Clinical Experience With the HER1/EGFR Tyrosine Kinase Inhibitor Erlotinib

November 2, 2003

In phase I trials in healthy volunteers and patients with refractorycancers, erlotinib (Tarceva) was well tolerated and showed activityagainst non–small-cell lung cancer and other tumors. The dose identifiedfor further clinical development was 150 mg/d; at this dose, erlotinibachieves high exposure, with maximum concentrations greater than2,000 ng/mL and 24-hour area under the concentration-time curvegreater than 35,000 ng • h/L. In a phase II trial in 57 patients withpreviously treated advanced non–small-cell lung cancer, erlotinib treatmentproduced an objective response rate of 12.3% and a stable diseaserate of 38.6%, with median duration of response of 19.6 weeks;median overall survival was 8.4 months and 1-year survival was 40%,with 9 patients remaining alive over follow-up of greater than 18 months.No grade 4 toxicity was observed, and grade 3 toxicity was minimal. Inan ongoing phase II trial in bronchioloalveolar carcinoma, erlotinibtreatment has produced objective response in 26% of 50 evaluable patients,with median duration of response not yet having been reached.An ongoing phase II trial is examining the combination of erlotinibwith the angiogenesis inhibitor bevacizumab (Avastin) in previouslytreated non–small-cell lung cancer; phase I evaluation revealed no doselimitingtoxicities at tested doses and provided evidence of antitumoractivity. Two phase III trials are examining erlotinib in combinationwith carboplatin (Paraplatin)/paclitaxel (the TRIBUTE trial) orcisplatin/gemcitabine (Gemzar) (the TALENT trial) as first-line treatmentin advanced non–small-cell lung cancer. The phase III BR.21trial is assessing erlotinib monotherapy in advanced refractory non–small-cell lung cancer. Results of these phase II trials will soon beavailable.

ABSTRACT: In phase I trials in healthy volunteers and patients with refractorycancers, erlotinib (Tarceva) was well tolerated and showed activityagainst non–small-cell lung cancer and other tumors. The dose identifiedfor further clinical development was 150 mg/d; at this dose, erlotinibachieves high exposure, with maximum concentrations greater than2,000 ng/mL and 24-hour area under the concentration-time curvegreater than 35,000 ng
• h/L. In a phase II trial in 57 patients withpreviously treated advanced non–small-cell lung cancer, erlotinib treatmentproduced an objective response rate of 12.3% and a stable diseaserate of 38.6%, with median duration of response of 19.6 weeks;median overall survival was 8.4 months and 1-year survival was 40%,with 9 patients remaining alive over follow-up of greater than 18 months.No grade 4 toxicity was observed, and grade 3 toxicity was minimal. Inan ongoing phase II trial in bronchioloalveolar carcinoma, erlotinibtreatment has produced objective response in 26% of 50 evaluable patients,with median duration of response not yet having been reached.An ongoing phase II trial is examining the combination of erlotinibwith the angiogenesis inhibitor bevacizumab (Avastin) in previouslytreated non–small-cell lung cancer; phase I evaluation revealed no doselimitingtoxicities at tested doses and provided evidence of antitumoractivity. Two phase III trials are examining erlotinib in combinationwith carboplatin (Paraplatin)/paclitaxel (the TRIBUTE trial) orcisplatin/gemcitabine (Gemzar) (the TALENT trial) as first-line treatmentin advanced non–small-cell lung cancer. The phase III BR.21trial is assessing erlotinib monotherapy in advanced refractory non–small-cell lung cancer. Results of these phase II trials will soon beavailable.

Erlotinib (Tarceva) is an inhibitorof HER1/epidermal growthfactor receptor (EGFR) tyrosinekinase, a new class of targeted anticancerdrugs currently being investigatedin the clinical setting. The antitumoractivity of erlotinib in preclinicalstudies provided strong support foran extensive clinical development program.This article summarizes earlyphaseclinical investigations oferlotinib and describes ongoing trialsin non-small-cell lung cancer.Erlotinib Phase I TrialsOrally administered erlotinib hasbeen evaluated as monotherapy in fourphase I studies, consisting of twosingle-dose and multiple-dose studiesin healthy volunteers and two multiple-dose studies of daily and weeklydosing in patients with refractory cancers,including non-small-cell lungcancer.[1,2] Diarrhea at the 200-mg/ddose in daily dosing studies was identifiedas the dose-limiting toxicity.Other observed toxicities consisted ofa dose-related acneiform rash localizedabove the waist (grade 1 or 2),headache, and nausea/vomiting. Nodose-limiting toxicities were observedin weekly dosing studies at doses ofup to greater than 1,600 mg. The maximumtolerated dose of 150 mg/d in thedaily dosing studies was identified forevaluation in subsequent phase II tri-als.Evidence of antitumor effect wasobserved in patients with refractorycancers, with 8 of 40 patients receivingdaily doses exhibiting stable diseasefor longer than 5 months and 4

of 27 receiving weekly doses havingstable disease for longer than 6months. Similar findings were madein initial studies in Japanese patients.Evaluation of erlotinib pharmacokineticsin daily dosing studies showeddose-proportional maximum plasmaconcentrations (Cmax) and area underthe concentration-time curve (AUC),with no drug accumulation occurringwith repeated daily dosing. High drugexposure was observed at the 150-mgdose, which resulted in Cmax greaterthan 2,000 ng/mL; as shown in Figure1, Cmax and AUC values with erlotinibat 150 mg were comparable to thoseobserved with gefitinib (Iressa) at 700mg/d, a dose substantially higher thanthe currently accepted gefitinib doseof approximately 250 mg/d.[1,3]Erlotinib currently is being evaluatedin phase I studies of combinationswith chemotherapeutic agents andother targeted agents. Preclinical studieshave shown at least additive antitumoreffects of erlotinib in combinationwith other chemotherapeuticagents, with no increase in toxicity.[4]Ongoing phase Ib combination trialsinclude those evaluating the combinationof erlotinib with docetaxel(Taxotere), carboplatin (Paraplatin)/paclitaxel, and cisplatin/gemcitabine(Gemzar).[5-7] Initial findings includeabsence of pharmacokinetic interactionsbetween erlotinib and otheragents and preliminary evidence ofantitumor effects.Erlotinib Phase II Trials inNon-Small-Cell Lung CancerPreviously Treated AdvancedNon-Small-Cell Lung Cancer
Erlotinib has been evaluated in aphase II trial in patients with previouslytreated non-small-cell lung cancer.[8] The primary objective of thetrial was to determine the objectiveresponse rate in patients with HER1/EGFR-positive advanced or recurrentnon-small-cell lung cancer who hadfailed prior platinum-based chemotherapy.Secondary objectives includeddetermining the stable diseaserate, duration of response, progression-free, overall, and 1-year survival,and safety and tolerability. Eligiblepatients had histologically confirmedstage IIIB/IV disease, Eastern CooperativeOncology Group (ECOG) performancestatus of 0 to 2, and life expectancyof at least 12 weeks; all patientswere required to be EGFR-positive.Erlotinib was given at 150 mg/dfor up to 52 weeks or until clinical deteriorationor disease progression. Atotal of 57 patients (34 female, 23male) were studied: median age was62 years (range: 31 to 83 years);ECOG performance status was 0 in 6patients (11%), 1 in 44 (77%), and 2in 7 (12%); 9 (16%) had stage IIIB diseaseand 48 (84%) had stage IV disease;and HER1/EGFR expression wasstrong in 32 patients (56%), weak tostrong in 19 (33%), and weak in 6(10.5%).The objective response rate was12.3% (95% confidence interval [CI]= 5.1%-23.7%), with two completeresponses and five partial responsesbeing observed (Table 1). Stable diseasewas observed in 22 patients(38.6%), yielding an overall diseasecontrol rate of 51%. Response durationswere 18 and 80 weeks in patientswith complete response and 12, 14,20, 24+, and 56 weeks in those withpartial response; the median durationof response was 19.6 weeks (95%CI = 11.6-97.3 weeks). Medianoverall survival was 8.4 months(95% CI = 4.8-13.9 months) andthe 1-year survival rate was 40%(95% = CI 28%-54%) (Figure 2),with 9 patients remaining alive overfollow-up of greater than 18 months.

Median progression-free survival was9 weeks (95% CI = 8-15 weeks).Baseline predictors of response oroverall survival included time frominitial diagnosis, time from last chemotherapy,and ECOG performancestatus, but not extent of prior chemotherapy.Occurrence of grade 1 or 2/3rash during treatment was predictiveof survival. Treatment was well tolerated,with the most common adverseevents being grade 1 or 2 rash and diarrhea(Table 2). No grade 4 toxicitywas observed, and grade 3 toxicityconsisted of pruritus in 2 patients andrash, diarrhea, and dry skin in 1 patienteach. Five patients discontinuedtreatment due to toxicity.The disease control rate (51%) andsurvival rates (overall survival 8.4months, 1-year survival 40%) observedwith erlotinib in this trial comparefavorably with those reported inthe phase II IDEAL 1 and IDEAL 2trials of gefitinib in advanced NSCLC.In the IDEAL 1 trial, disease controlrates were 54%/51%, median overallsurvival durations were 7.6/8.0months, and 1-year survival rates were35%/30% with doses of 250 mg/500mg per day; in IDEAL 2, disease controlrates were 43%/36%, overall mediansurvival durations were 6.5/5.9months, and 1-year survival rates were29%/24% with doses of 250 mg/500 mg per day.[9,10] The findingswith erlotinib also compare wellwith the 54% disease control rate,7.5-month median overall survival,and 37% 1-year survival rate observedwith docetaxel 75 mg/m2 treatmentin a phase III trial vs best supportivecare in this setting reported byShepherd et al[11], recognizing, however,the limitations of comparing theresults of a phase II trial with those ofa phase III trial.BronchioloalveolarCell Carcinoma
In an ongoing phase II trial, the effectsof erlotinib at 150 mg/d are beingevaluated in patients withbronchioloalveolar cell carcinoma(BAC).[12,13] Eligibility requirementsincluded disease characterizedas pure BAC, BAC with focal invasion,or adenocarcinoma with BAC features;0 or 1 course of prior chemo-chemotherapy;and Karnofsky performancestatus of at least 60. Thus far, data areavailable from a total of 50 evaluablepatients (34 female, 16 male). Patientcharacteristics include median age 66years (range 32 to 85 years);Karnofsky performance status of 90or 100 in 17 (34%), 80 in 30 (60%),and 70 in 3 (6%); history of cigarettesmoking (former/current smoker) in37 (74%) vs no history (< 100 cigaretteslifetime) in 13 (26%); and noprior chemotherapy in 38 (76%) vsone prior course in 12 (24%).Of these patients, 13 (26%, 95% CI= 13%-40%) have exhibited a partialresponse; the median duration of followup for responding patients is 6months, and median duration of responsehas not yet been reached. Onecase of response is shown in Figure 3.Treatment was well tolerated, with themost significant adverse events consistingof 4 cases of grade 3 rash, 2cases of intolerable grade 2 rash, grade3 arthralgia in 1 patient, and grade 3diarrhea in 1 patient. One patient discontinuedtreatment due to adverseevents, and all other adverse eventswere managed by dose reduction orinterruption. It is noteworthy that astrong trend was observed for responsein patients with no history of smoking(46% vs 19%, P = .07). Multivariateanalyses of gefitinib trials involving

non-small-cell lung cancer patientshave shown both presence of BAC features(P = .005) and absence of smokinghistory (P = .007) to be predictiveof response.[14] Such findings suggestthat BAC may have a different biologyin patients with no history ofsmoking.

Phase I/II Trial of Erlotinib/Bevacizumab in Non-Small-CellLung CancerThe combination of erlotinib andthe vascular endothelial growth factor(VEGF) inhibitor bevacizumab(Avastin) currently is being evaluatedin a phase II trial in patients with advancednon-small-cell lung cancer.[15,16] Preclinical data indicatethat the combination of HER1/EGFRinhibitors and VEGF inhibitors pro-duces an at least additive antitumoreffect. The rationale for such a combinationincludes the potential for improvedtolerance with fewer nonspecifictoxicities and augmentation ofefficacy via the targeting of two pathwayscritical to tumor growth.In the phase I portion of the trial,patients with grade IIIB/IV locallyadvanced or metastatic non-squamouscell non-small-cell lung cancerwho had received at least one priorchemotherapy regimen were treatedwith oral erlotinib once daily and intravenousbevacizumab on day 1 every21 days at three dose levels: (1)erlotinib at 100 mg plus bevacizumabat 7.5 mg/kg; (2) erlotinib at 100 mgplus bevacizumab at 15.0 mg/kg; anderlotinib at 150 mg plus bevacizumabat 15.0 mg/kg. Dose escalation wasperformed according to a standard 3+ 3 study design, with three patientsper cohort being treated unless doselimitingtoxicity was observed.Among the 12 patients (8 female, 4male) assessed in the phase I study:median age was 55 years (range: 37to 72 years); 1 had stage IIIB and 11had stage IV disease; 12 had priorchemotherapy, 5 had prior surgery,and 7 had prior radiation therapy; andthe number of prior chemotherapyregimens was 1 in 2 patients, 2 in 7,and 3 or more in 3.Treatment was well tolerated, withno dose-limiting toxicities observed.The most frequent adverse eventswere grade 1/2 rash in 10 patients(83%), diarrhea in 9 (75%), nausea in7 (58%), pruritus in 5 (42%), and proteinuriain 4 (33%), with no grade 3toxicities observed. The maximumtolerated dose was defined as the highestdose studied, consisting of dailyerlotinib at 150 mg plus bevacizumabat 15.0 mg/kg every 21 days. Antitumoractivity was observed in the phaseI study, with partial response occurringin 3 patients (25%) and stable diseaseobserved in 5 (42%). An exampleof response in this portion of the studyis shown in Figure 4. Preliminary dataindicate absence of a pharmacokineticinteraction between erlotinib andbevacizumab. Additional patientshave been recruited to the ongoingphase II portion of the trial.Ongoing Erlotinib Phase IIITrials in Non-Small-CellLung CancerErlotinib has an additive antitumoreffect in combination with cytotoxicagents, including cisplatin,paclitaxel, capecitabine (Xeloda),irinotecan (Camptosar), and gemcitabine(Gemzar) in human cancerxenograft models. The toxicity profilesof erlotinib and chemotherapy(carboplatin/paclitaxel or gemcita-bine/cisplatin) are essentiallynonoverlapping. Currently, two phaseIII trials of erlotinib combined withstandard chemotherapy as first-linetreatment of non-small-cell lungcancer are in progress (Figure 5). Boththe TALENT and TRIBUTE trialsenrolled patients with HER1/EGFR-positive or -negative stage IIIB/IV disease.

In the TALENT trial, 1,137 patientswere randomized to cisplatin/gemcitabineplus erlotinib at 150 mg/d orplacebo for six cycles of chemotherapyfollowed by daily erlotinib orplacebo until disease progression. Inthe TRIBUTE trial, 1,079 patientswere randomized to carboplatin/paclitaxel plus erlotinib at 150 mg/dor placebo for six cycles of chemotherapyfollowed by daily erlotinib orplacebo until disease progression.Both trials have 80% power to detecta 25% survival benefit at an α = .05level and similar power to detect a 33%difference between treatments in 1-year survival. Preliminary reports indicatethat survival is negative, butformal presentation of the data isawaited.Erlotinib is also being evaluated asmonotherapy in an ongoing NationalCancer Institute of Canada phase IIItrial in patients with advanced, refractorynon-small-cell lung cancer. In theBR.21 trial, patients with stage IIB/IVdisease who have failed one or twoprior chemotherapy regimens and havean ECOG performance status of 0 to3 have been randomized 2:1 toerlotinib at 150 mg/d or placebo. Accrualto this trial is complete, with 731patients having been randomized. Thetrial has 90% power to detect a 33%survival benefit. Results of this trial arealso expected in early 2004.ConclusionErlotinib is an active and well-toleratedagent in advanced non-smallcelllung cancer. It currently is beingevaluated as part of combination treatmentwith cytotoxic chemotherapeuticagents as first-line treatment in advanceddisease, as monotherapy in refractorydisease, and in combinationwith the angiogenesis inhibitorbevacizumab in pretreated patients.Additional studies are under way orplanned to identify predictors of responseto erlotinib, to investigate combinationsof erlotinib with other biologicagents, and to define optimaldosing strategies, including identificationof optimal dosing in concurrentand sequential combination therapyregimens and development of potentialweekly dosing schedules.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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