Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer

Lung Cancer 99 (2016) 31–37

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Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer Federico Cappuzzo a , Alessandro Morabito b , Nicola Normanno c , Paolo Bidoli d , Alessandro Del Conte e , Laura Giannetta f , Agnese Montanino b , Francesca Mazzoni g , Roberta Buosi h , Marco Angelo Burgio i , Giulio Cerea f , Rita Chiari j , Diego Cortinovis d , Giovanna Finocchiaro k , Luisa Foltran e , Maria Rita Migliorino l , Marcello Tiseo m , Silvia Ferrari n , Filippo De Marinis o,p,∗ a

Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Viale Alfieri 36, 57100 Livorno, Italy Thoracic Medical Oncology, Istituto Nazionale Tumori “Fondazione G Pascale”-IRCCS, Via Semmola, 80131 Naples, Italy Cell Biology & Biotherapy Unit, Istituto Nazionale Tumori “Fondazione G Pascale”-IRCCS, Via Semmola, 80131 Naples, Italy d Department of Oncology, San Gerardo Hospital, Monza, Via Pergolesi 33, 20900 Monza, Italy e Medical Oncology, Azienda per l’Assistenza Sanitaria No. 5 (AAS5) – Friuli Occidentale – Presidio Ospedaliero di Pordenone, Via Montereale 24, 33170 Pordenone, Italy f Oncologia Falck, Division of Medical Oncology, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy g Medical Oncology, University Hospital Careggi, L. go Brambilla 3, 50134 Florence, Italy h Division of Oncology, Department of Translational Medicine, University of Eastern Piedmont “Amedeo Avogadro”, 28100 Novara, Italy i Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy j Department of Medical Oncology, “Santa Maria della Misericordia” Hospital, Azienda Ospedaliera di Perugia, 06132 Perugia, Italy k Department of Medical Oncology, Istituto Clinico Humanitas IRCCS, Via Manzoni 56, 20089 Rozzano, Milan, Italy l Department of Thoracic Oncology, 1st Pulmonary Oncological Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy m Division of Medical Oncology, University Hospital of Parma, Via Gramsci, 14, 43126 Parma, Italy n AstraZeneca, Palazzo Ferraris, Via Ludovico il Moro 6/C, 20080 Basiglio, Milan, Italy o Thoracic Oncology Division, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, 20141 Milan, Italy, Italy p Formerly Department of Thoracic Oncology, 1st Pulmonary Oncological Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy b c

a r t i c l e

i n f o

Article history: Received 16 March 2016 Received in revised form 6 June 2016 Accepted 11 June 2016 Keywords: Gefitinib Rechallenge EGFR mutation Advanced stage NSCLC

a b s t r a c t Objectives: Although patients with advanced non-small cell lung cancer (NSCLC) and an activating epidermal growth factor receptor (EGFR) mutation benefit from the use of EGFR-tyrosine kinase inhibitors (TKI), most of them progress within 12 months from treatment start due to acquired resistance. In clinical practice, many physicians frequently offer these patients retreatment with EGFR-TKIs after a chemotherapy break, based on small or retrospective studies. Materials and methods: A phase II trial was conducted in patients with stage III/IV NSCLC, to assess the efficacy, safety and impact on quality of life (QoL) and disease-related symptoms of gefitinib rechallenge. Eligible patients had initially responded to first-line gefitinib and progressed after second-line chemotherapy. Results: Of 61 enrolled patients, 73.8% were female, 100% had EGFR-mutated adenocarcinoma and 67.2% were never-smokers. Thirty-two (52.5%) patients obtained a clinical benefit, with 3 (4.9%) achieving a partial response and 29 (47.5%) having stable disease. Median progressionfree survival was 2.8 months, overall survival 10.2 months and duration of gefitinib treatment 3.6 months. The most common all grade-adverse events were diarrhea (27.6%), nausea and/or vomiting (20.3%), rash (14.7%) and dyspnea (10.3%); no new toxicities were apparent.

∗ Corresponding author at: Thoracic Oncology Division, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, 20141 Milan, Italy. E-mail addresses: [email protected] (F. Cappuzzo), [email protected] (A. Morabito), [email protected] (N. Normanno), [email protected] (P. Bidoli), [email protected] (A. Del Conte), [email protected] (L. Giannetta), [email protected] (A. Montanino), [email protected] (F. Mazzoni), [email protected] (R. Buosi), [email protected] (M.A. Burgio), [email protected] (G. Cerea), [email protected] (R. Chiari), [email protected] (D. Cortinovis), giovanna.fi[email protected] (G. Finocchiaro), [email protected] (L. Foltran), [email protected] (M.R. Migliorino), [email protected] (M. Tiseo), [email protected] (S. Ferrari), fi[email protected] (F. De Marinis). http://dx.doi.org/10.1016/j.lungcan.2016.06.008 0169-5002/© 2016 Elsevier Ireland Ltd. All rights reserved.

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Conclusion: Findings from this study indicate that gefitinib rechallenge offers modest benefit and may be taken into consideration only for patients for whom no other treatment option exists. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction To date, lung cancer remains the most frequently diagnosed malignancy and the leading cause of cancer death worldwide [1]. Approximately 80% of patients are diagnosed with non-small cell lung cancer (NSCLC) and about 55% of these present with locally advanced or metastatic disease, the 5-year survival rate being <5% [2]. Indeed, in these patients, therapy aims to prolong survival while improving health-related quality of life (QoL) and cancer-related symptoms [3]. The choice of optimal therapy takes into account different factors, such as tumour histology [4,5] and the presence of mutations [6]. In particular, the frequent deregulation of epidermal growth factor receptor (EGFR) [7,8] has prompted the development of EGFR-targeted therapies, that have indeed improved the management of certain patient subsets. Gefitinib, a potent and selective first-generation EGFR-tyrosine kinase inhibitor (TKI) has shown superiority for progressionfree survival (PFS) in first-line phase III trials in patients with EGFR mutations (EGFR-M+), compared to platinum-based doublet chemotherapy (CT). Indeed, the IPASS study reported a median PFS of 9.5 months following treatment with gefitinib vs 6.3 months with CT (p < 0.0001) [9], the NEJ002 study 10.8 vs 5.4 months, respectively (P < 0.001) [10] and the WJTOG3405 study 9.2 vs 6.3 months (P < 0.0001) [11]. Regarding overall survival (OS), no significant difference was reported following gefitinib and CT [9–11] or placebo [12] but, compared to the latter, gefitinib provided a benefit in never-smokers (OS: 8.9 vs 6.1 months, respectively, P = 0.012) and in patients of Asian origin (OS: 9.5 vs 5.5 months, P = 0.01) [12]. A major concern remains acquired resistance to TKIs, as it leads to disease progression within one year from the start of treatment in the vast majority of initial responders [13]: in this scenario, in which no standard of care exists for patients who have already received an EGFR-TKI, establishment of salvage treatment is an urgent issue. The mechanisms responsible for resistance are complex and heterogeneous (e.g. SCLC transformation, epidermal to mesenchimal transition, HER2 amplification/mutation and cMET amplification [14–20]), but in approximately 50% of cases it relies on the T790M mutation, which in some patients is already present at low levels before TKI treatment [21]. Actually, new agents such as osimertinib (AZD9291), rociletinib and HM61713 have shown activity in NSCLC patients with the EGFR T790M mutation who failed prior EGFRTKI [22–24], but, except for osimertinib that has recently received approval in the US and in Europe, these drugs have not been approved yet. Indeed, compelling evidence has pointed towards the coexistence of sensitive and resistant clones in NSCLC: upon TKI administration, a fraction of sensitive cells is eradicated, whereas resistant clones proliferate, leading to clinical resistance. Secondline cytotoxic CT acts on these cells while sparing TKI-sensitive clones, whose re-growth leads to progressive disease. However, as they retain sensitivity to TKI, subsequent rechallenge with the inhibitor should provide clinical benefit [17,25–30]. Few studies have assessed the efficacy and safety of second-line cytotoxic therapy after development of TKI resistance, and contrasting data have been published on the influence of a prior treatment with TKI on subsequent CT [31,32]. Notably, a recent multicenter, retrospective study has shown significantly prolonged PFS in EGFR-M+ NSCLC patients who failed first-line TKI and underwent second-line

pemetrexed monotherapy (n = 37), compared to platinum-based doublet CT (n = 46; 4.2 vs 2.7 months, respectively, P = 0.008) [33]. Encouraging results have been obtained by re-administering gefitinib to NSCLC patients who have progressed following secondline CT after failure of initial TKI treatment [34–38], but a prospective study testing this strategy in a sufficient number of patients is still lacking. The ICARUS (Iressa re-Challenge in Advanced NSCLC EGFR-M+ patients who Responded to gefitinib USed as first-line or previous treatment) study assessed the efficacy and safety of gefitinib rechallenge in 61 selected patients with advanced stage EGFR-M+ NSCLC, who achieved objective response upon first-line gefitinib and subsequently progressed following CT. 2. Methods 2.1. Study design ICARUS trial (NCT01530334) is a phase II, open label, multicentre, single arm study conducted to investigate the efficacy, safety and tolerability of oral gefitinib 250 mg/day as treatment rechallenge in patients with EGFR-M+ locally advanced or metastatic NSCLC, who responded to first-line gefitinib and progressed after second-line CT. Primary end-points were objective response rate (ORR) and clinical benefit rate (CBR). Secondary end-points included PFS, duration of therapy and overall survival (OS). Pre-planned exploratory objectives comprised assessment of QoL and symptom improvement during gefitinib treatment and 4 weeks post-progression. 2.2. Patient population Inclusion criteria were: age ≥18 years; life expectancy ≥12 weeks; histologically or cytologically confirmed EGFR-M+ locally advanced or metastatic stage IIIB/IV NSCLC unsuitable for therapy of curative intent; a previous first-line treatment with gefitinib with a documented complete response (CR) or partial response (PR) or stable disease (SD) >12 weeks as the best response; progression during or after a subsequent CT; World Health Organization (WHO) performance status (PS) of 0–2 [39]; measurable disease defined according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 [40]. Exclusion criteria included any history of interstitial lung disease, inadequate organ function, symptomatic brain metastases, any unresolved chronic toxicity greater than Common Toxicity Criteria (CTC) grade 2 from previous anti-cancer therapy, and any evidence of severe or uncontrolled systemic disease. All patients provided informed consent prior to any study specific procedures. Study approval was obtained by independent ethics committees at each institution. The study was conducted in accordance with the Declaration of Helsinki. 2.3. Treatment Patients received gefitinib (250 mg/day orally) until objective progression of disease (PD), discontinuation for toxicity or consent withdrawal. After progression, patients could receive gefitinib for as long as they were deriving clinical benefit (CB) as judged by the investigator. After discontinuation, further treatments were

F. Cappuzzo et al. / Lung Cancer 99 (2016) 31–37

provided at discretion of the physician. Any systemic anti-cancer treatment, radiotherapy or cancer surgery conducted during gefitinib treatment or after discontinuation was collected until death, loss to follow-up, consent withdrawal or until the end of study. Provision was made for patients who had not progressed at the time of data cut-off and had benefited from gefitinib, so that they could continue treatment outside this clinical study.

Patients screened N = 61

Patients enrolled N = 61 Treatment not started N=3 Reasons: • Refusal to be treated

2.4. Assessments Following treatment start, patients attended for visits every 3 weeks until week 12, and every 6 weeks from week 12 as long as they were receiving gefitinib. Radiological assessment was performed using the RECIST 1.1 [40] at screening and every 6 weeks after treatment start until objective PD. In case of treatment discontinuation for reasons other than objective PD, assessments continued according to the original schedule until objective progression or data cut-off. Immediately following data cut-off, the survival status of patients remaining in the study was confirmed and recorded in the electronic case report forms. The ORR (confirmed CR or PR) and CBR (confirmed CR or PR or SD) were defined according to the RECIST 1.1. PFS was the time from the first dose of gefitinib until the date of objective PD as defined by RECIST 1.1, or death from any cause in the absence of progression. Patients who had neither progressed nor died were censored for PFS at the time of their last evaluable assessment. Treatment duration was the period from the first to the last intake. OS was the time from the first dose until the day of death from any cause. Any patient not known to have died at the time of data analysis was censored at the time of the last follow-up date. Toxic effects were assessed according to the NCI-CTC, version 4.0, and collected up to 30 days after the last dose of gefitinib. 2.5. Quality of life assessment The Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire examines the physical, social/family, emotional, and functional well-being [41,42], and includes the lung cancer subscale (LCS). The sum of physical and functional well-being and LCS is the trial outcome index (TOI). Pulmonary symptoms were assessed in symptomatic patients by the 4 specific items of LCS. Baseline FACT-L was the questionnaire closest, but not subsequent, to the first gefitinib intake. Overall QoL improvement was defined as a change from baseline of ≥6 points in the FACT-L and TOI, and of ≥2 points in the LCS, sustained for ≥21 days. No more than one assessment in this interval of improvement could be missed. Worsening was considered as a change from baseline of <6 points for FACT-L and TOI and <2 for LCS; a change in score different from those specified above was considered as “no change.” 2.6. Statistical analysis Efficacy was evaluated by an intention-to-treat (ITT) analysis performed in all screened patients who entered the study regardless of whether they received gefitinib; safety analysis was performed considering all entered patients who received ≥1 dose of gefitinib. One Arm Binomial Sample Size method [43] was used to calculate the number of subjects required. A sample size of 54 subjects was estimated to be sufficient to give a 90% probability of rejecting a baseline CBR of 20% with an exact 5% two-sided significance test, when the true level of CBR was at the clinically relevant rate of 40%. Continuous variables were summarized by descriptive statistics, and categorical variables by frequencies. Median OS, PFS, and treatment duration, along with the 95% confidence interval (CI), were estimated through the Kaplan-Meier method, ORR and CBR were simply summarized, and the 95%CI was derived using Wilson

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Treatment started N = 58

Discontinued treatment N = 51 Reasons: • PD (N = 47) • AE (N = 3) • Other (N = 1)

Discontinued study N = 46 Reasons: • Death (N = 37) • Lost to follow-up (N = 3) • Missing (N = 1) • Other (N = 5) Fig. 1. Disposition of patients enrolled into the ICARUS study. PD, progression of disease; AE, adverse events.

score intervals (CIs for a single proportion). Exploratory analyses were performed according to baseline histology (squamous cell vs all remaining types of carcinoma), smoking status (never vs current and former smoker), gender, age class (≤65 vs >65 years) and WHO-PS (0 vs 1–2). All AEs were assigned a Preferred Term (PT) and were classified by primary System Organ Class according to the MedDRA thesaurus version 17. Statistical analysis was performed using the SAS System software version 9.2. 3. Results 3.1. Patient population Overall, 61 patients were enrolled from July 2012 to January 2014 from 25 sites across Italy: of these, 58 received gefitinib (Fig. 1). Baseline characteristics of eligible patients are summarized in Table 1. Mean age was 67 years (range 40–86), 73.8% were females, 32.8% had a WHO-PS of 0 and 65.6% of 1–2, 96.7% had a stage IV NSCLC and all of them had a diagnosis of adenocarcinoma. 3.2. Previous treatment and response Prior to study entry, all patients had received first-line gefitinib for a median of 11.5 months (range 4.1–34.3), and the best response observed was CR in 4 cases (6.6%), PR in 34 (55.7%) and SD in 23 (37.7%), the latter with a median duration of 10.4 months (range 3.2–24.9).

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Table 1 Baseline characteristics of patients in the ITT population. Values are reported as frequency (n [%]) or as mean (range).

Gender Females Age, yrs ≤65 yrs >65 yrs

45 (73.8) 67 (40–86) 22 (36) 39 (64)

WHO-PS 0 1 2 n.a.

20 (32.8) 30 (49.2) 10 (16.4) 1 (1.6)

Stage at study entry IIIB IV

2 (3.3) 59 (96.7)

Extend of disease Locally advanced Metastatic Both

4 (6.6) 51 (83.6) 6 (9.8)

Smoking status Never Current Former Missing

Survival probability

ITT population (n = 61)

0.8 0.6 0.4 0.2

0

3

No. patients at risk Gefitinib 61

6 9 Time (months)

24

9

12

15

2

0

7

Fig. 2. Kaplan-Meier curve for progression-free survival. In shaded grey, the 95% confidence interval limits.

1.0

41 (67.2) 3 (4.9) 16 (26.2) 1 (1.6)

Previous line efficacy First line gefitinib -ORR -CBR Second line CT -ORR -CBR 1st line gefifitib duration, weeks 2nd line CT number of cycles

Median PFS: 2.8 months (95% CI: 2.4-3.1)

0.0

Survival probability

Variable

1.0

38 (62.3) 61 (100)

Median OS: 10.2 months (95% CI: 8.8-14.1)

0.8 0.6 0.4 0.2 0.0

14 (23) 40 (65.6) 55 (18–149) 4.69 (1–18)

0

Abbreviations: ITT, intention-to-treat; WHO-PS, World Health OrganizationPerformance Status; ORR, objective response rate; CBR, clinical benefit rate; CT, chemotherapy.

As second-line therapy, patients received CT, the most common regimens being cisplatin plus pemetrexed (n = 20, 32.8%), pemetrexed plus carboplatin (n = 11, 18.0%) and carboplatin plus gemcitabine (n = 9, 14.8%). The mean number of cycles was 4.7 ± 1.7 (range: 1–11), with 16 (26.2%) patients receiving ≤3 cycles and 45 (73.8%) >3 cycles. The best response observed throughout CT was CR in 1 patient (1.6%), PR in 13 (21.3%), SD in 26 (42.6%), and PD in 21 (34.4%). 3.3. Efficacy of third-line gefitinib 3.3.1. Primary endpoints In the ITT analysis, a response was seen in 3 patients, with an ORR of 4.9% (95% CI: 1.7–13.5), and a CB in 32 patients, with a CBR of 52.4% (95% CI: 40.2–64.5). The median duration of best response was 4.8 months (range:4.4–12.2) for PR, and 2.3 months for SD (range: 1.3–10.0). None of the exploratory analysis showed a statistically significant result, neither as to the probability of achieving a

No. patients at risk Gefitinib 61

3

6 9 12 Time (months)

52

43

32

19

15

7

18 20

1

Fig. 3. Kaplan-Meier curve for overall survival. In shaded grey, the 95% confidence interval limits.

response in third-line between patients who had obtained CR, PR or SD following second-line treatment and those who had experienced PD (55% vs 47.5%, respectively).

3.3.2. Secondary endpoints As of data cut-off, the median follow-up was 9 months (range 0–19). Median PFS, OS and duration of treatment with gefitinib were 2.8 months (95%CI: 2.4–3.1; Fig. 2), 10.2 months (95% CI: 8.8–14.1; Fig. 3) and 3.6 months (95% CI: 3–5.6), respectively. The median time to worsening of disease-related symptoms was 3.1 months (95% CI: 2.3–3.6). The FACT-L score showed an improvement of symptoms for 8 (13.1%) patients, whereas 6 (9.8%) experienced a worsening. The TOI score showed a worsening in just 2 (3.3%) cases (Table 2).

Table 2 Overall results of quality of life (QoL) assessment by the Functional Assessment of Cancer Therapy-Lung total score and its domains. Patients’ QoL and symptom improvement were evaluated during gefitinib treatment and 4 weeks post-progression. Pulmonary symptoms were determined in symptomatic patients only (n = 15). Values are reported as frequencies (n [%]). Best overall response

Total FACT-L

TOI

LCS

Pulmonary symptoms

Improvement No change Worsening Other n.a.

8 (13.1) 29 (47.5) 6 (9.8) 16 (26.2) 2 (3.3)

1 (1.6) 41 (67.2) 2 (3.3) 15 (24.6) 2 (3.3)

7 (11.5) 24 (39.3) 11 (18) 17 (27.9) 2 (3.3)

12 (80) 1 (6.7) 2 (13.3)

Abbreviations: FACT-L, Functional Assessment of Cancer Therapy-Lung; TOI, Trial Outcome Index; LCS, Lung Cancer Subscale; n.a., not available.

F. Cappuzzo et al. / Lung Cancer 99 (2016) 31–37 Table 3 Adverse events reported in ≥5% of patients evaluable for safety (n = 58) by preferred terms (PT). Values are expressed as frequencies (n [%]). Adverse event

All grades

Grades ≥3

Rash or acneiform dermatitis Diarrhea Dry skin or pruritus Vomiting Decreased appetite Dyspnea Nausea Asthenia Conjunctivitis Fatigue Musculoskeletal pain Pyrexia Chest pain General physical health deterioration Hypertension Cough Paronychia Abdominal pain

21 (36.2) 16 (27.6) 11 (19) 9 (15.5) 6 (10.3) 6 (10.3) 6 (10.3) 5 (8.6) 5 (8.6) 5 (8.6) 5 (8.6) 5 (8.6) 4 (6.9) 4 (6.9) 4 (6.9) 3 (5.2) 4 (5.2) 3 (5.2)

2(3.4) 0 1 (1.7) 0 0 3 (5.2) 0 0 0 0 0 0 1 (1.7) 2 (3.4) 1 (1.7) 0 1 (1.7) 0

Notes: Only the most severe common terminology criteria for adverse event (AE) grade is counted for multiple occurrences of the same AE in one individual. Each patient is counted at most once within each PT.

3.4. Safety and tolerability of third-line gefitinib 52 patients reported 263 AEs, the most common being skin toxicity and diarrhea (Table 3), and 10 reported 13 serious AEs. AEs of grade ≥3 were observed in a limited number of cases, the only grade 5 being an episode of sepsis in a 86 year-old woman. Transaminase increase was recorded in 2 cases (3.4%), grade 2 and 3, respectively. 9 patients (15.3%) were hospitalized due to AEs, and 11 (18%) temporarily discontinued gefitinib treatment, mainly for diarrhea, rash and mucositis; a 58 year-old man interrupted definitively gefitinib due to a myocardial infarction judged as gefitinib-unrelated. 4. Discussion The prognosis of stage III/IV NSCLC patients harbouring EGFR mutations remains dismal, despite clinical improvement provided by the development of EGFR-TKI. In fact, within one year from treatment start, most patients acquire resistance and experience PD [13]. Due to the lack of a standard of care, different options have been tested as possible salvage strategies to prolong OS and improve QoL. Among these, TKI rechallenge in subjects who initially responded to a first-line inhibitor and subsequently progressed following CT has provided encouraging results, but published reports rely on a small sample size and, in some cases, on retrospectively collected data. To the best of our knowledge, ICARUS is the first prospective study assessing re-administration of gefitinib as thirdline therapy in selected patients. Our findings are in line with previous reports, although published results are quite heterogeneous likely due to the small sample size (n = 16 [34] to 23 [36]), prospective vs retrospective analysis, patient characteristics and therapy regimen taken into account [34–37]. Indeed, ORR ranged from 0% [34] to 25% [37] and CBR from 44% [34] to approximately 65% [36,37]. PFS was 2 [35] and 2.5 months [34] and OS 10 [37] and 14.7 months [34]. The low ORR of 4.9% observed upon third-line gefitinib may be partly explained by the regrowth of EGFR-TKIsensitive cells, reported in <10% of cases. Indeed, one limitation of our study is the lack of patients’ selection according to their mutational status, as it was not possible to obtain pre-treatment samples. Several groups investigated the effect of rechallenging with a different first-generation TKI. When various treatment sequences were tested in 120 NSCLC patients given a TKI twice, those who

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benefited from prior EGFR-TKI more likely attained benefit from the second administration (regardless of the sequence), and ORR, CBR, PFS and OS were 10%, 52.5%, 2.3 months and 8 months, respectively [44]. Becker et al. retrospectively reviewed data from 14 stage IV NSCLC patients retreated with erlotinib after initial TKI administration followed by CT [30]: 36% of patients achieved PR, 50% SD and 14% PD, with a median PFS of 6.5 months [30]. In the LUX-Lung1 trial, afatinib was given to patients with advanced NSCLC who failed a first-line TKI and one or two subsequent CT lines. Median PFS was 3.3 months, OS 10.8 months and CBR 61% [45]. Moreover, a retrospective study on 96 patients with EGFR-M+ advanced NSCLC given afatinib after failure of CT and TKI documented a RR of 11.6%, with a median PFS and OS of 3.9 and 7.3 months, respectively [46]. A significant difference in PFS (9.5 vs 5 months, respectively) but not in disease control rate (85.7% and 84.6%, respectively) was recently reported between groups given a different inhibitor (n = 14) or the same (n = 13) in first-line [38]. Finally, two trials (NCT02025218 and NCT01933347) investigating the rechallenge with TKIs are ongoing. Approximately 50% of EGFR-M+ TKI-resistant cases carry the T790M substitution, which identifies a subset of patients with a relatively favorable prognosis and a more indolent progression. Yet, preliminary results obtained in 51 patients rechallenged with the same EGFR-TKI used in first-line and subjected to rebiopsy after TKI failure suggest that the presence of the T790M substitution is not predictive nor prognostic in this setting [46]. In fact, no difference in terms of PFS and OS was found between patients with (n = 18) or without (n = 33) the mutation (PFS: 1.8 months and 2 months,respectively, P = 0.261; OS: 7.7 months and 6.8 months, respectively, P = 0.565). However, the sample size is small and further studies are needed to confirm these results. Recent studies conducted in patients harbouring the T790M mutation have highlighted the importance of EGFR profiling and rebiopsy, which, however, are not yet standard of care [47]. Nevertheless, biopsy is an invasive procedure that may provide insufficient material for mutation analysis, and is inadequate in the case of heterogeneous tumors. Currently, different techniques are under development, to detect mutations with high specificity and sensitivity (e.g. analysis of circulating tumour DNA) [48–50]. Performing molecular analysis on serial samples may help identifying patients that are more likely to benefit from a particular therapeutic strategy [17]. Preliminary results from phase I/II trials exploring the efficacy and safety of new potent, selective irreversible EGFR-TKIs have shown clinical activity and a good safety profile in EGFR-M+ NSCLC patients, especially those harbouring the T790M mutation, after failure of first-generation EGFR-TKIs [22–24]: however, these agents are not available yet in clinical practice. Conversely, the anti-PD-L1 inhibitor nivolumab has provided no clinical benefit, compared to docetaxel, in the subset of EGFR-M+ patients [51]. Therefore, at least in subgroups of patients selected by molecular analyses conducted on rebiopsy, gefitinb rechallenge remains a reasonable option in later lines of treatment. As for safety of gefitinib rechallenge, the most commonly reported AEs were diarrhea and rash, and no new areas of toxicity surfaced, indicating that, despite the setting of heavily pretreated subjects, treatment was well tolerated. In conclusion, our findings indicate that rechallenge with gefitinib after first-line treatment with the same TKI has modest activity, and might be considered as a salvage treatment solely for selected patients with no other option available. The implementation of third-generation TKI in the therapeutic armamentarium of EGFR+ NSCLC may offer the possibility of rechallenge in patients carrying the T790M substitution. In this context, EGFR molecular profiling also in the later stage of disease is crucial to identify patients who may benefit from novel treatment strategies.

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Acknowledgements We thank all the patients who participated in this study, and the following investigators for their contribution: G. Fasola (Department of Medical Oncology, University and General Hospital, Udine), C. Pinto (Unit of Medical Oncology, S. Orsola-Malpighi Hospital Bologna; currently: S.C. Oncologia, IRCCS Santa Maria Nuova, Reggio Emilia), A. Frassoldati (Medical Oncology, University Hospital, Ferrara), G. Romano (U.O. Oncologia, Ospedale Vito Fazzi, Lecce), A. Santo (Department of Medical Oncology, University of Verona), L. Latini (Oncology Unit, Macerata Hospital, Macerata), L. Ciuffreda (Division of Oncology, Department of Oncology and Hematology, Città della Salute edella Scienza, Molinette Hospital, Turin), C. Battiloro (Monaldi Hospital, Naples), F. Grossi (Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa), G. Rosti (Medical Oncology, S Maria di Ca’ Foncello Hospital, Treviso), A. Caprioli (A.O.R.N. San Giuseppe Moscati Pneumologia, A.O. Spedali Civili, Brescia), P.L. Piovano (Division of Medical Oncology, Department of Oncology and Haematology, Ospedale SS Antonio e Biagio e C Arrigo, Alessandria), Claudio Dazzi (Medical Oncology, Hospital of Ravenna, Ravenna), M. Papi (U.O. di Oncologia, Ospedale Infermi Rimini, Ospedale Cervesi, Azienda USL di Rimini, Rimini, Cattolica), S. Siena (Oncologia Falck, Division of Medical Oncology, Niguarda Ca’ Granda Hospital, Milan), F. Di Costanzo (Medical Oncology, University Hospital Careggi, Florence) and F. Cecere (Regina Elena National Cancer Institute, Rome, Italy). This study was sponsored by AstraZeneca. Medical writing support and editorial assistance was provided by Clara Ricci, PhD (Primula Multimedia S.r.L., Pisa) and funded by AstraZeneca (no grant number). IRESSA is a trademark of the AstraZeneca group of companies.

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