Efficacy and Safety of Neratinib (HKI-272) in Combination with Paclitaxel in Her2+ Metastatic Breast Cancer

Abstract Background: Neratinib (HKI-272), an irreversible inhibitor of the tyrosine kinase receptors Her1, -2 and -4, has shown antitumor activity in patients with Her2+ disease, with or without prior trastuzumab exposure. In preclinical models, neratinib inhibits Her receptor signaling via the phosphatidyl inositol-3-kinase (PI3K) and MAPK pathways. PI3K signaling activity may mediate resistance to trastuzumab and endocrine therapy in breast cancer. The objective of this ongoing phase 1/2 study is to evaluate the efficacy and safety of neratinib combined with paclitaxel in patients with solid tumors and Her2+ metastatic breast cancer. Material and Methods: This was an open-label, 2-part study. In part 1, patients with solid tumors received ascending daily oral dosages of neratinib (160 mg, 240 mg) plus IV paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle to determine the maximum tolerated dose [MTD]. In part 2, patients with Her2+ metastatic breast cancer in the first-to fourth-line setting received neratinib plus paclitaxel at the MTD. Tumor response (assessed using modified RECIST criteria), safety, and pharmacokinetic (PK) parameters were evaluated. Results: Full doses of both neratinib (240 mg) and paclitaxel (80 mg/m2) were well tolerated in part 1 and evaluated in patients with Her2+ breast cancer in part 2. As of 26 April 2010, data were available for 102 patients in part 2 (median age [range], 50.5 years [20.0-76.0]; 100% were female). The objective response rate (ORR; complete plus partial responses) among 99 evaluable patients in part 2 was 71% (95% confidence interval [CI], 60.7-79.4); ORR in the first-line subset (n = 33) was 70% (95% CI, 51.3-84.4). Median progression-free survival was 55.6 weeks in the overall population and 57.0 weeks in the first-line subset. Of 38 patients treated with prior Her2-directed therapy, 26 responded (ORR, 68% [95% CI, 51.3-82.5]), including 10 of 14 patients treated with prior lapatinib (ORR, 71% [95% CI, 41.9-91.6]). Responses were observed in 31 of 39 patients with prior endocrine therapy (ORR, 79% [95% CI, 63.5-90.7]) and 49 of 62 patients with prior taxane treatment (ORR, 79% [95% CI, 66.8-88.3]). The most common treatment-emergent adverse events (TEAEs) in part 2 were diarrhea (91%), neutropenia (53%), peripheral sensory neuropathy (52%), alopecia (48%), and leukopenia (44%). Common grade ≥3 TEAEs were diarrhea (28%) and neutropenia (22%). Median time to onset of diarrhea was 3 days, and median duration was 35.5 days. Three patients discontinueddue to an AE (mouth ulceration, fatigue, ejection fraction reduction); 4 deaths were reported (AE, n = 2; disease progression, n = 2). Evaluation of PK parameters suggested no interaction between the 2 drugs; exposures were similar to those observed for each drug as monotherapy. Discussion: High clinical responses were observed in patients with Her2+ breast cancer, including the first-line subset and patient subsets with prior Her2-directed, endocrine, and taxane therapies. The combination of neratinib 240 mg and paclitaxel 80 mg/m2 was tolerable, with a toxicity profile similar to each drug given as monotherapy. A phase 3 trial is ongoing to study this combination in the first-line setting compared with trastuzumab plus paclitaxel. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-04.

Neratinib, an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced ErbB2-Positive Breast Cancer

Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer-those with and those without prior trastuzumab treatment-in an open-label, multicenter, phase II trial. Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review. The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naïve cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported. Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.

Safety of Neratinib (HKI-272) in Combination with Capecitabine in Patients with Solid Tumors: A Phase 1/2 Study.

Abstract Background: Neratinib (HKI-272) is an oral irreversible pan-ErbB tyrosine kinase inhibitor that blocks downstream signaling of ErbB1, -2, and -4 by binding to the intracellular ATP binding sites of these receptors. Other available ErbB inhibitors include the ErbB2-specific monoclonal antibody trastuzumab and the reversible small molecule inhibitor lapatinib, which is directed against ErbB1 and -2. Neratinib may have advantages over other inhibitors because of its pan-ErbB inhibition and ability to irreversibly inhibit the intracellular tyrosine kinase domains. The objective of this ongoing multicenter, open-label, phase 1/2 study is to evaluate the safety, tolerability, and preliminary antitumor activity of neratinib in combination with capecitabine in patients with solid tumors.Material and Methods: Patients with advanced solid tumors are being enrolled in part 1 of this 2-part study to assess safety and tolerability (ie, adverse events and dose-limiting toxicities [DLTs]) and to determine the maximum tolerated dose (MTD) of neratinib in combination with capecitabine. Part 2 will further assess safety and tolerability, as well as objective response rates and pharmacokinetic parameters at the MTD in patients with metastatic or locally advanced ErbB2+ breast cancer. The dose escalation scheme for part 1 includes 3 ascending dose levels: neratinib 160 or 240 mg/day plus capecitabine 750 mg/m2 twice daily (bid) on days 1-14 of a 21-day cycle (levels 1 and 2) and neratinib 240 mg/day plus capecitabine 1,000 mg/m2 bid on days 1-14 of a 21-day cycle (level 3). Each patient participates at only 1 dose level. If dose level 1 is tolerated, but dose level 2 is not, an intermediate dose level of neratinib 200 mg plus capecitabine 750 mg/m2 bid can be evaluated as a potential MTD.Results: Data as of 1 May 2009 for patients treated at dose levels 1, 2, and 3 (n = 6, 5, and 4, respectively) are presented. Median (range) ages for patients at the respective dose levels were 46 (37-69), 56 (41-58), and 53 (39-80) years. Two DLTs have been observed at dose level 3; one patient each experienced grade 3 elevated alanine aminotransferase and grade 3 diarrhea. Common treatment-emergent adverse events (all grades, ≥10% of patients) included diarrhea (50.0%), nausea (25.0%), vomiting (25.0%), fatigue (16.7%), and pyrexia (16.7%). One patient at dose level 3 experienced a drug-related adverse event of grade ≥3 diarrhea. No patients have withdrawn from the study because of adverse events; 3 patients have died (disease progression, n = 3).Discussion: Based on preliminary results from part 1, the combination of neratinib and capecitabine was well tolerated. Accrual of patients will continue and a fourth cohort of patients (neratinib 200 mg/day plus capecitabine 1,000 mg/m2 bid) will be added to further evaluate this therapeutic combination and establish a recommended dose level for part 2 of this study and for future later-stage clinical studies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5108.