ESMO 2016 Press Release: Ceritinib Provides Longer Progression-free Survival Than Chemotherapy in Phase III Trial of ALK Rearranged Lung Cancer Treatment

LUGANO-COPENHAGEN – Ceritinib provides longer progression-free survival than chemotherapy in crizotinib-pre-treated patients with non-small-cell lung cancer harbouring an ALK rearrangement, according to results of the phase III ASCEND-5 study presented today at the ESMO 2016 Congress in Copenhagen.

“Patients with non-small cell lung cancer (NSCLC) should receive front line therapy with the anaplastic lymphoma kinase (ALK) inhibitor crizotinib,” said lead author Professor Giorgio Scagliotti, head of the Department of Oncology, University of Turin, Italy. “Most patients develop resistance to crizotinib and currently second line treatment is represented by chemotherapy alone.”

He continued: “This was the first phase III study to assess whether the second generation ALK inhibitor ceritinib was superior to chemotherapy upon progression on crizotinib therapy in NSCLC.”

The open-label ASCEND-5 study included 231 patients with NSCLC who had received crizotinib. Patients were randomised 1:1 to receive therapy with ceritinib or chemotherapy (pemetrexed or docetaxel). Patients who discontinued chemotherapy due to disease progression could crossover to ceritinib. The primary endpoint was progression-free survival, assessed by a blinded independent review committee.

Median progression-free survival was significantly improved with ceritinib compared to chemotherapy (5.4 vs 1.6 months, hazard ratio [HR] 0.49, p<0.001). Ceritinib increased overall response rate compared to chemotherapy (39.1% vs 6.9%). There was no improvement in overall survival with ceritinib compared to chemotherapy.

Of the patients who discontinued chemotherapy due to disease progression, 75 crossed over to ceritinib.

Scagliotti said: “Progression-free survival was significantly lengthened with ceritinib compared to chemotherapy. We did not observe an improvement in overall survival with ceritinib, probably because the patients who crossed over diluted the potential benefit.”

Patients taking ceritinib had similar toxicities to those observed in phase I and II studies. The most frequent grade 3/4 adverse events with ceritinib were nausea (7.8%), vomiting (7.8%) and diarrhoea (4.3%), and with chemotherapy were neutropaenia (15.5%), fatigue (4.4%) and nausea (1.8%). Ceritinib significantly improved patient-reported outcomes including lung cancer-specific symptoms and overall health status, compared to placebo (p<0.05).

“This study opens up a new treatment paradigm after crizotinib failure,” said Scagliotti. “It would be logical now to give a sequence of active drugs, starting with crizotinib in first line and moving to ceritinib in second line.”

Commenting on the trial, Dr Alice Shaw, director of thoracic oncology at the Massachusetts General Hospital Cancer Centre in Boston, US, said: “This is the first randomised study to examine how a second generation ALK inhibitor compares to standard second line chemotherapy in ALK positive patients who failed the standard first line therapy, which currently is crizotinib.”

“Single arm studies have suggested that ceritinib and alectinib could be standard options in the second line setting after crizotinib has failed,” continued Shaw. “But the positive effect on progression-free survival in this phase III study confirms that there is greater benefit using a second ALK inhibitor over standard chemotherapy. This will establish sequential crizotinib followed by a second generation ALK inhibitor as the standard treatment for patients with metastatic ALK positive lung cancer.”

She concluded: “We are now waiting on the results of trials testing the second generation ALK inhibitors ceritinib (versus chemotherapy) and alectinib (versus crizotinib) in the first line setting. The latter trial addresses one of the most fundamental questions in the field, which is what should be the first ALK inhibitor that patients receive.”

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Notes to Editors

References

Abstract LBA42_PR ‘Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): results from the confirmatory phase 3 ASCEND-5 study,‘will be presented by Dr Giorgio Scagliotti during the Proffered Paper Session NSCLC, metastatic 1 on Sunday, 9 October 2016, 11:00 to 12:30 (CEST) in Room Copenhagen.

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Abstract for LBA42_PR

Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): results from the confirmatory phase 3 ASCEND-5 study

G. Scagliotti1, T.M. Kim2, L. Crinò3, G. Liu4, C. Gridelli5, S. Novello1, K. Kiura6, A. Bearz7, O. Gautschi8, E. Felip9, M. Nishio10, D.R. Spigel11, T.S.K. Mok12, P. Urban13, S. Deudon13, C. Zheng14, A.T. Shaw15
1Department of Oncology, University of Torino, Turin, Italy, 2Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea, 3Medical Oncology, University Medical School of Perugia, Perugia, Italy, 4Medicine, Princess Margaret Cancer Centre, Toronto, ON, Canada, 5Medical Oncology, SG Moscati Hospital, Avellino, Italy, 6Department of Allergy and Respiratory Medicine (Thoracic Oncology), Okayama University Hospital, Okayama, Japan, 7Division of Medical Oncology, IRCCS-CRO, Aviano, Italy, 8Department of Medicine, Medical Oncology, Cantonal Hospital Lucerne, Lucerne, Switzerland, 9Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain, 10Thoracic Medical Oncology, Cancer Institute Hospital of JFCR, Tokyo, Japan, 11Medical Oncology, Sarah Cannon Research Institute, Nashville, TN, USA, 12Clinical Oncology, Chinese University of Hong Kong, Shatin, China, 13Clinical Research, Novartis Pharma AG, Basel, Switzerland, 14Biostatistics, Novartis Pharma, East Hanover, NJ, USA, 15Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA, USA

Background: The ALK inhibitor CRZ is effective in ALK+ NSCLC pts, but most develop resistance and progressive disease (PD). Ceritinib showed robust efficacy in CRZ-pretreated pts in phase 1 & 2 studies. This multicenter, open-label phase 3 study (NCT01828112) compared efficacy of ceritinib vs CT in ALK+ NSCLC pts pretreated with CT & CRZ.

Methods: ALK+ NSCLC pts pretreated with 1–2 CT regimens & CRZ were randomized to oral ceritinib 750 mg/d or CT (pemetrexed [PEM] 500 mg/m2 or docetaxel [DOC] 75 mg/m2), stratified by WHO PS (0 vs 1–2) & brain metastasis at screening. Pts discontinuing CT due to PD could crossover to ceritinib. Primary endpoint was progression-free survival (PFS), assessed by blinded independent review committee (BIRC) per RECIST v1.1.

Results: Of 231 pts (median age 54 y), 115 were randomized to ceritinib and 116 to CT (PEM, n=40; DOC, n=73; 3 not treated). Median treatment exposure was 30.3 wk for ceritinib and 6.3 wk for CT. Median follow-up duration was 16.5 mo. Ceritinib showed statistically significant improvement in PFS (BIRC: median 5.4 vs 1.6 mo, HR=0.49, P<0.001) and increased overall response rate [95% CI] (BIRC: 39.1% [30.2, 48.7] vs 6.9% [3.0, 13.1]) vs CT (Table). Of pts discontinuing CT due to PD, 75 crossed over to ceritinib. Most frequent AEs (% any grade [% grade 3/4]) were diarrhoea (72.2 [4.3]), nausea (66.1 [7.8]) & vomiting (52.2 [7.8]) with ceritinib; fatigue (28.3 [4.4]), nausea (23.0 [1.8]), alopecia (21.2 [0]) & neutropenia (20.4 [15.0]) with CT. 6 (5.2%) ceritinib- and 8 (6.9%) CT-treated pts discontinued due to AEs. Ceritinib significantly improved lung cancer-specific symptoms (LCSS & QLQ-LC13) & overall health status (EQ-5D) vs CT (P<0.05). 

Conclusions: Ceritinib showed a clinically meaningful and statistically significant improvement in PFS vs CT in pretreated ALK+ NSCLC.

Clinical trial identification: NCT01828112

Legal entity responsible for the study: Novartis Pharmaceutical Corporation

Funding: Novartis Pharmaceutical Corporation

Disclosure:

G. Scagliotti: Honoraria: Eli Lilly, AZ, Pfizer, Roche, Clovis Oncology Consulting/advisory, Speaker fees: Eli Lilly Travel/accommodation/expenses: Bayer.
L. Crinò: Honoraria: Novartis, AstraZeneca, Boheringer Consulting/Advisory: Pfizer, Novartis AstraZeneca
G. Liu: Honoraria for advisory board membership: Astra Zeneca, Novartis, Roche, Pfizer.
C. Gridelli: Honoraria for advisory board membership: Novartis.
S. Novello: Speaker Bureau: Eli Lilly, BMS, MSD, BI, Astra Zeneca.
K. Kiura: Corporate-sponsored research: Chugai, AZ, Boehringer, Daiichi-Sankyo, and Shionogi Personal fees (including honoraria): Novartis, Chugai, Pfizer, Lilly, and Taiho. 
E. Felip: Consulting/Advisory: Lilly, Roche, BI, BMS, Novartis.
M. Nishio: Research: Novartis/ONO Pharmaceutical/Chugai Pharmaceutical/BMS/Taiho. Pharmaceutical/Eli Lilly, Pfizer/Astellas Pharma/AstraZeneca Honoraria: Pfizer/BMS/Ono Pharmaceutical/Chugai Pharmaceutical/Eli Lilly/TAIHO pharmaceutical/AstraZeneca.
D.R. Spigel: Consulting/Advisory: Novartis, Pfizer, Genentech/Roche; Speaker’s bureau: Novartis;  Travel/Expenses: Novartis, Pfizer, Genentech/Roche.
T.S.K.Mok: Employment: CUHK Stock: Sanomics Ltd Honoraria/Research: AZ, Roche/Genentech, Pfizer, Lilley, BI, Merck Serono, MSD, Jenssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ, Acta Biosciences, Vertex, Aveo, Biodesix, BMS, GeneDecode.
P. Urban, S. Deudon: Employment: Novartis Pharma AG.
C. Zheng: Employment: Novartis Pharmaceuticals Corporation.
A.T. Shaw: Honoraria: Novartis, Pfizer, Roche Consulting/advisory: Ariad, Daiichi-sankyo, EMD Serono, Genentech, Ignyta, Novartis, Pfizer, Roche, Taiho, Blueprint Medicine Research funding: Genentech/Roche, Pfizer, Novartis.
All other authors have declared no conflicts of interest.

Keywords: ALK positive, ALK pretreated, NSCLC, Ceritinib