original articles

Annals of Oncology

Annals of Oncology 25: 409–415, 2014 doi:10.1093/annonc/mdt536 Published online 23 December 2013

Phase II study of everolimus–erlotinib in previously treated patients with advanced non-small-cell lung cancer 1 Department of Cancer Medicine/Thoracic Unit, Institut Gustave Roussy, Villejuif; 2Department of Oncology Medicine, South-Paris University, Paris, France; 3Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada; 4Department of Medical Oncology, Institut de Cancérologie de L’Ouest, Nantes, France; 5 Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA; 6Centre Intégré de Cancérologie du CHUM, Montréal, Canada; 7University of Wisconsin Carbone Cancer Center, Madison, USA; 8Novartis Pharma AG, Basel, Switzerland; 9Lowe Center for Thoracic Oncology, DanaFarber Cancer Institute, Boston, USA

Received 23 April 2013; revised 18 October 2013; accepted 29 October 2013

Background: Preclinical data suggest combining a mammalian target of rapamycin inhibitor with erlotinib could provide synergistic antitumor effects in advanced non-small-cell lung cancer (NSCLC). Patients and methods: In this multicenter, open-label, phase II study, patients with advanced NSCLC that progressed after one to two previous chemotherapy regimens were randomized 1:1 to erlotinib 150 mg/day ± everolimus 5 mg/day. Primary end point was the disease control rate (DCR) at 3 months; secondary end points included progression-free survival (PFS) and safety. Results: One hundred thirty-three patients received everolimus–erlotinib (n = 66) or erlotinib alone (n = 67). The DCR at 3 months was 39.4% and 28.4%, respectively. The probability for the difference in disease control at 3 months to be ≥15% was estimated to be 29.8%, which was below the prespecified probability threshold of ≥40%. Median PFS was 2.9 and 2.0 months, respectively. Grade 3/4 adverse events occurred in 72.7% and 32.3% of patients, respectively. Grade 3/4 stomatitis was observed in 31.8% of combination therapy recipients. Conclusions: Everolimus 5 mg/day plus erlotinib 150 mg/day was not considered sufficiently efficacious per the predefined study criteria. The combination does not warrant further investigation based on increased toxicity and the lack of substantial improvement in disease stabilization. Key words: disease control rate, erlotinib, everolimus, non-small-cell lung cancer, progression-free survival, stomatitis

introduction Epidermal growth factor receptor (EGFR) inhibition has been extensively studied in preclinical and clinical non-small-cell lung cancer (NSCLC), and the EGFR tyrosine kinase inhibitors (EGFR-TKIs) erlotinib and gefitinib are approved in different parts of the world for treating EGFR mutation-positive NSCLC [1]. For patients with NSCLC whose disease progressed after first- or second-line chemotherapy, erlotinib significantly improved overall survival (OS) in a phase III study of 731 patients with advanced NSCLC, regardless of EGFR mutation status [2]. Activated EGFR signals through the phosphatidylinositol-3kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, a central regulator of cell growth and proliferation,

*Correspondence to: Dr Benjamin Besse, Department of Cancer Medicine/Thoracic Unit, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France. Tel: +33-1-42114322; Fax: +33-1-4211-5219; E-mail: [email protected]

cellular metabolism, and angiogenesis [3]. The mTOR pathway has been implicated in NSCLC development [4, 5], and alterations in mTOR pathway signaling appear to affect NSCLC response to chemotherapy, radiotherapy, and EGFR-targeted therapy [6–9]. As monotherapy, the oral mTOR inhibitor everolimus demonstrated modest antitumor activity in patients with advanced NSCLC enrolled in a phase II study (N = 85), leading to a partial response in ∼5% of patients and controlling disease progression in almost 50% [10]. Everolimus has also been shown to restore sensitivity to EGFR inhibition in resistant NSCLC cell lines [3]. Preclinical data from both NSCLC cell lines and murine NSCLC xenograft models suggest mTOR inhibitors and erlotinib might have synergistic antitumor activity [11, 12]. To assess clinical activity of dual mTOR and EGFR inhibition, a phase I/II study of everolimus and erlotinib for chemotherapyrefractory, advanced NSCLC was initiated. In the dose-finding portion, no pharmacokinetic interaction between everolimus and erlotinib was observed, and the maximum tolerated

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B. Besse1,2*, N. Leighl3, J. Bennouna4, V. A. Papadimitrakopoulou5, N. Blais6, A. M. Traynor7, J.-C. Soria1,2, S. Gogov8, N. Miller8, V. Jehl8 & B. E. Johnson9

original articles doses were everolimus 5 mg/day or 50 mg/week plus erlotinib 150 mg/day; daily therapy provided greater evidence of antitumor efficacy [13]. Herein, results of the randomized, phase II follow-on study are presented.

methods patients

study design and treatment In this international, randomized, open-label, phase II study (ClinicalTrials. gov identifier NCT00456833), eligible patients were randomized (1:1) to everolimus 5 mg/day plus erlotinib 150 mg/day or erlotinib 150 mg/day alone. Treatment was continued until disease progression, intolerable toxicity, or investigator or patient decision. Randomization was stratified by smoking history (never versus ever) and tumor histology (adenocarcinoma versus other). All patients provided written informed consent. The study protocol and all amendments were approved by the ethics body of each center. The study was conducted in accordance with good clinical practice guidelines, the Declaration of Helsinki, and all applicable local and federal regulations.

patients was estimated to be sufficient to correctly conclude efficacy with 80% probability under the assumption of a 20% treatment benefit over control; the 3-month DCR for erlotinib was assumed to be 30%. Primary efficacy analyses were carried out in the full analysis set (i.e. all randomized patients). Safety was evaluated in the safety set (i.e. all patients who received ≥1 dose of any study drug and had ≥1 postbaseline safety assessment).

results patients Between July 2008 and April 2009, 133 patients were randomly assigned to receive everolimus–erlotinib (N = 66) or erlotinib monotherapy (N = 67) (Figure 1). Except for two patients in the erlotinib arm, all patients received ≥1 dose of assigned study medication and were included in the safety set. Demographic and baseline characteristics were relatively well balanced across treatment arms (Table 1). Although 80.5% of patients smoked at some point during their lives, only 13.5% were current smokers. Adenocarcinoma was the most common histology. More patients enrolled in the monotherapy arm received treatment with two previous chemotherapy regimens (35.8% versus 21.2%). At the time of analysis (27 June 2009), 10 (15.2%) everolimus– erlotinib recipients and 13 (19.4%) erlotinib recipients were still receiving study treatment (Figure 1). The most common reason for discontinuation was disease progression. More patients in the combination arm discontinued because of AEs or consent withdrawal compared with erlotinib monotherapy. Median duration of exposure to study treatment was 2.60 months with combination therapy (range 0.2–9.1 months) and 1.84 months with erlotinib (range 0.2–9.8 months).

assessments Tumor assessments were carried out by computed tomography every 4 weeks for the first 16 weeks and every 8 weeks thereafter. All scans were assessed by the local investigator and an independent central radiology review (data not shown). Tumor response was assessed per RECIST version 1.0. Initial assessment of response required confirmation 28 days later. Safety was assessed throughout the study by monitoring and recording all adverse events (AEs) and regularly assessing vital signs, physical condition, and laboratory tests. AE severity was assessed according to the Common Terminology Criteria for Adverse Events, version 3.0.

statistical analysis Primary end point was the 3-month disease control rate (DCR), defined as the proportion of patients with stable disease (SD) or better at 3 months. The primary efficacy decision rule was based on assessing the probability that combination therapy with everolimus and erlotinib ensured a clinically meaningful treatment benefit of ≥15% over erlotinib alone in the 3-month DCR. The probability for the difference in DCR at 3 months to exceed the 40% proof-of-efficacy threshold was estimated using the posterior distribution of the difference estimated using a standard Bayesian conjugate β-binominal model. Secondary end points included best overall response per RECIST, progression-free survival (PFS) (i.e. time from randomization to first documented disease progression according to RECIST or death due to any cause), and overall survival (OS) (i.e. time from randomization to death due to any cause). Sample size was determined by simulations to ensure appropriate conclusions could be drawn with sufficient confidence. One hundred twenty

 | Besse et al.

efficacy DCR at 3 months was 39.4% with erlotinib–everolimus and 28.4% with erlotinib monotherapy (Table 2). The odds of experiencing disease control at 3 months with combination therapy versus monotherapy was 1.64 [95% confidence interval (CI) 0.8–3.39]. The probability for the difference in disease control at 3 months to be ≥15% was estimated to be 29.8%, below the prespecified 40% probability threshold. Best overall response was PR in eight patients (12.1%) treated with everolimus–erlotinib and seven patients (10.4%) treated with erlotinib (Table 2). The overall DCR was 57.6% with combination therapy and 38.8% with erlotinib. More patients who received erlotinib experienced early disease progression (i.e. progression within 8 weeks of randomization) (Table 2). The percentage of patients who experienced a decrease as their best change from baseline in tumor size was higher with combination therapy (46.4% versus 37.1%) (Figure 2A). Median PFS was 2.9 months (95% CI 2.4–3.9 months) for everolimus–erlotinib and 2.0 months (95% CI 1.1–2.8 months) for erlotinib [hazard ratio (HR) 0.769; 95% CI 0.506–1.167; log-rank P = 0.228] (Figure 2B). The percentage of patients who experienced a PFS event was 63.6% with combination therapy and 71.6% with erlotinib. In both arms, the number of PFS events was comparatively higher in patients with a history of smoking (57.6% with combination therapy and 61.2% with erlotinib) than in patients who never smoked (6.1% and 10.4%);

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Eligible patients were those aged ≥18 with unresectable or metastatic, histologically confirmed NSCLC; documented disease progression following one or two previous chemotherapy regimens, including ≥1 platinum-based regimen; WHO performance status ≤1; measurable disease according to RECIST; and adequate bone marrow and liver function. Patients were excluded if they had previously received an EGFR inhibitor; had leptomeningeal or uncontrolled brain metastases; were receiving chronic treatment with steroids or immunosuppressive agents; or had active grade >1 skin, mucosal, gastrointestinal or ocular disorders or other severe medical conditions.

Annals of Oncology

original articles

Annals of Oncology

Randomized N = 133

Everolimus 5 mg/d + Erlotinib 150 mg/d n = 66

Full analysis set Safety population

10 (15.2) 56 (84.8) 7 (10.6) 1 (1.5) 8 (12.1) 1 (1.5) 0 39 (59.1)

n = 66 n = 66

Ongoing, n (%) Discontinued Adverse events Protocol violation Withdrew consent Death Administrative problems Disease progression

Full analysis set Safety population

13 (19.4) 53 (79.1) 3 (4.5) 0 2 (3.0) 0 2 (3.0) 46 (68.7)

n = 67 n = 65

Figure 1. Patient disposition.

in patients with adenocarcinoma (42.4% and 44.8%) versus other histologies (21.2% and 26.9%); and in males (55.6% and 51.5%) versus females (40.0% and 45.5%). At the time of analysis, 23 (34.8%) everolimus–erlotinib recipients and 18 (26.9%) erlotinib recipients had died (HR 1.279; 95% CI 0.690–2.371; log-rank P = 0.433). Median OS at final analysis was 9.1 months (95% CI 7.5–11.1 months) with combination therapy and 9.7 months (95% CI 6.9–13.7 months) with erlotinib (Figure 2C).

safety All patients in the safety set except for one treated with erlotinib monotherapy experienced ≥1 AE. The most commonly reported AEs in everolimus–erlotinib recipients were diarrhea (72.7% versus 55.4% with erlotinib), stomatitis (72.7% versus 23.1%), and rash (53.0% versus 46.2%) (Table 3). One patient treated with combination therapy experienced pneumonitis (1.5%; grade 3), compared with no patients treated with erlotinib. Grade 3/4 AEs were reported for 72.7% and 32.3% of patients treated with combination therapy and erlotinib, respectively (Table 3). Ten (15.2%) everolimus–erlotinib recipients and four (6.2%) monotherapy recipients died while on study treatment or within 28 days of the last dose. With combination therapy, nine deaths were due to lung cancer; the remaining death was due to cardiac arrest. With erlotinib, three deaths were due to lung cancer and one death was due to anaphylactic shock [occurred the day after study drug discontinuation for disease progression and receipt of furosemide for acute renal failure (not considered to be related to study medication)].

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AEs leading to study drug discontinuation were reported for seven (10.6%) everolimus–erlotinib recipients and three (4.6%) erlotinib recipients. Dose reductions or interruptions overall were more frequent with combination therapy (57.6% versus 18.5% with erlotinib), as were dose reductions or interruptions primarily attributable to AEs (45.5% versus 15.4%). Erlotinib median relative dose intensities were comparable between treatment arms [0.995 (range 0.46–1.05) for combination therapy and 1.00 (range 0.71–1.00) for erlotinib monotherapy]. Everolimus median relative dose intensity was 0.984 (range 0.19–1.05).

discussion In this phase II study of everolimus–erlotinib versus erlotinib for advanced NSCLC that progressed after platinum-containing chemotherapy, the prespecified threshold required to conclude that everolimus–erlotinib was efficacious and worthy of further study was not met. In the pivotal phase III trial of erlotinib for previously treated NSCLC, DCR for erlotinib monotherapy was slightly higher compared with what was observed in this trial (45% versus 39%), whereas median PFS was similar (2.2 and 2.0 months, respectively) [2]. In the phase II study of everolimus monotherapy for heavily pretreated advanced NCSLC, DCR was 52.4% after progression on one or two chemotherapy regimens and 41.9% after progression on one or two chemotherapy regimens and gefitinib or erlotinib [10]. In chemotherapy-refractory patients enrolled in a phase II study of everolimus plus the EGFR-TKI gefitinib, the response rate was similar to that observed in the current trial for everolimus–erlotinib (13% and

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Ongoing, n (%) Discontinued Adverse events Protocol violation Withdrew consent Death Administrative problems Disease progression

Erlotinib 150 mg/d n = 67

original articles

Annals of Oncology

Table 2. Tumor response according to investigator assessment per RECIST (full analysis set)

Characteristic

n (%)

Everolimus 5 mg/day + erlotinib 150 mg/day (N = 66)

Erlotinib 150 mg/day (N = 67)

Disease control ratea at 3 months 95% CI Disease control ratea based on best overall response Overall response rateb 95% CI Best overall response Complete response Partial response Stable disease Progressive disease Unknown Early progressionc

26 (39.4)

19 (28.4)

27.6–52.2 38 (57.6)

18.0–40.7 26 (38.8)

8 (12.1) 5.4–22.5

7 (10.4) 4.3–20.3

0 8 (12.1) 30 (45.5) 17 (25.8) 11 (16.7) 18 (27.3)

0 7 (10.4) 19 (28.4) 36 (53.7) 5 (7.5) 31 (46.3)

Everolimus 5 mg/day + erlotinib 150 mg/day (N = 66)

Erlotinib 150 mg/day (N = 67a)

Age (years), median 60.0 (28–77) 60.5 (35–80) (range) Sex, n (%) Male 36 (54.5) 33 (49.3) Female 30 (45.5) 33 (49.3) Race, n (%) White 54 (81.8) 57 (85.1) Black 4 (6.1) 6 (9.0) Asian 7 (10.6) 2 (3.0) Other 1 (1.5) 1 (1.5) Smoking history, n (%) Ever smoker 53 (80.3) 54 (80.6) Current smoker 8 (12.1) 10 (14.9) Histology/cytology, n (%) Adenocarcinoma 46 (69.7) 46 (68.7) Squamous cell 10 (15.2) 10 (14.9) carcinoma Large cell 3 (4.5) 6 (9.0) carcinoma Other 7 (10.6) 4 (6.0) Stage at diagnosis/current stage, n (%) IIIb 8 (12.1)/2 (3.0) 13 (19.4)/2 (3.0) IV 52 (78.8)/64 (97.0) 42 (62.7)/63 (94.0) Number of previous chemotherapy regimens, n (%) 1 51 (77.3) 41 (61.2) 2 14 (21.2) 24 (35.8) 3 1 (1.5) 1 (1.5) Prior therapy, n (%) Platinum 65 (98.5) 66 (98.5) containing Docetaxel 5 (7.6) 10 (14.9) Paclitaxel 29 (43.9) 23 (34.3) Bevacizumab 10 (15.2) 9 (13.4) a

Data are not available for one patient, who was randomized to receive erlotinib monotherapy but never entered the study.

12%, respectively), as was the DCR (55% and 58%, respectively) [14]. Notably, the everolimus–gefitinib study, completed after this trial was initiated, also failed to meet the protocol-specified threshold of a 19% response rate for declaring the combination worthy of further study. Thus, despite preclinical evidence suggesting synergistic antitumor activity for dual mTOR and EGFR inhibition [11, 12] and preliminary antitumor activity in phase I studies [13, 15], combination therapy with everolimus and EGFR-TKIs does not appear to provide significant efficacy for molecularly unselected patients with advanced NSCLC following chemotherapy. The AE profile observed in this study was consistent with the known profiles of everolimus and erlotinib given as monotherapy, although the AE incidence was higher than expected [2, 16, 17]. Grade 3/4 AEs were more frequent with combination

 | Besse et al.

a

Defined as complete or partial response or stable disease. Defined as a best overall response of complete or partial response. c Defined as progressive disease ≤8 weeks after the randomization date. CI, confidence interval, calculated using the Clopper–Pearson method. b

therapy, as were AEs leading to discontinuation and dose reductions or interruptions. Despite greater toxicity with combination therapy, median relative dose intensities for erlotinib were comparable between treatment arms. However, the fact that almost three quarters of patients treated with combination therapy reported stomatitis is cause for concern because oral ulcers are associated with increased risk of weight loss and may have a deleterious impact on quality of life [18]. The increased highgrade stomatitis incidence may be an example of supra-additive toxicity resulting from the combination of two molecularly targeted agents [19]. Supra-additive toxicity has been observed with other mTOR inhibitor-based combinations [20], although it is not universal [21]. The grade 3/4 stomatitis rate with erlotinib–everolimus in the phase I portion of this study was only 12.8% [13], which may have resulted from stricter patient selection or closer follow-up and more aggressive stomatitis management. Although our study does not suggest a significant benefit for everolimus–erlotinib in previously treated advanced NSCLC, it is possible a specific subpopulation might derive benefit. This study was planned in 2006 and 2007, and routine testing for EGFR mutations was not widely adopted until 2009 [1]. Therefore, systematic assessment of EGFR mutations and other biomarkers was not mandated. The assumptions regarding efficacy are limited by this lack of EGFR assessment and the lack of predictive biomarkers for mTOR inhibitors [1]. Given that adding everolimus to trastuzumab provides clinical benefit in women with HER2-positive advanced breast cancer that

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Table 1. Patient demographics and baseline characteristics (full analysis set)

original articles

Annals of Oncology

Probability of progression-free survival (%)

B

125

Everolimus 5 mg/d + erlotinib 150 mg/d (n = 56)

100 75 50 25 0 –25 –50 –75 –100 –125 100 90 80 70 60

Everolimus + erlotinib (n/N = 42/66)

50 40 Erlotinib (n/N = 48/67) 30 20 10 0 0

C

Erlotinib 150 mg/d (n = 62)

20

40

60

80

100

120 140 160 Time (days)

180

200

220

240

260

280

100

Probability of survival (%)

90

Erlotinib (n/N = 18/67)

80 70 Everolimus + erlotinib (n/N = 23/66)

60 50 40 30 20 10 0 0

20

40

60

80 100 120 140 160 180 200 220 240 260 280 300 320 340 Time (days)

Figure 2. Efficacy results (full analysis set). (A) Waterfall plot of best percentage change from baseline in tumor sizes. (B) Kaplan–Meier plot of progressionfree survival. (C) Kaplan–Meier plot of overall survival. For (A), changes >125% are shown as 125%. Patients who had a best percentage change from baseline of zero are represented by open circles. Patients for whom best percentage change in target lesions was inconsistent with overall lesion response suggesting progressive disease are represented by an asterisk. For parts (B) and (C), n/N, number of events/total number of patients in the treatment group. Circles represent censored observations.

progressed on trastuzumab-based therapy [22], it is possible everolimus might provide benefit when added to erlotinib in patients with specific genomic changes. To hasten identification and validation of potential biomarkers in NSCLC, future trials should incorporate mandatory tissue sampling.

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Overall, this study suggests that administering combination therapy with everolimus and erlotinib to patients with advanced NSCLC does not warrant further study in a molecularly unselected population, as it led to detrimental toxicity and no improvement in disease stabilization.

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Best percentage change from baseline (measurable lesions)

A

original articles

Annals of Oncology

Table 3. Adverse events occurring in ≥15% of patients in either treatment arm regardless of relationship to study drug (safety set) Adverse event, n (%)

Erlotinib 150 mg/day (n = 65) Any grade Grade 1 Grade 2

Grade 3

Grade 4

48 (72.7) 48 (72.7) 35 (53.0) 26 (39.4) 24 (36.4) 20 (30.3) 19 (28.8) 18 (27.3) 16 (24.2) 15 (22.7) 14 (21.2) 13 (19.7) 13 (19.7) 12 (18.2) 11 (16.7) 11 (16.7) 10 (15.2) 10 (15.2) 10 (15.2) 10 (15.2)

36 (55.4) 15 (23.1) 30 (46.2) 11 (16.9) 23 (35.4) 22 (33.8) 13 (20.0) 3 (4.6) 23 (35.4) 13 (20.0) 2 (3.1) 17 (26.2) 14 (21.5) 16 (24.6) 14 (21.5) 3 (4.6) 14 (21.5) 4 (6.2) 4 (6.2) 2 (3.1)

3 (4.6) 0 2 (3.1) 0 0 0 1 (1.5) 1 (1.5) 0 0 0 1 (1.5) 0 0 0 0 2 (3.1) 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 (3.1) 0 0 0

27 (40.9) 11 (16.7) 14 (21.1) 17 (25.8) 14 (21.1) 14 (21.2) 6 (9.1) 3 (4.5) 15 (22.7) 7 (10.6) 8 (12.1) 2 (3.0) 8 (12.1) 9 (13.6) 9 (13.6) 10 (15.2) 3 (4.5) 5 (7.6) 9 (13.6) 4 (6.1)

16 (24.2) 16 (24.2) 17 (25.8) 9 (13.6) 10 (15.2) 5 (7.6) 9 (13.6) 12 (18.2) 1 (1.5) 4 (6.1) 5 (7.6) 4 (6.1) 4 (6.1) 3 (4.5) 2 (3.0) 1 (1.5) 5 (7.6) 5 (7.6) 1 (1.5) 5 (7.6)

5 (7.6) 21 (31.8) 4 (6.1) 0 0 1 (1.5) 4 (6.1) 2 (3.0) 0 4 (6.1) 1 (1.5) 7 (10.6) 1 (1.5) 0 0 0 2 (3.0) 0 0 1 (1.5)

0 0 0 0 0 0 0 1 (1.5) 0 0 0 0 0 0 0 0 0 0 0 0

31 (47.7) 11 (16.9) 20 (30.8) 6 (9.2) 14 (21.5) 21 (32.3) 6 (9.2) 0 20 (30.8) 7 (10.8) 2 (3.1) 8 (12.3) 12 (18.5) 8 (12.3) 13 (20.0) 2 (3.1) 6 (9.2) 4 (6.2) 4 (6.2) 1 (1.5)

2 (3.1) 4 (6.2) 8 (12.3) 5 (7.7) 9 (13.8) 1 (1.5) 6 (9.2) 2 (3.1) 3 (4.6) 6 (9.2) 0 8 (12.3) 2 (3.1) 8 (12.3) 1 (1.5) 1 (1.5) 4 (6.2) 0 0 1 (1.5)

Adverse events are listed by preferred term in descending order of frequency (any grade) in the everolimus–erlotinib treatment arm.

acknowledgements The authors thank Melanie Leiby, PhD, and Sally Mitchell, PhD (ApotheCom, Yardley, PA, USA), for writing and editorial assistance, which was funded by Novartis Pharmaceuticals Corporation.

funding This study was supported by Novartis Pharmaceuticals Corporation.

disclosure JB has declared conflicts related to Roche and BoehringerIngelheim. NB has received consulting fees from Roche Canada and Novartis Pharmaceuticals (not related to the conduct of this study). AMT is the primary investigator of clinical studies assessing other agents being developed by Novartis Pharmaceuticals, including panobinostat and LDK378. The University of Wisconsin Board of Regents has receiving funding for these clinical trials from Novartis. These studies were not open while the present study of everolimus and erlotinib was active. JCS has served as a consultant to Roche and Novartis Pharma AG. BEJ has received postmarketing royalties from Dana-Farber for EGFR mutation testing, has equity in the KEW Group, a group founded to provide genomic testing guidance for private oncologists, and has served as a consultant to AstraZeneca, Genentech, Sanofi, Millennium, and Transgenomics. SG, NM, and VJ are employees of Novartis Pharma AG. BB has received research grants

 | Besse et al.

from Roche and Novartis Pharmaceuticals. VAP has received research grants from Astellas and Novartis Pharmaceuticals. NL declares no conflicts of interest.

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Diarrhea Stomatitis Rash Weight decreased Anorexia Nausea Dermatitis acneiform Anemia Dry skin Fatigue Hyperglycemia Asthenia Pruritus Cough Vomiting Epistaxis Dyspnea Pyrexia Rhinitis Lymphopenia

Everolimus 5 mg/day + erlotinib 150 mg/day (n = 66) Any grade Grade 1 Grade 2 Grade 3 Grade 4

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Annals of Oncology 25: 415–422, 2014 doi:10.1093/annonc/mdt572

Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC S.-H. I. Ou1*, †, P. A. Jänne2,†, C. H. Bartlett3, Y. Tang4, D.-W. Kim5, G. A. Otterson6, L. Crinò7, P. Selaru4, D. P. Cohen4, J. W. Clark8 & G. J. Riely9 1 Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine; 2Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston; 3Pfizer Oncology, New York; 4Pfizer Oncology, La Jolla, USA; 5Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 6Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, USA; 7 Department of Oncology, University Hospital of Perugia, Perugia, Italy; 8Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston; 9 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA

Received 25 September 2013; revised 22 November 2013; accepted 27 November 2013

Background: Crizotinib is approved to treat advanced ALK-positive non-small-cell lung cancer (NSCLC), but most patients ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition with crizotinib beyond PD (CBPD) is clinically beneficial and attempted to identify clinicopathologic characteristics associated with patients who experience clinical benefit. Patients and methods: Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials who developed RECIST-defined PD were allowed to continue crizotinib if they were deriving ongoing clinical benefit. In the present retrospective analysis, continuation of CBPD was defined as >3 weeks of crizotinib treatment after PD documentation. Patients who had PD as best response to initial crizotinib treatment were excluded. Baseline and postprogression characteristics, sites of PD, and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed. Results: Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A significantly higher proportion of patients who continued CBPD than patients who did not had an ECOG performance status (PS) of 0/1 at PD (96% versus 82%; P = 0.02). CBPD patients had significantly longer OS from the time of PD [median 16.4 versus 3.9 *Correspondence to: Dr Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, 101 City Drive, Bldg 56, RT81, Orange, CA 92868, USA. Tel: +1-714-456-8104; Fax: +1-714-456-2242; E-mail: [email protected]

Both authors contributed equally.

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Downloaded from http://annonc.oxfordjournals.org/ at UCSF Library and Center for Knowledge Management on March 18, 2015

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Phase II study of everolimus-erlotinib in previously treated patients with advanced non-small-cell lung cancer.

Preclinical data suggest combining a mammalian target of rapamycin inhibitor with erlotinib could provide synergistic antitumor effects in advanced no...
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