Cancer Therapy: Clinical
A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor Tyrosine Kinase Inhibitor, in Patients with Solid Tumors Kwok-K.Wong,1Paula M. Fracasso,2 Ronald M. Bukowski,3 Thomas J. Lynch,4 Pamela N. Munster,5 GeoffreyI. Shapiro, 1Pasi A. Ja« nne,1Joseph P. Eder,1Michael J. Naughton,2 Matthew J. Ellis,2 Suzanne F. Jones,7 Ta r e k M e k h a il , 3 Charles Zacharchuk,6 Jennifer Vermette,6 Richat Abbas,6 Susan Quinn,6 Christine Powell,6 andHowardA.Burris7
Abstract Purpose: The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminaryantitumor activityof neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors. Experimental Design: Neratinib was administered orallyas a single dose, followed bya1-week observation period, and then once dailycontinuously.Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration. Results: Dose-limiting toxicitywas grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacoki- netic profile of neratinib supports a once-a-daydosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease z24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non ^ small cell lung cancer patients. Conclusion:Themaximumtolerateddose ofonce-dailyoralneratinibis 320 mg.Themost common neratinib-related toxicitywas diarrhea. Antitumor activitywas observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensityof 2+ or 3+.The antitumor activity, tolerable toxicityprofile, and pharmacokinetic properties of neratinib warrant its further evaluation.
Novel therapeutic agents that target growth factor pathways therapies. In particular, agents targeting members of the human dysregulated in tumors may offer alternative treatment options epidermal growth factor receptor (EGFR)family (ErbB-1/EGFR for patients who are chemo-intolerant or refractory to standard and ErbB-2)have shown encouraging therapeutic efficacy. The first to be approved by the U.S. Food and Drug Administration in 1998 was trastuzumab, a humanized monoclonal antibody Authors’ Affiliations: 1Dana-Farber Cancer Institute, and Brigham and Women’s that binds to the extracellular domain of ErbB-2, for the Hospital, Harvard Medical School, Boston, Massachusetts; 2Siteman Cancer treatment of ErbB-2–positive breast cancer. Later, small Center,Washington UniversitySchool of Medicine, St. Louis, Missouri; 3Cleveland 4 molecules that specifically inhibit EGFR tyrosine kinase were Clinic Foundation, Cleveland, Ohio; Massachusetts General Hospital, Boston, approved, including erlotinib and gefinitib, for advanced or Massachusetts; 5H. Lee Moffitt Cancer Center,Tampa, Florida; 6Wyeth Research, Cambridge, Massachusetts; and 7Sarah Cannon Research Institute, Nashville, metastatic non–small cell lung cancer (NSCLC; refs. 1, 2). Tennessee However, these targeted agents have limitations. Trastuzu- Received 7/30/08; revised 11/11/08; accepted 12/30/08; published OnlineFirst mab shows only 15% to 26% response as monotherapy and 3/24/09. 38% response when used in combination with paclitaxel in Grant support: Wyeth Research, Collegeville, PA, and royalties from Genzyme (J. Eder). metastatic breast cancer (3, 4). Trastuzumab treatment is also P.M. Fracasso is currentlyaffiliated with the Universityof Virginia Cancer Center, associated with heart failure in some patients, particularly those Charlottesville, Virginia. P.N. Munster is currentlyaffiliated with the University pretreated with anthracyclines (4, 5). Gefinitib and erlotinib ofCalifornia,SanFrancisco,California.J.P.Ederiscurrentlyemployedby have objective response rates of only 12% and 18%, respec- AstraZeneca, LP. The costs of publication of this article were defrayed in part by the payment of page tively, in patients with advanced NSCLC; the benefit from charges. This article must therefore be herebymarked advertisement in accordance these drugs occurs largely in the subgroup of patients whose with 18 U.S.C. Section 1734 solelyto indicate this fact. cancers harbor activating EGFR kinase domain mutations (6, 7). Requests for reprints: Kwok-Kin Wong, Dana-Farber Cancer Institute, 44 Binney Preclinical data suggest that different tyrosine kinase inhib- Street, Dana Building 810B, Boston, MA 02115. Phone: 617-632-5301; Fax: 617- 632-5786; E-mail: [email protected]. itors have different potencies against various EGFR and ErbB- F 2009 American Association for Cancer Research. 2–activating mutations, and clinical data with reversible doi:10.1158/1078-0432.CCR-08-1978 and irreversible tyrosine kinase inhibitors on patients with
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of lung cancer patients that have the EGFR kinase domain Translational Relevance sensitizing mutation after initial response to either gefitinib or erlotinib treatment and subsequent progression (9–12). Successful clinical development of novel therapeutics Neratinib targets a conserved cysteine residue (Cys 797) that specificallytarget the ErbB growth factor receptor within the catalytic cleft of the ErbB receptors and irreversibly pathways might offer new treatment options for cancer inhibits its kinase activity (13). Neratinib is expected to inhibit patients with ErbB-pathwaydysregulated cancers. Nerati- tumors that express high (+3)and intermediate (+2)levels of nib (HKI-272) is an orallyavailable, small molecule, irrevers- ErbB-2. Tumors that express low levels of ErbB-2 are resistant to ible ErbB inhibitor of the ErbB-2/HER2 and ErbB-1/ trastuzumab treatment. epidermal growth factor receptor proteins that has shown The primary purpose of this study was to assess the tolerability potent preclinical activityin tumor cells and xenograft and safety and to define the maximum tolerated dose of models. Here, we present the safetyand efficacydata neratinib administered orally in patients with advanced-stage from a phase I studyof 73 patients with solid tumors. tumor types that express ErbB-2 or ErbB-1/EGFR. In addition, We show that neratinib is well tolerated at the maximal the pharmacokinetic profile and the antitumor activity of orally tolerated dose of 320 mg once daily. The major dose- administered neratinib in patients with advanced stage ErbB-2 limiting toxicities are diarrhea, fatigue, and vomiting. or ErbB-1/EGFR tumors were assessed. Strikingly, partial response is observed in 8 (32%) patients with refractoryHER2-positive breast cancer and stable disease >24 weeks is observed in 6 (43%) patients with refractorynon ^ small cell lung cancer. These clinical data Materials and Methods stronglyimplicate neratinib as an effective treatment option for these two common types of cancers. Trial design. This was a phase I, open-label study wherein patients with ErbB-2– or ErbB-1/EGFR–positive tumors initially received single oral doses of neratinib, followed by 1 wk of observation to assess single- dose pharmacokinetic profiles and adverse events. Patients continued refractory solid tumors have been conflicting. Preclinical data on the same dose level if neratinib was well tolerated with no evidence of progressive disease. with neratinib [HKI-272; a potent (8), orally administered, Patients. Eligible patients had to have previous histologic/cyto- small-molecule, irreversible pan ErbB inhibitor that inhibits logic diagnosis of metastatic or advanced-stage ErbB-2– or ErbB-1/ ErbB-1, -2, -4] suggest that this irreversible tyrosine kinase EGFR–positive cancer that had failed standard effective therapy. inhibitor can potentially overcome the acquired resistance of Patients also had to have tumors for which +1, +2, or +3 levels of EGFR T790M mutation. This mutation developed in the tumors ErbB-2 or EGFR were documented by immunohistochemistry
Table 1. Patients’ characteristics
Characteristic, n (%) Dose group (neratinib) 40 mg 80 mg 120 mg 180 mg 240 mg 320 mg 400 mg MTD Total (n =3) (n =4) (n =4) (n =6) (n =3) (n =7)* (n =6) (n = 39) (n = 72) Sex Female 2 (67) 4 (100) 3 (75) 6 (100) 2 (67) 5 (71) 4 (67) 26 (67) 52 (72) Male 1 (33) 0 1 (25) 0 1 (33) 2 (29) 2 (33) 13 (33) 20 (28) Age, median (range) 51 52 57.5 56.5 60 66 49.5 57 57 (39-64) (48-64) (34-76) (46-90) (47-64) (34-82) (42-63) (34-80) (34-90) ECOG performance status 0 0 2 (50) 1 (25) 3 (50) 2 (67) 2 (29) 3 (50) 18 (47) 31 (44) 1 3 (100) 2 (50) 1 (25) 3 (50) 1 (33) 4 (57) 2 (33) 19 (50) 35 (49) 2 0 0 2 (50) 0 0 1 (14) 1 (17) 1 (3) 5 (7) Missingc 000000011 Primary cancer diagnosis Breast 0 3 (75) 3 (75) 6 (100) 1 (33) 2 (29) 3 (50) 11 (28) 29 (40) Non–smallcelllung000001(14) 3 (50) 11 (28) 15 (21) Ovarian 2 (67) 00001(14) 0 3 (8) 6 (8) Colorectal 1 (33) 0000003(8)4(6) Glioblastoma00000004(10) 4 (6) Renal 00002(67) 0 0 1 (3) 3 (4) Pancreatic 00000002(5)2(3) Other 0 1 (25) 1 (25) 0 0 3 (43) 0 4 (10) 9 (13) Previous chemotherapy regimens, any setting 1-2 0 0 0 4 (67) 1 (33) 1 (14) 2 (33) 12 (31) 20 (28) 3 0 1 (25) 1 (25) 1 (17) 0 1 (14) 1 (17) 3 (8) 8 (11) z4 3 (100) 3 (75) 3 (75) 1 (17) 2 (67) 5 (71) 3 (50) 24 (62) 44 (61)
Abbreviations: MTD, maximum tolerated dose; ECOG, Eastern Cooperative Oncology Group. *The 320-mgcohort had seven patients because one patient in the groupwas not evaluable for safety and efficacy and had to be replaced. cOne patient’s ECOG performance status was missingbecause one site did not report the data.
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Table 2. Treatment-emergent and treatment-related adverse events that occurred in z10% patients, all grades
Adverse event Neratinib dose, patients, n (%) Any causality 40 mg 80 mg 120 mg 180 mg 240 mg 320 mg 400 mg MTD Total (n =3) (n =4) (n =4) (n =6) (n =3) (n =7) (n =6) (n = 39) (n = 72) Abdominal pain 2 (67) 1 (25) 0 1 (17) 0 4 (57) 1 (17) 8 (21) 17 (24) Diarrhea 1 (33) 2 (50) 3 (75) 6 (100) 3 (100) 7 (100) 5 (83) 36 (92) 63 (88) Nausea 2 (67) 2 (50) 4 (100) 3 (50) 3 (100) 5 (71) 6 (100) 21 (54) 46 (64) Vomiting1 (33) 1 (25) 2 (50) 2 (33) 2 (67) 3 (43) 6 (100) 19 (49) 36 (50) Fatigue 3 (100) 3 (75) 3 (75) 4 (67) 2 (67) 6 (86) 5 (83) 19 (49) 45 (63) Anorexia 1 (33) 3 (75) 0 1 (17) 3 (100) 5 (71) 3 (50) 13 (33) 29 (40) Rash 0 1 (25) 1 (25) 1 (17) 1 (33) 3 (43) 2 (33) 3 (8) 12 (17)
(Ventana). ErbB-2–positive tumors had staining intensities of z2on adverse event. If none of three to six patients had a dose-limiting a scale of 0 to 3 and percent positive tumor cells z10%; EGFR- toxicity by day 14 of continuous daily administration, then dose positive tumors had staining intensities z1 with percent positive escalation proceeded to the next level. If one of three to six patients had tumor cells z10% or any percentage of cells staining z2+. EGFR a dose-limiting toxicity, then the cohort was expanded to six required mutation analyses were done on the six NSCLC patients with stable patients. If two or more of three to six patients in a cohort had a dose- disease using heteroduplex analyses combined with Surveyor endoc- limiting toxicity, dose escalation was stopped and the previous dose nuclease digestion (14). level was the maximum tolerated dose. Patients had to have measurable disease (Response Evaluation Criteria Dose reduction was recommended if a patient had a neratinib- In Solid Tumors), an Eastern Cooperative Oncology Group performance related grade 3 or 4 adverse event, except in the case of nausea, status of 0 to 2, and adequate bone marrow and organ functions. vomiting, or rash wherein dose reduction occurred only if the patient The study protocol was approved by the institutional review boards was receiving appropriate medical therapy, and if a patient had grade 2 of the participating institutions, and all patients gave written informed or 3 diarrhea lasting >2 d on medical therapy or associated with fever or consent. This study was conducted according to the Declaration of dehydration. Doses were reduced by dropping back one dose level. No Helsinki and its amendments. more than two dose reductions were allowed for any patient. Dose escalation. Dose escalation followed a modified Fibonacci Up to 40 additional patients, including 10 patients with NSCLC who scheme with three to six patients in each cohort. The planned dose- had progressed following z8 wks of treatment with either erlotinib or escalation schedule was 40, 80, 120, 180, 240, 320, 400, and 500 mg of gefitinib and 10 patients with breast cancer, were treated at the neratinib (cohort 1-8)daily with food. maximum tolerated dose to better define the tolerability and The decision for dose escalation was made after three to six patients preliminary activity of neratinib. in a cohort were evaluated for adverse events through day 14 of Evaluation of patients. All enrolled patients had radiologic tumor continuous daily administration. In previous studies with other tyrosine assessments done at screening and after every two cycles (i.e., cycles 2, kinase inhibitors, gastrointestinal toxicity was reported soon after 4, etc), according to the modified Response Evaluation Criteria In Solid dosing began, and therefore, 14 d was selected as the safety assessment Tumors guideline (15). period for acute toxicities for dose escalation. Adverse events were The primary efficacy parameter assessed in the trial was the best graded based on the National Cancer Institute Common Terminology overall response, recorded from the start of treatment until disease Criteria for Adverse Events version 3.0. progression/recurrence. Progression-free survival was also measured, A dose-limiting toxicity was defined as any neratinib-related and safety evaluations were based on the occurrence of adverse events. grade 2 diarrhea lasting >2 d on medical therapy or associated with The efficacy evaluable population included all patients who received fever or dehydration (maximum tolerated dose); nonhematologic grade two or more consecutive weeks of treatment, and had one or more 3 adverse event excluding grade 3 nausea, vomiting, or diarrhea (unless tumor assessment f8 wks after beginning continuous daily dosing or patients were receiving appropriate medical therapy); or any grade 4 patients who received one or more dose of neratinib but discontinued
Table 3. Grade z3 treatment-emergent and treatment-related adverse events
Adverse event Neratinib dose, patients, n (%) Any causality 40 mg 80 mg 120 mg 180 mg 240 mg 320 mg 400 mg MTD Total (n =3) (n =4) (n =4) (n =6) (n =3) (n =7) (n =6) (n = 39) (n = 72) Diarrhea 0 0 1 (25) 1 (17) 0 0 5 (83) 16 (41) 23 (32) Vomiting0 0 0 0 0 1 (14) 2 (33) 2 (5) 5 (7) Nausea 0 0 0 0 0 1 (14) 1 (17) 1 (3) 3 (4) Fatigue 0 0 1 (25) 1 (17) 0 2 (29) 2 (33) 0 6 (8) Asthenia 0 0 0 0 0 0 0 1 (3) 1 (1) Dehydration 0 0 0 0 0 1 (14) 0 3 (8) 4 (6) Anorexia 0 0 0 0 0 0 0 1 (3) 1 (1)
NOTE: There were no grade 4 – related toxicities.
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Table 2. Treatment-emergent and treatment-related adverse events that occurred in z10% patients, all grades (Cont’d)
Neratinib dose, patients, n (%) Neratinib related 40 mg 80 mg 120 mg 180 mg 240 mg 320 mg 400 mg MTD Total (n =3) (n =4) (n =4) (n =6) (n =3) (n =7) (n =6) (n = 39) (n = 72) 1 (33) 0 0 1 (17) 0 3 (43) 0 4 (10) 9 (13) 1 (33) 2 (50) 3 (75) 6 (100) 3 (100) 7 (100) 5 (83) 36 (92) 63 (88) 2 (67) 2 (50) 2 (50) 3 (50) 2 (67) 4 (57) 5 (83) 18 (46) 38 (53) 0 1 (25) 2 (50) 2 (33) 1 (33) 2 (29) 5 (83) 15 (39) 28 (39) 3 (100) 2 (50) 2 (50) 4 (67) 2 (67) 4 (57) 5 (83) 12 (31) 34 (47) 1 (33) 2 (50) 0 1 (17) 2 (67) 2 (29) 3 (50) 12 (31) 23 (32) 0 1 (25) 1 (25) 1 (17) 1 (33) 2 (29) 2 (33) 3 (8) 11 (15) the study because of early progressive disease, symptomatic deteriora- study in January 2007. One patient in the expanded maximum tion, or death. tolerated dose cohort was not treated because she withdrew Pharmacokinetic analyses. Timed blood samples for pharmacoki- consent. Of the 72 patients who were treated with neratinib, netic analyses of neratinib were collected after the administration of the 72% were female with a median age of 57 years (Table 1). The first single dose on day 1 and after 14 days of continuous daily predominant primary cancer diagnoses were breast cancer administration (study day 21 F 2 d). Samples were obtained at predose and at 1, 2, 3, 4, 5, 6, 8, and 24 h postdose on days 1 and 21, and a (40%)and NSCLC (21%).All had previous chemotherapy. sample was also taken 48 h postdose on day 1 of the single-dose period. Most of the patients were heavily pretreated, with 34% patients Plasma concentrations were measured using a validated liquid having four or more previous cytotoxic therapy regimens in the chromatography/tandem mass spectrometry method. The bioanalytic metastatic setting. method used 0.250 mL of plasma and was linear over the range of 3 to Dose escalation of neratinib. Diarrhea was the primary dose- 250 ng/mL (lower limit of quantitation (LLQ)was 3 ng/mL).The mean limiting toxicity in this study. Patients at the 40- to 120-mg interday variabilities (coefficient of variation)of neratinib quality doses had no dose-limiting toxicities; one patient at the 180-mg control samples were V7.8%, and intraday variabilities were V8.8%. dose had grade 3 diarrhea. Four patients at the 400-mg dose Mean interday accuracy was within the range of 98.4% to 103.2%, and had grade 3 diarrhea, and per protocol, the maximum tolerated mean intraday accuracy was within the range of 100.0% to 106.6%. dose was determined to be 320 mg. The 320-mg cohort was Mean accuracy at the LLQ of 3 ng/mL (104.0%)indicated that expanded to include an additional 39 patients to confirm the variability was acceptable (8.8%). No interferences were observed in blank plasma or plasma spiked with internal standard. The plasma safety and tolerability of the maximum tolerated dose. samples were stored at -70jC until analysis. Safety. All 72 (100%)patients experienced adverse events. Pharmacokinetic analyses were done using WinNonLin Enterprise Those, of any grade, that occurred during the study in z10% application version 4.1 (Pharsight Corporation). Standard noncom- patients are summarized in Table 2. The most common adverse partmental method (16)was used to calculate the peak plasma events were diarrhea (88%), nausea (64%), fatigue (63%), C C t concentration ( max), time to max ( max), the total area under the vomiting (50%), and anorexia (40%). Neratinib-related adverse concentration-time curve (AUC = AUC0-1), the area under the events were similar. concentration-time curve to the 24 h postdose (AUC0-24 hr)or at steady Grade 3 or higher neratinib-related adverse events occurred t state (AUCss), and the elimination half-life ( 1/2). in 39% of all patients. The most common grade 3 or higher related adverse events were diarrhea (32%), fatigue (4%), and Results vomiting (4%; Table 3). The median onset of diarrhea was 8.5 days (range, 1.0-22.0 Patients. Seventy-three patients were enrolled from Novem- days). One patient, in the 320-mg cohort, on day 338 of the ber 2003 until December 2005. The last patient completed the study, experienced grade 3 pneumonitis considered related to
Table 3. Grade z3 treatment-emergent and treatment-related adverse events (Cont’d)
Neratinib dose, patients, n (%) Neratinib related 40 mg 80 mg 120 mg 180 mg 240 mg 320 mg 400 mg MTD Total (n =3) (n =4) (n =4) (n =6) (n =3) (n =7) (n =6) (n = 39) (n = 72) 0 0 1 (25) 1 (17) 0 0 5 (83) 16 (41) 23 (32) 0 000001(17) 2 (5) 3 (4) 0 0000001(3)1(1) 0 0 0 1 (17) 0 1 (14) 1 (17) 0 3 (4) 0 0000001(3)1(1) 0 0 0 0 0 1 (14) 0 1 (3) 2 (3) 0 0000001(3)1(1)
www.aacrjournals.org 2555 Clin Cancer Res 2009;15(7) April 1, 2009 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2009 American Association for Cancer Research. Cancer Therapy: Clinical neratinib. This patient was hospitalized and withdrew from the with NSCLC showed reductions from baseline in tumor size study but eventually recovered. (Fig. 1). All patients discontinued treatment. Discontinuations were The median duration of response was 4.8 months [95% due mainly to adverse events 13 (18%), disease progression confidence interval (95% CI): 1.9, 9.5] in the eight breast cancer 40 (56%), and symptomatic deterioration 7 (10%). The most patients with partial response. The median duration of stable common adverse events leading to treatment discontinuation disease was 5.8 months (95% CI: 3.7, 8.1)in patients with breast were diarrhea in 10 patients (14%)and fatigue in 2 (3%). cancer (n = 14)and 9.0 months (95% CI: 7.4, 9.2)in patients Nine (9)of 10 patients discontinued due to diarrhea during with lung cancer (n = 8). The median progression-free survival the first cycle and the tenth did so during cycle 4. A total of 15 was 3.6 months (95% CI: 1.7, 5.6)in patients with breast cancer patients died during the study; 14 of the deaths (19%)were and 3.5 months (95% CI: 1.2, 9.0)in patients with lung cancer. within 30 days of the last dose of neratinib, and all of deaths were attributed to progressive disease. A total of 22 (31%) patients had dose reductions; 18 patients had one reduction, Discussion and four patients had two reductions. Diarrhea was the cause of the dose reduction in 19 of these patients. Fourteen (36%) In this phase I study, neratinib was orally administered to patients had dose reductions at the maximum tolerated dose patients with solid tumors. No dose-limiting toxicities were of 320 mg, and, therefore, 240 mg neratinib was designated observed in doses ranging from 40 to 120 mg; but one patient the therapeutic dose. in the 180-mg dose group and four patients in the 400-mg dose Pharmacokinetics. Neratinib pharmacokinetic parameters group experienced grade 3 diarrhea. Hence, the maximum are summarized in Table 4. Following treatment with single tolerated dose was determined to be 320 mg. This cohort was doses ranging from 40 to 400 mg, absorption of neratinib was expanded to include an additional 39 patients for evaluation of relatively slow, with a median tmax of 3 to 6.5 hours. On safety and tolerability. Neratinib was found to have an study day 1, following single oral doses of 40 to 400 mg, acceptable safety profile. The most common related adverse neratinib exposure increased in a dose-dependent manner. For events were gastrointestinal in nature, mainly diarrhea. the same respective doses on study day 21 at steady state, the However, diarrhea was managed by use of antidiarrheal agents mean Cmax ranged from 5.8 to 119 ng/mL, and the mean and dose reductions. Fourteen percent of patients had to AUCss ranged from 76.0 to 1,704 ng h/mL. Interpatient discontinue treatment because of diarrhea. variability (coefficient of variation)estimates for neratinib The frequency and severity of rash seem to be significantly Cmax and AUC were small to moderate. In general, the steady less than with erlotinib (17)or with gefitinib (18).One patient state Cmax and AUC of neratinib increased with increasing had grade 3 pneumonitis and discontinued the study but dose but in a nonlinear fashion because of a plateau bet- eventually recovered. Pharmacokinetic analyses showed that ween 320- to 400-mg doses. The mean accumulation ratio, the steady state Cmax and AUC of neratinib increased in a dose- R (AUCss/AUC0-24 hr), was about one- to two-fold when dependent manner from 40 to 320 mg, but there was no further comparing the multiple dose exposures to the single dose increase in exposure when the dose was increased from 320 to exposures (40-400 mg). The R value was 1.14 following daily 400 mg. This could be due to low solubility of neratinib, and administration of 240 mg neratinib, indicating no major the saturable low solubility of the drug might be the main accumulation of neratinib after repeated daily administration contributor to the absorption plateau at the high doses. Eight in patients with cancer at the therapeutic dose of 240 mg. The patients with metastatic breast cancer had a partial response. Six mean elimination t on day 1 following oral administration patients were in the 320-mg dose group with AUCs ranging 1/2 of therapeutic dose of 240 mg neratinib with food was 14 h, from 532 to 2,752 ng h/mL; one patient was in the 180-mg and the half-life supports once-a-day dosing regimen. dose group with an AUC of 946 ng h/mL; and one patient was Antitumor activity. A total of 60 patients were considered in the 120-mg dose group with an AUC of 713 ng h/mL. In the evaluable for efficacy, 25 patients with breast cancer and 14 nonclinical efficacy model in nude mice, the exposure at the minimum efficacious dose was 431 ng h/mL. Partial responses patients with NSCLC. Among 25 evaluable patients with breast in all eight patients occurred at or above minimum efficacious cancer, partial response was observed in 8 (32%)and one z dose exposure, and the mean steady-state exposure at the patient showed stable disease 24 weeks (Table 5). All therapeutic dose of 240 mg was f2.2-fold higher than the responders had previous treatment with trastuzumab, anthra- minimum efficacious dose exposure in nude mice. Diarrhea cyclines, and taxanes, and tumors with a baseline ErbB-2 seems, to some extent, related to neratinib dose and exposure. immunohistochemical staining intensity of 2+ or 3+ (seven of However, because of the small number of patients in this study, eight responders had a 3+ score). Among 14 evaluable patients no clear relationships between the dose or exposure and the with NSCLC, 6 (43%)showed stable disease z24 weeks. severity of major adverse events (i.e., diarrhea, nausea, or rash) Among the six patients with stable disease z24 weeks, five were observed. patients had tumors with EGFR staining intensity of 3 and all The efficacy results were very promising in breast cancer had failed at least one regimen of an EGFR inhibitor (gefitinib patients. Partial response was observed in 8 (32%)patients or erlotinib). The six patients with stable disease had the with breast cancer. Stable disease z24 weeks was observed in following EGFR kinase domain mutations: del L747-750del, one breast cancer patient and six NSCLC patients. insP; L858R; E746-P753delinsVS; L747-S752del, P753S; del Preliminary results from a phase II trial comprised of breast L747-751C; and del L747-S752, T790M. cancer patients with tumors positive for ErbB-2, who either had or Maximum percentage decrease from baseline in tumor size had not undergone previous trastuzumab therapy, support that (sum of measured lesions)was evaluated separately for all neratinib is efficacious. Among trastuzumab-experienced patients. Thirteen patients with breast cancer and five patients patients, 59% had received one previous trastuzumab-containing
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Table 4. Pharmacokinetic parameters of neratinib for patients with advanced solid tumors
Dose group, mg Study day 1, Study day 21, mean F SD (CV%) [n] mean F SD (CV%) [n]
C max, t max, h t 1/2, h AUC0-24 hr C max, AUCss, ng/mL ng h/mL ng/mL ng h/mL 40 5.0 F 2.2 4.0 8.2 F 5.3 43.1 F 6.57 5.8 F 0.5 76.0 F NC (44) [3] (3.0, 5.0) [3] (65) [2] (15) [2] (8) [3] (NC) [1] 80 17.3 F 7.3 6.5 14.7 F 2.7 230 F 105 32.9 F 5.3 435 F 155 (42) [4] (2.0, 8.0) [4] (18) [2] (46) [4] (16) [4] (36) [4] 120 47.6 F 33.9 5.0 16.3 F 2.4 464 F 295 52.1 F 23.1 807 F 239 (71) [4] (3.0, 8.0) [4] (15) [3] (64) [4] (44) [4] (30) [4] 180 65.9 F 34.7 3.0 16.0 F 4.6 734 F 291 70.1 F 33.7 975 F 633 (53) [6] (2.0, 5.0) [6] (29) [6] (40) [6] (48) [6] (65) [6] 240 75.9 F 12.9 4.0 13.9 F 1.1 823 F 291 73.5 F 27.0 939 F 316 (17) [3] (4.0, 5.0) [3] (8) [3] (35) [3] (37) [3] (34) [3] 320 118 F 47.6 4.0 15.1 F 2.7 1582 F 800 119 F 61.3 1,644 F 1,014 (40) [7] (2.0, 8.0) [7] (18) [7] (51) [7] (51) [5] (62) [5] MTD (320) 83.5 F 51.6 4.0 14.9 F 4.1 994 F 580 85.8 F 44.8 1,280 F 739 (62) [39] (2.0, 8.0) [39] (27) [38] (58) [38] (52) [31] (58) [31] 400 76.5 F 39.5 5.5 16.9 F 4.2 1116 F 582 105 F 45 1,704 F 340 (52) [6] (2.0, 8.0) [6] (25) [6] (52) [6] (43) [2] (20) [2]
Abbreviations: NC, not calculated; CV%, coefficient of variation. regimen, 34% received 2 to 3 regimens, and 6% received 4 time to progression, or overall survival (22, 23). Rather, studies regimens. In this phase II study, patients with previous with gefitinib and erlotinib have indicated that clinical trastuzumab therapy had objective response rates of 33% and response is correlated to specific somatic mutations in the patients with no previous trastuzumab had objective response tyrosine kinase domain of the EGFR gene, and indeed, disease rates of 49%. Corresponding 16-week progression-free survival progression can occur with the development of a secondary rates of 53% (95% CI: 40, 65)and 72% (95% CI: 56, 83)were erlotinib/gefitinib acquired resistance mutation, T790M. It is observed in the respective treatment groups (19). By compar- interesting to note that all six NSCLC patients with stable ison, objective responses of 15% to 26% were observed disease had clinical responses to gefitinib/erlotinib before when patients with metastatic breast cancer were treated progression and enrollment into the neratinib trial, and their with monotherapeutic trastuzumab. Another dual ErbB-2/EGFR lung cancers had documented activating EGFR kinase domain inhibitor, lapatinib, showed only 4.3% response as mono- mutations. Thus, neratinib may be beneficial to this subset of therapy in metastatic breast cancer (20). lung cancer patients. The lack of partial responses for NSCLC patients was disappointing, but 43% showed stable disease z24 weeks. This lack of association of EGFR expression and clinical outcome is not unexpected. Another irreversible ErbB pan inhibitor CI- 1033 showed marginal efficacy in patients with advanced NSCLC with a response rate of 2% to 4% and failed to meets its primary statistical end point (21). In addition, others have shown that protein expression is a poor predictor for response,
Table 5. Tumor response in evaluable population
Response Breast (n = 25) NSCLC (n = 14) Partial response 8 (32%) 0 (0) Stable disease z24 wk 1 (4%) 6 (43%) Stable disease z16 wk 1 (4%) 0 (0) Stable disease z8 wk 4 (16%) 2 (14%) Progressive disease 11 (44%) 6 (43%)
NOTE: Patients who had received at least two consecutive weeks of neratinib treatment and who had undergone at least one tumor Fig. 1. Effect of neratinib on tumor burden of patients with breast and NSCLC. assessment f8 wk after initiatingneratinib treatment or patients Maximum percentage decrease from baseline in tumor size for 21of 25 evaluable who received at least one dose of neratinib but discontinued the breast cancer and 10 of 14 evaluable NSCLC patients are shown (remaining study because of early progressive disease, death, or symptomatic patients had earlyprogressive disease). Red, breast cancer patients with +3 deterioration were considered evaluable for efficacy. immunohistochemical levels of ErbB-2; yellow, lung cancer patients with known EGFR mutational status.
www.aacrjournals.org 2557 Clin Cancer Res 2009;15(7) April 1, 2009 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2009 American Association for Cancer Research. Cancer Therapy: Clinical
The tolerable toxicity profile, pharmacokinetic properties, patent on EGFR mutation testing. P. Fracasso and T. Lynch are consultants for and encouraging antitumor activity in patients with advanced Wyeth. T. Lynch is a consultant for Genentech, Bristol-Myers Squibb, Boehringer- Ingelheim, and Exelixis. solid tumors warrant further evaluation of neratinib for the treatment of patients with solid tumors. Acknowledgments Disclosure of Potential Conflicts of Interest We thank the patients, their families, and the clinical personnel who participated J.Vermette, R. Abbas, S. Quinn, C. Powell, and C. Zacharchuk are employed by in this study; and Tricia Gooljarsingh and Susan Leinbach for the assistance with Wyeth. T. Lynch is a member of the speakers’ bureau for Wyeth. P. Munster has a article preparation.
References 1. Cohen MH, Johnson JR, ChenY-F, Sridhara R, Pazdur quired resistance to gefitinib. Proc Natl Acad Sci Erlotinib in previouslytreated non-small-cell lung R. FDA drug approval summary: Erlotinib (TarcevaR) U S A 2005;102:7665 ^ 70. cancer. N Engl J Med 2005;353:123^ 32. Tablets. Oncologist 2005;10:461 ^ 6. 10. Ji H, Li D, Chen L, et al. The impact of human EGFR 18. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus 2. Cohen MH,Williams GA, Sridhara R, Chen G, Pazdur kinase domain mutations on lung tumorigenesis and best supportive care in previouslytreated patients R. FDA drug approval summary: Gefitinib (ZD1839) in vivo sensitivityto EGFR-targeted therapies. Cancer with refractoryadvanced non-small-cell lung cancer: (IressaR) Tablets. Oncologist 2003;8:303 ^ 6. Cell 2006;9:485 ^ 95. results from a randomised, placebo-controlled, multi- 3. Cobleigh MA, Vogel CL, TripathyD, et al. Multina- 11. Ji H, Zhao X, YuzaY, et al. Epidermal growth factor centre study(Iressa Survival Evaluation in Lung tional studyof the efficacyand safetyof humanized variant III mutations in lung tumorigenesis and sensi- Cancer). Lancet 2005;366:1527 ^ 37. anti-HER2 monoclonal antibodyin women who tivityto tyrosine kinase inhibitors. Proc Natl Acad Sci 19. Burstein H, Awada A, Badwe R, et al. HKI-272, have HER2-overexpressing metastatic breast cancer U S A 2006;103:7817^22. an irreversible pan ErbB receptor tyrosine kinase in- that has progressed after chemotherapyfor meta- 12. ShimamuraT,JiH,MinamiY,etal.Non-small-celllung hibitor: preliminaryphase 2 results in patients with static disease. J Clin Oncol 1999;17:2639 ^ 48. cancer and Ba/F3 transformed cells harboring the advanced breast cancer. Breast Cancer Res Treat 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of ERBB2 G776insV_G/C mutation are sensitive to the du- 2007;106:S268, (suppl1, abstr 6061). chemotherapyplus a monoclonal antibodyagainst al-specific epidermalgrowthfactorreceptorandERBB2 20. Burstein H, Storniolo AM, Franco S, et al. A HER2 for metastatic breast cancer that overexpresses inhibitor HKI-272. Cancer Res 2006;66:6487^91. phase II studyof lapatinib monotherapyin chemo- HER2. N Engl J Med 2001;344:783 ^ 92. 13. Tsou H-R, Overbeek-Klumpers EG, Hallet WA, et al. therapy-refractory HER-2 positive and HER-2 nega- 5. Seidman A, Hudis C, Pierri MK, et al. Cardiac dys- Optimization of 6,7-disubstituted-4-(arylamino)qui- tive advanced or metastatic breast cancer. Ann function in the trastuzumab clinical trials experience. noline-3-carbonitriles as orallyactive, irreversible Oncol 2008;19:1068^74. J Clin Oncol 2002;20:1215 ^ 21. inhibitors of human epidermal growth factor recep- 21. Ja« nne PA, von Pawel J, Cohen RB, et al. Multicenter, 6. Fukuoka M, Yano S, Giaccone G, et al. Multi-institu- tor-2 kinase activity. J Med Chem 2005;48:1107 ^ 31. randomized, phase II trial of CI-1033, an irreversible tional randomized phase II trial of gefinitib for previ- 14. Janne PA, Borras AM, Kuang Y, et al. A rapid and pan-ERBB inhibitor, for previouslytreated advanced ouslytreated patients with advanced non-small-cell sensitive enzymatic method for epidermal growth fac- non small-cell lung cancer. J Clin Oncol 2007;25: lung cancer. J Clin Oncol 2003;21:2237 ^ 46. tor receptor mutation screening. Clin Cancer Res 3936^44. 7. Perez-Soler R, Chachoua A, Hammond LA, et al. 2006;12:751 ^ 8. 22. Cortes-Funes H, Soto Parra H. Extensive experi- Determinants of tumor response and survival with 15. Therasse P, Arbuck SG, Eisenhauer EA, et al. New ence of disease control with gefitinib and the role of erlotinib in patients with non-small-cell lung cancer. guidelines to evaluate the response to treatment in prognostic markers. Br J Cancer 2003;89:S3 ^ 8, J Clin Oncol 2004;22:3238 ^ 47. solid tumors: European Organization for Research (suppl 2). 8. Rabindran SK, Discafani CM, Rosfjord EC, et al. and Treatment of Cancer, National Cancer Institute of 23. BaileyLR,KrisM,WolfM,etal.TumorEGFRmem- Antitumor activityof HKI-272, an orallyactive, irre- Canada. J Natl Cancer Inst 2000;92:205 ^ 16. brane staining is not clinicallyrelevant for predicting versible inhibitor of the HER-2 tyrosine kinase. Cancer 16. Evans WE, Schentag JJ, Jusko WJ. Principles of response in patients receiving gefitinib (‘‘Iressa’’ Res 2004;64:3958^65. therapeutic drug monitoring (ed 3).Vancouver (WA): ZD1839) monotherapyfor pretreated advanced non- 9. Kwak EL, Sordella R, Bell DW, et al. Irreversible Applied Therapeutics Inc; 1992. small-cell lung cancer: IDEAL1and 2. Proc Am Assoc inhibitors of the EGF receptor maycircumvent ac- 17. Shepherd FA, Rodrigues Pereira J, CiuleanuT, et al. Cancer Res 2003;44:1362, (abstr LB-170).
Clin Cancer Res 2009;15(7) April 1, 2009 2558 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2009 American Association for Cancer Research. A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor Tyrosine Kinase Inhibitor, in Patients with Solid Tumors
Kwok-K. Wong, Paula M. Fracasso, Ronald M. Bukowski, et al.
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