Efficacy of erlotinib in patients with advanced Non-small-cell Lung Cancer (NSCLC): Analysis of the Australian subpopulation of the TRUST study

ORIGINAL ARTICLE

Efficacy of erlotinib in patients with advancedNon-small-cell Lung Cancer (NSCLC): Analysis of theAustralian subpopulation of the TRUST studyajco_1540 1..7

Michael BOYER,1 Keith HORWOOD,6 Nick PAVLAKIS,2 Paul DE SOUZA,3

Michael MILLWARD,7 Brian STEIN,8 Michael JOHNSTON,4 Fiona ABELL5 andDanny RISCHIN9

1Sydney Cancer Centre, 2Royal North Shore Hospital, 3St George Hospital, 4Roche Products, Sydney, 5Calvary Mater Hospital,Newcastle, New South Wales, 6John Flynn Private Hospital, Tugun, Queensland, 7Sir Charles Gardiner Hospital, Perth,Western Australia, 8Adelaide Cancer Centre, Kurralta, South Australia, and 9Peter MacCallum Cancer Centre, Melbourne;Victoria, Australia

Abstract

Aims: The efficacy of erlotinib (Tarceva, Roche Products, Dee Why, Australia) has been demonstrated inpatients with advanced non-small-cell lung cancer (NSCLC). Tarceva lung cancer survival treatment(TRUST) is an open-label, single-arm, phase IV global trial which investigated erlotinib in advanced NSCLCpatients who had failed prior therapy or were unsuitable for chemo/radiotherapy. The aim of this analysiswas to report the safety and efficacy of erlotinib in the Australian patient subpopulation.

Methods: Patients with stage IIIB/IV NSCLC progressing after standard systemic chemotherapy or unsuit-able to receive chemo/radiotherapy were eligible for the study. The patients were treated with erlotinib at150 mg/day orally, until disease progression or unacceptable toxicity.

Results: In Australia, 460 patients were recruited. Erlotinib was given as first-line (16%), second-line(49%) or third-line (35%) treatment. In the intent-to-treat population (N = 460), the median progression-free survival was 2.7 months (95% CI 2.3–3.4), 1-year survival was 35% (95% CI 30–39%) and medianoverall survival was 6.9 months (95% CI 5.7–8.0). Tumor response rates were available for 363 patients,with a disease control rate of 58%. Of the 460 patients included in the safety analysis, 24% had one or moreerlotinib-related adverse event (AE). Rash was reported in 77% of patients, most commonly grade 1/2(63%). Treatment-related serious AE were reported in 7% of patients; most commonly diarrhea (2%). Dosemodifications were required in 18% of patients.

Conclusions: Outcomes for Australian patients confirmed the efficacy and tolerability of erlotinib for thetreatment of advanced NSCLC in routine clinical practice.

Key words: Australian, carcinoma, erlotinib, non-small cell lung, safety.

INTRODUCTION

The over-expression of the human epidermal growthfactor receptor type 1 (EGFR, also known as HER1) has

been shown to play a major role in the pathogenesisof a number of malignancies, including non-small-celllung carcinoma (NSCLC).1–4 EGFR has been associatedwith chemoresistance and poor prognosis in NSCLC.5,6

Erlotinib inhibits the intracellular phosphorylation ofHER1/EGFR tyrosine kinase with nanomolar potency.7,8

The efficacy of erlotinib in patients with NSCLC hasbeen demonstrated in a number of clinical trials. In apivotal large phase III study (BR.21, NCT 00036647),erlotinib demonstrated improvements in overall survival

Correspondence: Dr Michael Boyer MBBS FRACP, SydneyCancer Centre, Royal Prince Alfred Hospital, Camperdown,NSW 2050, Australia.Email: [email protected]

Accepted for publication 3 February 2012.

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Asia–Pacific Journal of Clinical Oncology 2012 doi:10.1111/j.1743-7563.2012.01540.x

© 2012 Blackwell Publishing Asia Pty Ltd

(OS) and progression free survival (PFS) in comparisonwith supportive care alone.9,10 The most notable adverseevents (AE) were diarrhea and rash. As well as its sur-vival benefits, erlotinib treatment delayed symptomdeterioration and improved quality of life.

Erlotinib has been approved in more than 80 coun-tries worldwide for the treatment of NSCLC patientswho have received at least one line of chemotherapy.The Tarceva lung cancer survival treatment (TRUST)study, a large international, open label, phase IV study,was designed to provide advanced stage IIIB/IV NSCLCpatients access to erlotinib if they had previously failed,or were considered unsuitable for, standard chemo-therapy or radiotherapy and were ineligible for othererlotinib trials. In each of the 531 centers across 51countries, recruitment continued until erlotinib waslicensed. Results from the global TRUST study and asub-analysis of the East/South-east Asian patient popu-lation have recently been published.11,12

Of the total of 6665 patients in the global study, 460patients were recruited in Australia. The aim of thissub-analysis was to determine whether there were anysignificant differences in safety and/or efficacy of erlo-tinib treatment in the Australian population.

METHODS

Inclusion and exclusion criteria

Patients were eligible for enrolment in the TRUST studyif they were aged 18 years or older, had histologicallyor cytologically confirmed unresectable, stage IIIB/IVNSCLC (staging according to the 6th edition of thetumor node metastasis staging system for NSCLC)13 andhad received at least one previous course of standardchemotherapy or radiotherapy, or were deemed unsuit-able for chemotherapy (and could not participate inanother trial with erlotinib). Eligible patients also hadan Eastern Cooperative Oncology Group performancestatus (ECOG PS) of 0–3; had an estimated life expect-ancy of 12 weeks or more; and adequate hematological,renal and hepatic function. At least 3 weeks must haveelapsed from the last dose of previous therapy and thepatients must have recovered from any toxic effects oftherapies prior to enrolment. Patients who had fullyrecovered from previous surgery were eligible. Womenof child-bearing potential must have had negative preg-nancy tests and needed to use adequate contraception.

Key exclusion criteria included any evidence ofunstable systemic disease (including active infection,grade 4 hypertension, unstable angina, congestive heart

failure and hepatic, renal or metabolic disease); priortreatment with anti-EGFR agents (including small mol-ecules or monoclonal antibodies); previous malignancieswithin the last 5 years (other than cervical carcinomaor skin cancer that had been successfully treated);untreated brain metastases (newly diagnosed or pre-existing) or spinal cord compression; and any significantophthalmologic abnormalities (including severe dryeye syndrome, keratoconjunctivitis sicca, Sjögren’s syn-drome, severe exposure keratitis or any other disorderlikely to increase the risk of corneal epithelial lesions).

The study was conducted in accordance with localguidelines and in line with the principles of the Decla-ration of Helsinki and Good Clinical Practice Guide-lines. All participating patients provided their writteninformed consent. Ethics approval was obtained fromthe participating institutions.

Study design and treatment

TRUST was a phase IV, open-label, single-arm study,where oral erlotinib, at a dose of 150 mg, was adminis-tered once daily to all eligible patients until diseaseprogression, unacceptable toxicity or death. Dose inter-ruption or reduction (in 50 mg/day decrements) waspermitted in the event that an erlotinib-related AEwas not controlled by best supportive care or was nottolerated for any reason, regardless of severity. Dosere-escalation was permitted if the reason for the reduc-tion was erlotinib-related rash (�grade 2). Assignmentof causality of AE was at the discretion of the treatingphysician.

The primary objective was to provide access toerlotinib (prior to its approval) for patients with stageIIIB/IV NSCLC who had failed or were unsuitable forchemotherapy or radiotherapy. The secondary objec-tives were to assess safety, best response, PFS and OS.The incidence and severity of erlotinib-related rash wasalso a secondary endpoint for this study.

Clinical assessments

Outcomes included best response as per investigatorassessment (complete response [CR], partial response[PR] or stable disease [SD]), PFS, OS and safety. Clinicaland laboratory assessments were conducted at base-line, then every 4 weeks throughout the study. Tumorresponse was assessed at least every 2 months by com-puterized tomography, magnetic resonance imagingor X-ray, using response evaluation criteria in solidtumors (RECIST);14 radiological assessments were notcentrally reviewed. For tumors classed as responding, a

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© 2012 Blackwell Publishing Asia Pty Ltd Asia–Pac J Clin Oncol 2012

confirmatory evaluation was carried out at least 4 weeksafter the initial determination of response.

For safety and tolerability evaluations, AE and seriousAE (SAE) of any cause were assessed and graded usingthe National Cancer Institute common toxicity criteria(NCI-CTC) version 3.0. Treatment-related AE werereported if they were not included on a list of pre-specified AE defined in the study protocol (pruritus, dryskin, diarrhea, nausea, vomiting, stomatitis, abdominalpain, fatigue, dyspnea, cough, anorexia, infection, con-junctivitis and keratoconjunctivitis sicca). The incidenceand severity of erlotinib-related rash were recorded as asecondary end-point. Any treatment-related SAE wererecorded. Erlotinib-related AE or SAE leading to with-drawal, dose reduction or modification were recorded.

Statistical analysis

The overall response rate (ORR) was defined as the sumof CR and PR. Patients were assigned to the SD categoryif they had a response assessment of CR, PR or SD at �1visit, but were not confirmed as CR or PR (SD criteriato be maintained for 28 days). The disease control rate(DCR) was defined as the sum of CR, PR and SD. Theproportion of patients in each response category ofthe RECIST criteria (CR, PR, SD and PD), the ORR andDCR were calculated together with the two-sided 95%confidence intervals based on Fisher’s exact method. PFSwas determined from the date of erlotinib initiation untilthe date of first documented progression according toRECIST objective tumor assessment or until the date ofdeath for any reason in the absence of disease progres-sion. OS was determined from the date of the start oftreatment until the date of death (irrespective of cause).Median time-to-event for PFS and OS together withtheir respective two-sided 95% confidence intervalswere calculated using the Kaplan–Meier method. Differ-ences in OS and PFS according to clinical or diseasecharacteristics were analyzed using the log–rank test.

RESULTS

Patients

A total of 6665 patients were enrolled in the TRUSTstudy between November 2004 and June 2007, withstudy database lock on 17 April 2009.12 We report datafrom the 460 patients recruited at 19 sites in Australia,who had received at least one dose of erlotinib.

The baseline characteristics for the Australian popu-lation are summarized in Table 1. Most patients wereCaucasians (88%), male (53%), ECOG PS 0–1 (72%)

and former or current smokers (70%). In all 67% ofpatients had adenocarcinoma/bronchoalveolar carci-noma and 85% had stage IV disease. Erlotinib wasgiven as first-line (16%), second-line (49%) or third-line(35%) treatment. Baseline characteristics for patientswho received treatment in the second-line setting aresimilar to the overall Australian patient population(data not shown).

Response and survival

Response data were available for 363 patients, includingseven patients (2%) who were not evaluable as their

Table 1 Characteristics of the Australian trust population(N = 460)

Characteristics

Age, years (min–max) 63.1 (19.6–90.9)Sex, n (%)

Male 245 (53)Female 215 (47)

Ethnicity, n (%)White 403 (88)Asian 45 (10)Black –Other 12 (2)

Performance status, ECOG PS, n (%)0 90 (20)1 237 (52)2 92 (20)3 40 (9)No data 1 (<1)

Disease stage, n (%)IV 393 (85)IIIB 67 (15)Other –No data –

Histology, n (%)Adenocarcinoma/BAC 310 (67)Squamous cell 53 (12)Large cell/other 97 (21)No data –

Prior lines of chemotherapy, n (%)None 72 (16)One 226 (49)Two 160 (35)Other 2 (<1)

Smoking status, n (%)Non-smoker† 136 (30)Former/current smoker 324 (70)No data –

†Non-smoker is defined as having less than 100 lifetime cigarettes.BAC, bronchoalveolar carcinoma.

Erlotinib in an Australian population 3

© 2012 Blackwell Publishing Asia Pty LtdAsia–Pac J Clin Oncol 2012

response data were not collected at the first evaluation,and they were not evaluable for response at the secondevaluation (Table 2). The remaining 97 patients did nothave best response data reported and therefore wereexcluded from the response analyses. The ORR witherlotinib was 7.7% and the DCR was 58.1%.

The outcome for Australian patients was analyzedaccording to erlotinib lines of treatment (Table 2). Thedata show that patients who received erlotinib earlierin their disease course reported a higher best response.The observed ORR for patients receiving erlotinib asfirst-line, second-line and third-line therapy was 13.7,9.8 and 2.4%, respectively; while the DCR was 68.6,60.1 and 52.0% respectively.

Survival data were available for all 460 patients.The median PFS was 2.7 months (95% CI: 2.3–3.4) andthe median OS was 6.9 months (95% CI: 5.7–8.0). The1-year survival for the overall Australian populationwas 35% (95% CI: 30–39%).

Survival was also examined in subgroups, defined onthe basis of their sex, histology, smoking status, diseasestage and erlotinib line of treatment; results are pre-sented in Table 3. The median PFS and OS for non-smokers versus former/current smokers were 5.3 versus2.1 months (hazard ratio = 1.54; 95% CI: 1.25–1.89,P < 0.001) and 11.2 months versus 5.3 months (hazardratio = 1.78, 95% CI: 4.1–6.0, P < 0.001), respectively.The observed median PFS for patients with grade 2–4erlotinib-related rash was 5.2 months versus 1.9 monthsin patients with grade 1 erlotinib-related rash (hazardratio = 2.01, 95% CL: 0.41–0.610, P < 0.001). OS forpatients with grade 2–4 erlotinib-related rash was13.4 months (95% CI: 10.2–15.5) versus 5.1 months(95% CI: 3.9–6.0) in patients with grade 1 erlotinib-related rash (hazard ratio = 2.12, 95% CL: 0.38–0.58,P < 0.001).

Survival outcomes for patients receiving treatmentin the second-line setting were comparable to the

overall Australian subpopulation; the median PFS was2.7 months (95% CI: 2.1–3.7) and median OS was7.7 months (95% CI: 6.0–9.4). Analysis of the second-line patients according to ECOG PS (Table 3) showed ahigher median OS for the ECOG PS 0–1 patients(9.8 months; 95% CI: 7.8–13.1) than for ECOG PS 2–3patients (3.6 months, 95% CI: 2.5–6.0); hazardratio = 1.97; 95% CI: 1.44–2.70, P < 0.001).

Safety and tolerability

Safety data were available for 460 patients in theAustralian subpopulation. A total of 24% of patientshad one or more erlotinib-related AE, excluding thepre-specified AE defined in the protocol (Table 4); 8%of these were grade 3–5. Erlotinib-related SAE werereported in 7% of patients. The most common singleSAE was diarrhea, occurring in 2% of patients (Table 5).There was no reported interstitial lung disease.

Dose reductions were required in 18% of patients.Reductions to 100 mg/day were required in 17% ofpatients and to less than 100 mg/day in <2% of patients.Treatment withdrawal due to erlotinib-related AE wasreported in 31 patients (7%); the most common AEleading to discontinuation were rash (2%) and diarrhea(2%) (Table 6).

The incidence and severity of erlotinib-related rashwas monitored in all patients for whom safety data wereavailable and was captured as a separate entity on thecase report forms. Erlotinib-related rash of any gradewas reported in 353 patients (77%). Most patients(n = 289; 63%) had mild or moderate severity, grade 1or 2 rash. Grade 3 or 4 rash were reported in 64 patients(14%).

DISCUSSION

Recently results from the international phase IV trial,TRUST, for the overall patient population (n = 6580)

Table 2 Best response for erlotinib in Australian patients according to line of treatment

Best response N (%)

All patients(n = 363)

First-line(n = 51)

Second-line(n = 183)

Third-line(n = 127)

Complete response (CR) 1 (<1) 0 1 (0.5) 0Partial response (PD) 27 (7.4) 7 (13.7) 17 (9.3) 3 (2.4)Overall response rate (CR + PR) 28 (7.7) 7 (13.7) 18 (9.8) 3 (2.4)Stable disease (SD) 183 (50.4) 28 (54.9) 92 (50.3) 63 (49.6)Disease control rate (CR + PR + SD) 211 (58.1) 35 (68.6) 110 (60.1) 66 (52.0)Progressive disease (PD) 145 (39.9) 15 (29.4) 72 (39.3) 56 (44.1)Not evaluable 7 (1.9) 1 (2.0) 1 (0.5) 5 (3.9)

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and the Asian subpopulation (n = 1242), were pub-lished, confirming the safety and efficacy of erlotinib ina large heterogeneous cohort of patients with advancedNSCLC.11,12 This sub-analysis of the Australian patientpopulation has yielded results similar to the TRUSTglobal population and the phase III BR.21 studyresults.10

The median PFS of 2.7 months for the Australianpopulation was lower than the 3.25 months for theoverall global TRUST population12 and 5.78 months forthe East/South-east Asian population;11 the OS was 6.9,7.9 and 14.7 months, respectively. Both the ORR andthe DCR were lower for the Australian population (7.7and 58.1%, respectively) compared with the overallstudy population (13 and 69%, respectively) and theEast/South-east Asian population (27 and 78%, respec-tively).11,12 Survival outcomes for the Australian sub-population, with a majority of Caucasians, are moreconsistent with the outcomes for the non-East/South-east Asian patient population with PFS and OS of 2.92and 6.8 months, respectively.11 It is likely that both

response and survival data may be driven by the fre-quency of EGFR mutation in these patient populations;however, this was not investigated in this study.

The percentage of Australian patients receiving erlo-tinib as first-line treatment was slightly higher (16%)than the Asian (9%) and the global patient populations(13%);11,12 and response outcomes were consistent withthe overall study population; the ORR was 13.7 versus13% and the DCR was 68.6 versus 69%.12 Patients whoreceived erlotinib as first-line therapy had better survivaloutcomes than those receiving the treatment in thesecond-line and third-line settings. In part, this bettersurvival may be explained by these patients beingtreated earlier in the trajectory of their disease. In thesecond-line setting, erlotinib appears to have similar OSto chemotherapy in good performance status patients.15

No new safety signals were observed in the Australianpopulation; the majority of AE reported were of mildto moderate severity. Furthermore, only a small minorityof patients withdrew from treatment as a result oferlotinib-related AE. The safety and tolerability of

Table 3 Survival data in selected subgroups of patients

n Median PFS (months) 95% CI Median OS (months) 95% CI

All 460 2.7 2.3–3.4 6.9 5.7–8.0Male 245 2.3 1.8–2.8 5.5 4.4–7.1Female 215 3.4 2.5–4.6 8.8 6.7–10.8Smoking status

Non- smoker† 136 5.3 3.9–6.9 11.2 8.7–14.3Former/current smoker 324 2.1 1.8–2.8 5.3 4.1–6.0

HistologyAdenocarcinoma/BAC 310 3.0 2.5–3.9 7.8 6.2–9.0Squamous 53 2.3 1.8–3.7 5.1 3.4–6.2Large cell/other 97 1.9 1.8–2.8 5.8 3.4–8.7

StageIIIb 67 2.7 1.8–4.4 6.1 5.3–8.0IV 393 2.7 2.1–3.4 7.2 5.5–8.7

ECOG PS0–1 327 3.4 2.5–4.1 8.8 7.6–10.62–3 132 1.9 1.8–2.5 3.5 2.8–4.6

Erlotinib-related rashNone/grade 1 235 1.9 1.8–2.5 5.1 3.9–6.0Grade 2–4 191 5.2 3.9–6.2 13.4 10.2–15.5

Erlotinib line useFirst-line 72 3.4 2.5–5.3 10.0 4.8–15.4Second-line 226 2.7 2.1–3.7 7.7 6.0–9.4PS 0–1 165 2.8 2.1–4.4 9.8 7.8–13.1PS 2–3 61 1.9 1.8–3.4 3.6 2.5–6.0Third-line 160 2.5 1.8–3.4 5.3 4.1–6.7

†Non-smoker is defined as having less than 100 lifetime cigarettes. BAC, Bronchoalveolar carcinoma; ECOG, Eastern Cooperative Oncology Group;OS, overall survival; PFS, progression-free survival; PS, performance status.



erlotinib observed in the Australian population is onsis-tent with the BR.21 study10 and the global TRUST data,and they support the safety of erlotinib in patients withadvanced NSCLC in the real-life clinical setting.

The presentation of rash in patients who receiveEGFR inhibitors has been shown to be associated withimproved survival outcomes in patients.16 The analysis

of the survival data according to the severity of rash forthe Australian and the global TRUST populations hasshown that the PFS and OS was significantly higher inpatients who developed grade 2 or higher rash.12 There-fore, it is important for patients who develop a rash onerlotinib-based therapy to continue the erlotinib whilethe rash is being managed.17,18 It is unclear whether thedevelopment of rash is associated directly with thisimproved survival, or simply that patients who receivemore treatment cycles are at risk of developing a rash.Knowledge of the time course of the rash could helpclarify this. Data linking the early development of rashto response and survival exist for EGFR monoclonalantibodies;19 however, since these data were not col-lected in the TRUST study, a similar analysis was notperformed.

The TRUST study was performed prior to the wide-spread availability of EGFR mutation testing. With themore recent demonstration of the benefits of first-lineuse of EGFR tyrosine kinase inhibitors in patients withactivating EGFR mutations,20,21 first-line use of thesedrugs is likely to be restricted to this patient population.

Although there are limitations to the conclusionsthat can be drawn from this sub-analysis of a single armstudy, the overall TRUST results, together with thosefrom BR.21 and the recently reported TITAN study10,22

suggest that erlotinib can be of potential benefit in awide range of patients with previously treated NCSLC.

ACKNOWLEDGMENTS

The authors would like to thank all study investigators,coordinators and patients who participated in the study.We would also like to thank Daniel Gregory andthe Roche study team. Medical writing assistance was

Table 4 Treatment-related adverse events (AE)† (N = 460)

EventAny grade‡ Grade 3–5

n (%) n (%)

Patients with at least oneerlotinib-related AE

112 (24) 37 (8)

Blood and lymphatic systemdisorders

2 (<1) 0

Eye disorders 21 (5) 0Gastrointestinal disorders 35 (8) 11 (2)General disorders and

administration site conditions9 (2) 2 (<1)

Hepatobiliary disorders 1 (<1) 1 (<1)Infections and infestations 14 (3) 3 (<1)Metabolism and nutrition disorders 7 (2) 2 (<1)Musculoskeletal and connective

tissue disorders2 (<1) 0

Nervous system disorders 15 (3) 2 (<1)Respiratory, thoracic and

mediastinal disorders16 (3) 4 (<1)

Skin and subcutaneous tissuedisorders

36 (8) 12 (3)

†Other than the most frequently occurring pre-specified events. ‡Asdefined by National Cancer Institute common toxicity criteria vers. 3.0.

Table 5 Reported erlotinib-related serious adverse events(SAE) (n = 460)

EventAny grade† Grade 3–5

n (%) n (%)

Patients with at least oneerlotinib-related SAE

30 (7) 21 (5)

Gastrointestinal disorders 13 (3) 9 (2)General disorders and

administration site conditions5 (1) 1 (<1)

Infections and infestations 3 (<1) 2 (<1)Metabolism and nutrition

disorders5 (1) 2 (<1)

Respiratory, thoracic andmediastinal disorders

4 (<1) 4 (<1)

Skin and subcutaneous tissuedisorders

1 (<1) 1 (<1)

†As defined by National Cancer Institute common toxicity criteria vers.3.0.

Table 6 Erlotinib-related adverse events (AE) leading to treat-ment withdrawal in �1% of patients (N = 460)

EventsAny grade† Grades 3–5

n (%) n (%)

Patients with any AE leadingto withdrawal

31 (7) 18 (4)

Skin and subcutaneoustissue disorders

11 (2) 8 (2)

Rash 11 (2) 8 (2)Gastrointestinal disorders 10 (2) 5 (1)Diarrhea 7 (2) 4 (<1)†As defined by National Cancer Institute common toxicity criteria vers.3.0.

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provided by Dr Joseline Ojaimi from Roche Products,Australia. The TRUST study was sponsored by F.Hoffmann-La Roche.

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Efficacy of erlotinib in patients with advanced Non-small-cell Lung Cancer (NSCLC): Analysis of the Australian subpopulation of the TRUST study