Second and third line treatment in non-small cell lung cancer

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Critical Reviews in Oncology/Hematology 71 (2009) 117–126

Second and third line treatment in non-small cell lung cancer

Adolfo Favaretto a,∗, Giulia Pasello a, Cristina Magro a, Clorinda Schettino b, Cesare Gridelli b

a U.O. Oncologia Medica 2, Istituto Oncologico Veneto IOV IRCCS, Via Gattamelata 64, 35128 Padova, Italyb U.O. Oncologia Medica, Azienda Ospedaliera “S.G. Moscati”, Avellino, Italy

Accepted 29 January 2009

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172. Single agent chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

2.1. Docetaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182.2. Pemetrexed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182.3. Other single agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

3. Combination chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194. Targeted therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

4.1. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1204.2. Monoclonal antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214.3. Multitargeted tyrosine kinase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

5. New chemotherapeutic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide, and the advances in second and third linetreatment have led to prognostic improvements in the latest years.

Besides the two cytotoxic agents, docetaxel and pemetrexed, approved in NSCLC second line treatment, a new class of drugs againstspecific molecular targets seems to be an alternative to conventional treatment.

Many trials are ongoing to assess the activity of new drugs, alone or in association, and new combinations of third-generation chemother-apeutic agents.© 2009 Elsevier Ireland Ltd. All rights reserved.

Keywords: NSCLC; Second line; Docetaxel; Pemetrexed; Targeted therapies

1. Introduction

Non-small cell lung cancer (NSCLC) accounts for approx-imately 80% of all lung cancer cases; most patients (40–50%)present locally advanced or metastatic disease and their 5-year survival amounts to 5% [1].

∗ Corresponding author. Tel.: +39 0498215620; fax: +39 0498215963.E-mail address: [email protected] (A. Favaretto).

First line chemotherapy in advanced NSCLC usually con-sists of a combination of a platinum compound (cisplatin orcarboplatin) with a third-generation agent (paclitaxel, doc-etaxel, gemcitabine or vinorelbine). About 30% of patientstreated in first line with one of these associations achieve aresponse lasting 4–5 months.

At the end of the 1990s, the second line treatmentof advanced NSCLC was disappointing both in terms ofresponse rate and survival.

1040-8428/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.critrevonc.2009.01.009


118 A. Favaretto et al. / Critical Reviews in Oncology/Hematology 71 (2009) 117–126

Docetaxel (Taxotere®, Sanofi-Aventis) was the first drugshowing some efficacy. Two randomised trials were per-formed demonstrating the advantage of second line docetaxeltreatment both in terms of survival and quality of life (QoL),compared to best supportive care (BSC) [2] and to a singleagent like ifosfamide (Ifex®, Bristol-Myers Squibb Co.) orvinorelbine (Navelbine®, Pierre Fabre Pharmaceuticals) [3].

Recently pemetrexed (Alimta®, Eli Lilly and Co.), a multi-target antifolate agent, showed similar clinical response andbetter safety profile compared to docetaxel in second linetreatment of NSCLC patients [4]. Both agents provided amedian survival of about 8 months, 1-year survival of 30%and a response rate of 10%.

A recent phase III trial demonstrated a survival improve-ment in patients treated in second line with the tyrosine kinaseinhibitor (TKI) erlotinib (Tarceva®, Genentech Inc.) com-pared to best supportive care, with a response rate of 9%[5].

A phase III study comparing gefitinib (Iressa®, AstraZeneca Pharmaceuticals) with docetaxel in patients withlocally advanced or metastatic NSCLC pretreated withplatinum-based chemotherapy shows no difference in termsof progression free survival and median survival [6]. Table 1shows some meaningful phase III trials performed in the latestyears.

2. Single agent chemotherapy

2.1. Docetaxel

A phase III trial (TAX 317) by Shepherd has compareddocetaxel 100 mg/m2 every 3 weeks to BSC; only 49/104patients included in the treatment arm received that dosebecause of 5 toxic deaths (neutropenia and/or pneumonia)in the first 49 patients. The protocol was amended, so in thesecond part of the trial docetaxel was reduced to the dose of75 mg/m2.

Patients treated with chemotherapy (n = 55) demonstrateda better median survival and 1-year survival than the controlgroup [7.5 months versus 4.6 months (p = 0.047) and 37%versus 11% (p = 0.003) respectively]; in the group treatedwith docetaxel 75 mg/m2 there were no toxic death and onlyone febrile neutropenia. Docetaxel-based treatment was bet-

ter than BSC even in terms of pain control and quality of lifeimprovement [2].

A further phase III trial (TAX 320) performed by Fossellaet al. compared docetaxel 75 and 100 mg/m2 every 3 weeks tomonochemotherapy with ifosfamide 2 g/m2 for 3 days every3 weeks or vinorelbine 30 mg/m2 every week; although therewas not a meaningful difference in survival for the two treat-ment groups (5.5 and 5.7 months), 1-year survival was 32%and 21% in the patients treated with docetaxel 75 mg/m2 and100 mg/m2 respectively, and 19% in the patients treated withifosfamide or vinorelbine [3]. Docetaxel 100 mg/m2 every 3weeks was associated to a worse safety profile, in particu-lar for grade 3–4 neutropenia, febrile neutropenia, grade 3–4fatigue and alopecia.

Many randomised clinical trials [7–10] and two meta-analyses [11,12] showed less myelotoxicity with weeklydocetaxel when compared to docetaxel administered every3 weeks, with no significant differences in survival.

Particularly, the meta-analysis by Di Maio et al. [11]showed a similar rate of anaemia and thrombocytopeniaamong the two treatment schedules, with a lower rate of grade3–4 neutropenia and febrile neutropenia in the weekly arm.Bria et al. [12] found an advantage in terms of grade 3–4 neu-tropenia among the patients treated with weekly docetaxel.

2.2. Pemetrexed

A phase III trial by Hanna et al., designed to demonstratethe non-inferiority for survival time, compared the effective-ness of pemetrexed 500 mg/m2 versus docetaxel 75 mg/m2

every 21 days, in the second line treatment of advancedNSCLC [4]. The patients treated with pemetrexed were pre-medicated with vitamin B12 (1000 �g every 9 weeks) andfolate (350–1000 mg/day) to reduce toxicity. Superimpos-able response rate (9%) and median survival (8 months) werereported (p = not significant) in the two treatment groups,with less grade 3–4 neutropenia (5% versus 40%, p = 0.001),febrile neutropenia (2% versus 13%, p = 0.001) and G-CSFadministration (3% versus 19%, p = 0.001) in patients treatedwith pemetrexed.

A retrospective analysis evaluated the benefit related to theabsolute risk of death and to the risk of toxic death showingsimilar efficacy (a median survival time of 8.3 months withpemetrexed versus 7.9 months with docetaxel), but an event-

Table 1Main phase III randomised trials in pretreated NSCLC patients.

Second line regimen Number of patients RR (%) MST (months) 1-Year survival (%) TTP (months) Author and Ref.

Docetaxel (75) vs. placebo 55 vs. 100 6 vs. NV 7.5 vs. 4.6 37 vs. 11 2.5 vs. 1.5 Shepherd et al. [2]Docetaxel vs. ifosfamide/vinorelbine 125 vs. 89/34 7 vs. <1 5.7 vs. 5.5 32 vs. 19 2 vs. 2 Fossella et al. [3]Docetaxel vs. pemetrexed 288 vs. 283 9 vs. 9 7.9 vs. 8.3 30 vs. 30 3.5 vs. 3.4 Hanna et al. [4]Erlotinib vs. placebo 488 vs. 243 9 vs. <1 6.7 vs. 4.7 31 vs. 22 2.2 vs. 1.8 Shepherd et al. [5]Gefitinib vs. placebo 1129 vs. 563 8 vs. 1 5.6 vs. 5.1 27 vs. 21 3 vs. 2.6 Thatcher et al. [41]Gefitinib vs. docetaxel 733 vs. 733 NR 7.6 vs. 8.0 32 vs. 34 2.2 vs. 2.7 Kim et al. [6]Vinflunine vs. docetaxel 272 vs. 275 4.4 vs. 5.5 6.7 vs. 7.2 NR 2.3 vs. 2.3 Douillard et al. [63]Oral topotecan vs. docetaxel iv 414 vs. 415 5 vs. 5 7 vs. 7.8 25 vs. 29 2.8 vs. 3 Ramlau et al. [64]

RR: response rate; MST: median survival time; TTP: time to progression; NV: not valuable; NR: not reported; NSCLC: non-small cell ling cancer.

https://www.researchgate.net/publication/246662543_A_prospective_randomized_trial_of_Taxotere_versus_best_supportive_care_BSC_in_patients_with_non-small_cell_lung_cancer_NSCLC_previously_treated_with_platinum-based_chemotherapy_Survival_update?el=1_x_8&enrichId=rgreq-31df2d1f-4639-4242-baa1-bfe30329a9d6&enrichSource=Y292ZXJQYWdlOzI0MTQzODk2O0FTOjI2NDkzODM3MTQxNjA2NEAxNDQwMTc3NjM4NTY1




A. Favaretto et al. / Critical Reviews in Oncology/Hematology 71 (2009) 117–126 119

free survival of 5.8 and 1.2 months in the patients treatedwith pemetrexed and docetaxel respectively. The 6-monthsurvival was 49% and 22%, and the 1-year survival was24% and 12% for pemetrexed and docetaxel treated patientsrespectively [13]. Another retrospective analysis performedon Lung Cancer Symptom Scale data of this phase III trial,showed that non-progressive patients had symptom improve-ment and median time to worsening of symptoms (TWS)of 2.3 months for fatigue and 7.0 months for cough, withcorrelation between TWS, PFS and OS for both drugs [14].

A second phase III trial was performed to determineif increasing pemetrexed dosage improved efficacy with-out worsening toxicity [15]. Locally advanced or metastaticNSCLC patients previously treated with platinum-based ther-apy were randomised to receive pemetrexed 500 mg/m2 or900 mg/m2 every 3 weeks. No significant differences in termsof efficacy were observed in both arms. Median survival timewas 6.7 and 6.9 months, progression free survival was 2.6and 2.8 months, and response rate was 7.1% and 4.3% in500 mg/m2 and 900 mg/m2 arms respectively. Patients treatedwith the highest dose had more grade 3–4 toxicities and ahigher hospitalisation rate.

Elderly patients (>70-year old) may benefit by second linetherapy as younger patients, without unacceptable toxicity[16]. Pemetrexed treatment in older patients was associ-ated to a better overall and progression free survival, andto a lower incidence of febrile neutropenia compared todocetaxel, although the difference was not statistically sig-nificant. Clinical efficacy and toxicity were similar in thetwo groups, although elderly compared to younger (<70-yearold) patients treated with docetaxel, experienced more febrileneutropenia.

Because of its good toxicity profile, even PS 3 patients forwhich the ASCO guidelines contraindicate any chemother-apy could benefit from pemetrexed.

The first or second line treatment with pemetrexed500 mg/m2 every 3 weeks in NSCLC patients with PS 2–3showed promising results. Among the eight patients with PS3, five stable diseases, one minimal response and two dis-ease progressions were observed; among the 12 patients withPS 2, 1 partial response, 2 minimal responses, 3 stable dis-eases, 3 disease progressions were observed [17]. The studyby Hanna et al. showed that PS 0–1 was strongly correlatedwith increased survival, without any difference between thetwo arms [4].

When evaluated as second or third line treatment, peme-trexed showed a clinical benefit (CR + PR + SD) in 40% of160 patients, progression free survival of 3 months, and amedian survival time of 12 months with mild myelotoxicity(4.4% of grade 3) [18].

Another phase II randomised clinical trial evaluatingpemetrexed 500 mg/m2 and 1000 mg/m2, showed higherresponse rate and survival time in the standard dose treatmentarm (median survival time 15.7 and 12.6 months, 1-year sur-vival of 59.2% and 53.7%, and response rate of 18.5% and14.8%) [19].

Histology is emerging as an important issue in thetreatment selection both in first line and in the secondline chemotherapy. A retrospective analysis of the dataof the pemetrexed versus docetaxel phase III study indi-cated that the effect of treatment varied with histology:the squamous cell subgroup patients treated with docetaxelhad statistically better survival than patients treated withpemetrexed (p = 0.018). Conversely in the non-squamoussubgroup pemetrexed was statistically superior to docetaxel(p = 0.048) [20].

2.3. Other single agents

As a single agent gemcitabine (Gemzar®, Eli Lilly andCo.) shows promising activity and acceptable toxicity profilein the second line treatment of advanced NSCLC; among the83 patients included in a phase II trial, 16 obtained a partialresponse (RR of 19%), and 11 of them were responsive to thefirst line treatment. The median duration of response was 29weeks [21].

On the basis of the phase III TAX 320 trial results vinorel-bine in monotherapy is not currently used in NSCLC secondline treatment [3]. The activity and toxicity of oral vinorel-bine in the second line treatment was assessed in a phaseII study [22]. At the dosage of 60 mg/m2 (corresponding to25 mg/m2 intravenously) the drug is safe but inactive. Thedose of 80 mg/m2 (30 mg/m2 intravenously) is under inves-tigation.

Paclitaxel is an active and well-tolerated agent used in thetreatment of relapsed NSCLC; the response rate was 0–38%when administered every 21 days, and 8–38% in the weeklyadministration. Some patients seem to benefit more than otherfrom a second line treatment with paclitaxel (e.g. patientswith stable disease after a first line platinum-based therapy,or a longer time-to-relapse) [23].

3. Combination chemotherapy

Although many phase II trials showed that several combi-nation regimens induced similar survival and higher toxicitythan single agent chemotherapy, some combinations achievedencouraging results, as shown in Table 2.

Irinotecan, a topoisomerase inhibitor, has been studiedin association to several agents, as gemcitabine [24,25]or cisplatin [26,27] achieving promising response rate andmedian survival. Docetaxel with or without irinotecan pro-vides a similar benefit in terms of overall survival andresponse rate [28–31]. The associations irinotecan–docetaxeland irinotecan–gemcitabine, with or without the COX-2inhibitor celecoxib, were assessed in a phase II randomisedtrial with four treatment arms: irinotecan 60 mg/m2 plus doc-etaxel 35 mg/m2 or irinotecan 100 mg/m2 plus gemcitabine1000 mg/m2, both with or without celecoxib 400 mg bid.Among patients treated with celecoxib, median survival (6.3months) and 1-year survival (24%) were worse than in the



Table 2Main phase II randomised trials.

Second line regimen Number ofpatients

RR (%) MST (months) 1-Year survival (%) TTP (months) Author and Ref.

Irinotecan + gemcitabine vs.irinotecan

79 vs. 75 18.4 vs. 4.2 9 vs. 7 24.5 vs. 29 7.5 vs. 5 Georgoulias et al. [24]

Irinotecan + gemcitabine 40 14 7 20 4 Kosmas et al. [25]Irinotecan + DDP vs. DDP 74 vs. 73 23 vs. 7 8 vs. 9 34 vs. 32 NV Georgoulias et al. [26]Irinotecan + DDP 48 26 11 46 3 Takiguchi et al. [27]Irinotecan + docetaxel 40 10 7.4 24 2.8 Grossi et al. [28]Irinotecan + docetaxel 46 11 7.5 37 2.6 Molina et al. [31]Irinotecan + temozolomide 46 9 9.8 34 1.8 Choong et al. [66]Carboplatin + pemetrexed 26 38 12.6 NR 6 Charpidou et al. [67]Gemcitabine + paclitaxel 40 32 9.6 37.5 4.4 Mori et al. [37]Gemcitabine + docetaxel 52 28 8.2 25 4.4 Cobo et al. [33]Vinorelbine + docetaxel 50 10 6.5 18 2.7 Vazquez et al. [34]Mitomycin-C + docetaxel 38 8 10.4 35 3.6 Feliu et al. [68]Mitomycin-C + vinorelbine 42 12 8.5 NV 4 Babiak et al. [69]

RR: response rate; MST: median survival time; TTP: time to progression; NV: not valuable, NR: not reported.

chemotherapy alone arm (8.9 months and 36% respectively)[32].

Gemcitabine or vinorelbine combined to docetaxel[33,34], and gemcitabine combined to paclitaxel, wereassessed in many phase II trials [35–38].

Also for the 3-weekly combination of gemcitabine1000 mg/m2 and vinorelbine 25 mg/m2 (days 1, 8), a poorresult was seen in platinum–taxane pretreated patients(response rate of 22%, median survival of 5.3 months, withG3–4 neutropenia in 68% of the patients, and 12% febrileneutropenia) [39].

Gemcitabine combined with oxaliplatin (Eloxatin®,Sanofi-Aventis), every 15 days in the second or third lineof NSCLC treatment, provided a partial response of 10%,a stable disease of 40% and a symptomatic improvement in25% of the cases, with an acceptable toxicity profile [40].

4. Targeted therapies

4.1. Epidermal growth factor receptor (EGFR) tyrosinekinase inhibitors

The development of biologic agents active against specificmolecular targets, represents an innovation of the antitu-moral research. EGFR, expressed in most of the NSCLC,belongs to the ErbB cellular receptor family that plays a cen-tral role in cell growth, differentiation and survival pathways.The tyrosine kinase intracytoplasmatic subunit of EGFRis the molecular target of a new class of agents (tyrosinekinase inhibitors), recently introduced in NSCLC treatment.Most randomised trials are focused on gefitinib (Iressa®) anderlotinib (Tarceva®).

Gefitinib, approved in 2003 by FDA for the third linetreatment of NSCLC, and since 2005 limited to the patientsincluded in clinical trials, was then retired because a phaseIII randomised trial demonstrated no survival advantagecompared to placebo, when administered at the dose of

250 mg/day in pretreated patients. Although a response rate of8% and 1% of the patients treated with gefitinib and placebo,median survival was similar in the two groups (5.6 monthsversus 5.1 months); survival time favouring gefitinib was verydifferent in the two treatment groups for non-smoker (8.9months versus 6.1 months) and Asian patients (9.5 monthsversus 5.5 months) [41].

The NCI of Canada Clinical Trials Group, led a phaseIII trial (BR.21) in pretreated patients comparing erlotinib toBSC [5]. Median survival was different in the two groups, 6.7months versus 4.7 months (HR = 0.70, 95% CI: 0.58–0.85,p < 0.001); erlotinib improved 1-year survival and induceda response in the 9% of cases. Overall treatment was welltolerated. After the publication of the BR.21 trial, FDA in2004 and EMEA in 2005 approved erlotinib for the treat-ment of patients in second or third line setting. Althoughresponse to erlotinib was more frequent in women with ade-nocarcinoma, never-smokers or East-Asians, an exploratoryanalysis of BR.21 study showed that the survival benefit witherlotinib therapy was similar across multiple subgroups, withsmoking status as the most powerful predictor of a survivaleffect. Similar results were seen in the ISEL trial with signifi-cant benefit for gefitinib treated never-smoker and East-Asianethnicity patients. But differently by ISEL, in the BR.21 studyalso male and smoker patients with squamous cell histologycould benefit by erlotinib treatment.

Gefitinib and erlotinib are thought to have similar mech-anism of action, but they had different outcome in these twolarge phase III studies in pretreated patients, even if with-out striking differences: the response rate in the ISEL trial(about 8%) was similar to BR.21 and the survival bene-fit was statistically near-significant. How can this differentresult be explained? Both clinical, pathological and molec-ular factors can be involved. One explanation could be thatgefitinib was underdosed, even though previous data sug-gested that higher dose of gefitinib are unlikely to be moreeffective. Another possibility was that ISEL study had adifferent population with a highly refractory disease, not



present in the BR.21 study, even though the inclusion cri-teria in the latter trial required patients to be unfit for furtherchemotherapy.

Translational research has identified at least two poten-tial biomarkers, EGFR mutations and EGFR amplifications.Mutations of exons 19 and 21 have been associated withstriking responses to TKI, and these mutations are morefrequent in never smokers, women, patients of Asian ori-gin or with adenocarcinoma or bronchiolo-alveolar histology.Patients carrying those mutations had no survival advantagebut higher objective responses, although not statistically sig-nificant. EGFR immunohistochemical expression was notsignificantly related to response in former phase II trials,while in the BR.21 study EGFR expression was associatedwith response to erlotinib (p = 0.03) but not with survival [42].EGFR expression is commonly associated with amplificationor high polysomy of the EGFR gene. In the above men-tioned BR.21 trial the number of EGFR gene copy numberassessed by FISH seemed to be the most important pre-dictive factor of response and survival but the INTERESTtrial discussed below raised some doubts. A phase II trialevaluated the efficacy and toxicity of erlotinib in patientsaffected by advanced NSCLC pretreated with 2 or 3 cyclesof chemotherapy and in progression after gefitinib. Diseasecontrol and response rate were better in patients with previ-ous stable disease (75% versus 18% and 50% versus 0%),and non-mutated EGFR [43]. Similarly gefitinib, adminis-tered after erlotinib, showed a clinical benefit in the patientswith partial response or stable disease, conversely to whathappened in patients with immediate progression disease[44].

The primary objective of the “INTEREST” phase IIItrial was to show the non-inferiority of gefitinib 250 mg/daycompared to docetaxel 75 mg/m2 every 3 weeks in NSCLCprogressed or relapsed after one or two lines of chemotherapy,at least one of which platinum-based [6]. This trial performedfrom 2004 to 2006 enrolled 1466 patients. Between the twogroups neither survival (1-year survival 32% versus 34%,median survival 7.6 months versus 8 months, HR = 1.02) nortime to progression (2.2 months versus 2.7 months, p = 0.47)showed any difference but less toxicity and better qualityof life favoured gefitinib arm. Surprisingly no advantage wasobserved in terms of survival for gefitinib as compared to doc-etaxel in EGFR FISH positive patients rising doubts about itspredictive role: is it a prognostic and not a predictive fac-tor? But it has to be noted that the number of patients in thissubgroup was relatively small (n = 174).

Skin rash is the most common adverse event associatedwith erlotinib treatment and a major cause of treatment inter-ruption. So an early treatment of this side effect is important,but at present no guidelines for its management are available.A panel of Italian oncologists and dermatologists has sug-gested an optional topical treatment for grade 1 skin rash,while it has recommended the addition of a tetracycline andsteroid systemic treatment if necessary for grade 2. Recom-mendations for grade 3 and grade 4 skin rash were systemic

tetracycline plus steroids and intensive care in a burn-woundunit respectively [45].

4.2. Monoclonal antibodies

The use of monoclonal antibodies like cetuximab(Erbitux®, Bristol-Myers Squibb Co.), acting against theextracellular subunit of EGFR, represents an alternative wayto target this pathway. Cetuximab shows a promising antitu-moral activity in the first or second line treatment of NSCLC.

A new phase II trial studied a second line treatmentwith docetaxel (75 mg/m2 every 3 weeks) and cetux-imab (400 mg/m2 as charging dose, followed by weeklyadministration of 250 mg/m2) in 47 EGFR-positive andchemo-resistant patients. The preliminary results showed agood safety profile and 28% partial responses [46]. Cetux-imab was also evaluated as a single agent in the treatmentof relapsed NSCLC, in 60 EGFR-positive patients, showingresponse rate of 5%, median survival time of 8.9 months andprogression free survival of 2.3 months, without any correla-tion between EGFR mutations and sensitivity to cetuximab[47].

Target therapies development led to many trials deal-ing with the association of agents targeting the molecularpathways involved in tumor progression. Bevacizumab(Avastin®, Genentech Inc.) is a monoclonal antibody target-ing VEGF (vascular endothelial growth factor), involved inangiogenesis. Phase II trials show promising results with theassociation of erlotinib and bevacizumab, possibly with theaddition of a cytotoxic agent [48,49].

In the treatment of relapsed NSCLC after at least oneline of chemotherapy, bevacizumab (15 mg/kg) plus erlotinib(150 mg/day) obtained a higher benefit than the two sin-gle agents (response rate of 20%, median survival time of12.6 months, and progression free survival of 6.2 months)[48]. Recently, 120 relapsed NSCLC patients after one pre-vious platinum-based regimen, were randomised to receivemonochemotherapy with docetaxel or pemetrexed (arm 1,n = 41), bevacizumab plus chemotherapy (arm 2, n = 40), orbevacizumab plus erlotinib (arm 3, n = 39). A better pro-gression free survival was achieved in the two bevacizumabarms (arm 2, PFS = 4.8 months; arm 3, PFS = 4.4 months;arm 1, PFS = 3 months) even though not statistically signif-icant. The adjusted HR for PFS in the group treated withbevacizumab plus erlotinib and bevacizumab plus chemother-apy compared to the arm 1, was 0.66 and 0.72 respectively.Patients treated with bevacizumab survived longer (OS arm2 = 12.6 months; arm 3 = 13.7 months) than patients receiv-ing chemotherapy alone (OS arm 1 = 8.6 months). Theseencouraging results were associated with a favourable safetyprofile [49].

A monoinstitutional retrospective analysis showed no dif-ference in overall survival, time to progression and responserate between pemetrexed with or without bevacizumab, so atrial to assess whether bevacizumab improves the efficacy ofpemetrexed was planned [50].



4.3. Multitargeted tyrosine kinase inhibitors

Sunitinib (Sutent®, Pfizer Inc.) is an oral tyrosine kinaseinhibitor acting against VEGFR, PDGFR, KIT, RET, FLT3,approved for the treatment of renal cancer and imatinib-resistant GIST. A recent phase II multicenter trial withsunitinib 37.5 mg/day administered continuously in pre-treated patients with stage III–IV NSCLC, has shown a partialresponse in 2% of the patients, and a stable disease longerthan 3 months in 17% of cases [51]. Fatigue, nausea, vom-iting, dyspnea and pleural effusion were the main toxicities;among adverse events there were hypoxic respiratory failure(G3), heart failure (G4) and toxic shock syndrome (G5).

A more recent trial by Socinski et al. assessed the clinicalactivity and tolerability of sunitinib 50 mg/day for 4 weeksfollowed by two of no treatment; in the cohort of 63 pretreatedpatients affected by stage IIIb–IV NSCLC a response rateof 11.1% and 28.6% of stable diseases were achieved. ThePFS and OS were respectively 12 and 23.4 weeks. Sunitinibshowed an acceptable safety profile and the main toxicities(mild or moderate asthenia, myalgia, nausea and vomiting)did not interfere with the treatment [52].

The North Central Cancer Treatment Group (NCCTG)undertook a phase II study to assess the activity of the multi-kinase inhibitor sorafenib (Nexavar®, Bayer HealthcarePharmaceuticals) as a single agent in previously untreatedNSCLC. Response rate of 12%, median survival of 8.8months and time to progression of 2.9 months were observed[53].

In 2006 Gatzemeier et al. presented a phase II trial in which52 patients with relapsed advanced NSCLC were treated withsorafenib 400 mg/bid, achieving no partial response but 59%of stable disease and 29% of tumor shrinkage. OS and PFSwere respectively 29.3 and 11.9 weeks, even if PFS was 23.7weeks in the patients with stable disease. Sorafenib showedhypertension and hand-foot syndrome as the only grade 3toxicities [54]. A phase II trial [55] and a phase III study(Table 3) evaluating erlotinib with or without sunitinib inplatinum resistant patients are ongoing.

Vandetanib (Zactima®, Astra Zeneca Pharmaceuticals)is an antitumoral agent targeting the VEGFR-dependentangiogenesis, and the cell growth and survival mediatedby EGFR and RET. The promising results obtained in thephase II led to phase III trials evaluating this agent ver-sus placebo in patients pretreated with EGFR inhibitors,versus erlotinib and in association with docetaxel or peme-trexed [56]. A phase II trial compared vandetanib 100or 300 mg/day plus docetaxel 75 mg/m2 every 3 weeks todocetaxel as a single agent in patients pretreated with aplatinum-based therapy. The overall survival was not differ-ent in the three groups, whereas the primary objective wasachieved in the patients treated with vandetanib 100 mg/dayplus docetaxel, whose PFS was 18.7 weeks; PFS was 17weeks in the arm treated with vandetanib 300 mg/day plusdocetaxel, and 12 weeks in the patients treated with doc-etaxel alone [57]. These promising results led to a phase

III trial comparing docetaxel to docetaxel plus vandetanib100 mg/day.

5. New chemotherapeutic agents

New chemotherapeutic drugs are needed to overcome theintrinsic or acquired resistance limiting the efficacy of thecommonest antitumoral agents.

Epothilones A and B (patupilones) and their syntheticanalogs (ixabepilone, epothilone B, ZK-EPO, BMS-310705,and KOS-1584), represent a new class of tubulin stabilizingagents, functionally and structurally different from taxanes,which induce the arrest of cell cycle and subsequently cellapoptosis.

Phase II trials showed that ixabepilone, the first semisyn-thetic analogue of epothilone B, is slightly susceptive to thecommonest resistance mechanisms and has good antitumoralactivity. In one of these trials, performed in second line set-ting, ixabepilone was administered at 32 mg/m2 in 3 h every3 weeks or at 6 mg/m2 days 1–5 every 3 weeks [58]. The firstgroup had a response rate of 14.3% compared to 11.6% forthe second group, median survival of 8.3 months compared to7.3 months, and 1-year survival of 38% for both groups. Thesafety profile was good in both patient cohorts, with G3–4adverse events in less than 30% of the patients. Ixabepiloneseems very active in patients resistant to platinum-therapy andpretreated with taxanes, and so it is a good option for secondline treatment of NSCLC. A recent phase II trial assess-ing safety and activity of ZK-EPO 16 mg/m2 every 3 weeksshowed a response rate of 10.5% and 14% grade 3 neurotox-icity [59]. Patupilone at the dose of 10 mg/m2 every 3 weeksis active (38% response rate) and well-tolerated (rare G3 tox-icity) and has a possible role in the management of brainmetastases from NSCLC [60]. The preliminary results of aphase II trial of epothilone D showed a response rate lowerthan 8% but a better toxicity profile than other epothilones[61]. Although epothilones are active in taxane-resistant pre-clinical models, it is not clear if their activity is higher thandocetaxel or paclitaxel and if they have a different toxicityprofile.

Lipoplatin, 100 mg/m2 every 14 days, is a new platinumanalogue providing partial responses in 5% and stable dis-eases in 16% of patients with a median survival of 7 months[62]. Its toxicity profile leads to a dosage increase in furtherphase I–II trials.

A phase III randomised trial has compared vinflunine, anew vinca alkaloid, 320 mg/m2 to docetaxel 75 mg/m2 every3 weeks in platinum-pretreated advanced NSCLC patients[63]. There was no difference in QoL and clinical activ-ity between the two groups, as well as for median survival(6.7 and 7.2 months in patients treated with vinflunine anddocetaxel respectively). Myelotoxicity was more frequentin the vinflunine arm, while febrile neutropenia, diarrhoeaand peripheral neuropathy were commoner in the docetaxelgroup.



Table 3Main ongoing phase III randomised trials.

Clinical trial Sponsor Objective No. patients to be enrolled

Docetaxel + carboplatin vs. docetaxel Hellenic Oncology Research Group OS 130Erlotinib > DDP + gemcitabine vs.

DDP + gemcitabine > erlotinibNCI-C, Naples OS 900

Pemetrexed vs. erlotinib Hellenic Oncology Research Group OS 450Cetuximab + pemetrexed vs. pemetrexed vs.

cetuximab + docetaxel vs. docetaxelImClone Systems PFS 800

Erlotinib vs. erlotinib + sunitinib Pfizer OS 956Docetaxel vs. docetaxel + vandetanib Astra Zeneca PFS 1240Pemetrexed vs. pemetrexed + vandetanib Astra Zeneca PFS 510Erlotinib vs. erlotinib + bevacizumab Roche PFS 200

OS: overall survival; PFS: progression free survival.

Docetaxel 75 mg/m2 day 1 every 3 weeks was also com-pared to oral topotecan 2.3 mg/(m2 day) on days 1–5 in aphase III trial, showing that topotecan may be an option forpatients who require an orally available treatment [64]. SNS-595 is a cell cycle inhibitor that damages the DNA, blocksthe cell cycle in G2-phase and induces apoptosis. Preliminaryresults of two phase II trials showed that 48 mg/m2 is an activedose in the treatment of NSCLC with stable disease in morethan 50% of the patients [65]. Neutropenia, the most frequentG3–4 toxicity, was seen only in 8–18% of the patients.

6. Conclusions

Advanced NSCLC has still a bad prognosis, with a mediansurvival of about 12 months, nonetheless improved whencompared to the 6-month survival reported about 20 yearsago. The prognostic improvement in the latest years is clearlyassociated not only to the optimization of the first line treat-ment but also to the development of second and third linetherapies. Docetaxel (administered weekly or every 3 weeks)and pemetrexed are the two agents now commonly used assecond line treatment of NSCLC in clinical practice. To date,combination chemotherapy has shown no advantage as com-pared to single agents. Several trials are ongoing to assessthe efficacy of combinations among chemotherapy and targetdrugs (Table 3).

Erlotinib 150 mg/day is now used as third line treatmentof NSCLC, or in the second line mainly when chemotherapyis contraindicated, or in patients selected by clinical or bio-molecular findings.

Yet it is always convenient, in such therapeutic strategy,that the single decision be led by a careful cost/benefit anal-ysis.

Conflict of interest statement

Adolfo Favaretto, Giulia Pasello, Cristina Magro,Clorinda Schettino: none. Cesare Gridelli: Advisory Role andHonoraria by Eli Lilly, Roche.

Reviewers

Francesco Grossi, M.D., Deputy Head, National Institutefor Cancer Research, Medical Oncology A, Disease Man-agement Team - Lung Cancer, Largo Rosanna Benzi 10,IT-16132 Genoa, Italy.

Tom Stinchcombe, M.D., University of North Carolina atChapel Hill, Division of Hematology/Oncology, 3009 OldClinic Bldg, Chapel Hill, NC 27599-7305, United States.

Suresh Ramalingam, M.D., Emory Winship Cancer Insti-tute, Department of Medical Oncology, 1365C Clifton Road,Atlanta, GA 30322, United States.

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Biographies

Adolfo Favaretto, M.D., achieved first the Oncology Spe-cialty in 1987 and then Respiratory Disease Specialty in1994. Since 1990 Medical Oncologist at the University Hos-pital of Padua (Italy) and Consultant of Oncology at theGeriatric Hospital, Padua. Actively involved in several inter-national and national randomised clinical trials; affiliatedto ASCO, ESMO, EORTC, IASLC, AIOM. Reviewer forseveral journals covering lung cancer, anticancer therapyand pharmacology fields. Lecturer at numerous national andinternational conferences about small- and non-small celllung cancer and mesothelioma. A professor at the Tho-racic Surgery Specialty School of Padua University, he hascontributed to more than 40 publications on internationalindexed journals, and some chapters of books, particu-larly in the field of the chest, ENT, and hemato-oncologicneoplasms.

Giulia Pasello, M.D., qualified as a medical graduatein 2005 in Ferrara, Italy. From 2006 to 2007 she spentthe first year of postgraduate training at the Department ofOncologic and Surgical Sciences, Oncology Section (IstitutoOncologico Veneto, IRCSS, Padua) involved in the researchof molecular prognostic markers of esophageal adenocar-cinoma. Since 2007 she has been working at the MedicalOncology Department, Istituto Oncologico Veneto, involvedin lung cancer and mesothelioma Clinical Trials Research.

Cristina Magro, RN, qualified as a Professional Nursein 1993 in Padua, Italy. From 1994 to 2002 she worked asa Nurse in Critical Care Unit and Medical Oncology Dept.of Padua General Hospital. Since 2003 she is involved inClinical Research Trials as a Research Nurse, at the MedicalOncology Department of Istituto Oncologico Veneto IRCSS,Padua.



Cesare Gridelli, M.D., is currently Chief of Division ofMedical Oncology and Director of Department of Oncol-ogy/Hematology at the “S.G. Moscati” Hospital of Avellino(Italy). His areas of expertise are lung cancer, cancer in theelderly, antiemetics. He is involved in the clinical develop-ment of new anticancer agents. He is member of Advisory

Board of scientific journals and of several expert panels.Dr. Gridelli has been invited speaker of international con-ferences and educational activities of oncology societies(ASCO, ESMO, etc.). He is author or co-author of about450 papers, of which about 180 extended papers published oninternational indexed journals, and several chapters of books.

Second and third line treatment in non-small cell lung cancer

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Transcript of Second and third line treatment in non-small cell lung cancer