Alectinib: ALEX and ALUR Trials Show CNS Benefit in NSCLC

LUGANO-MADRID – Data from two separate phase 3 studies to be presented at the ESMO 2017 Congress in Madrid, show alectinib’s particular central nervous system (CNS) activity in patients with advanced non-small cell lung cancer involving a mutation of the anaplastic lymphoma kinase gene (ALK-positive NSCLC).

Findings from the ALUR trial (1), as well as a secondary analysis of the ALEX trial (2) show alectinib can significantly decrease CNS progression of NSCLC, both in the first-line as well as the second-line treatment setting.

“Patients with NSCLC have a high risk of CNS and brain metastases, commented Prof. Fiona Blackhall, from the University of Manchester and The Christie Hospital, UK.

“These trials provide an important evidence base for the CNS efficacy of alectinib that can be translated to routine clinical care.”

The ALUR results “support alectinib as a new standard-of-care for patients with previously treated ALK-positive NSCLC,” noted that study’s investigator Dr. Silvia Novello, from the University of Turin, Italy.

ALUR included 107 ALK-positive NSCLC patients whose disease had progressed after a previous first-line combination treatment of both platinum-based chemotherapy and crizotinib.

They were randomised to second-line therapy with either standard relapse chemotherapy or alectinib.

Median progression free survival (PFS) was significantly longer in the alectinib group compared to the chemotherapy group - 9.6 versus 1.4 months (hazard ratio [HR] 0.15, 95% CI 0.08–0.29; P<0.001), with a marked difference in CNS response, reported Novello.

Among patients who had measurable CNS disease at baseline, the CNS overall response rate (ORR) was 54.2% in those treated with alectinib compared to zero in the chemotherapy group (P<0.001).

The safety profile of alectinib compared favourably with chemotherapy, despite the substantially longer duration of treatment for patients on alectinib (20 weeks versus six weeks with chemotherapy).

“This is another important goal reached in the field of thoracic oncology,” said Novello. “ALK- positive patients represent 4% of patients with advanced NSCLC, which is the leading cause of solid cancer deaths in men and women in several countries. CNS data are extremely relevant for these patients – the brain is a frequent site of metastasis for them – and these results are important because if we’re aiming to prolong survival we must aim to preserve their neurocognitive capacity. A drug which has this activity on brain metastases can allow us to modify treatment and reduce the need for whole brain radiotherapy.”

Another study to be presented at the meeting, the ALEX trial (3), previously showed significantly better PFS among treatment-naive ALK-positive NSCLC patients who were randomised to alectinib compared to crizotinib (HR for disease progression or death, 0.47, 95% CI, 0.34-0.65; P<0.001).

This new subgroup analysis, focusing specifically on 122 patients who had CNS metastases at baseline, “suggests that alectinib controls existing CNS metastases and inhibits the formation of new metastases better than crizotinib,” said Dr. Shirish Gadgeel, from the University of Michigan, in Ann Arbor, Michigan, USA.

“Clearly this superiority against CNS metastases contributes to the overall efficacy of alectinib,” he added. “By its superior efficacy in the CNS alectinib limits the morbidity both from these metastases but also from treatments such as whole brain radiation.” 

ALK-positive NSCLC was discovered only 10 years ago and progress in identifying precision medicines has been rapid, noted Prof. Blackhall. “Early on, patients were observed to be at high risk of CNS disease and after the discovery of the first-in-class ALK-inhibitor, crizotinib, there has been a focus on development of next generation ALK-inhibitors with improved CNS penetration. The results of the ALUR and ALEX trials provide proof of clinically significant CNS efficacy for alectinib and indicate that CNS staging should be routine for optimal care of patients with ALK-positive lung cancer.”

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

Reference

1. Abstracts 1299O_PR ‘Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC)’ will be presented by Dr Shirish Gadgeel during Proffered Paper Session ‘NSCLC, metastatic 2’ on Monday, 11 September 2017, 09:30 to 10:30 (CEST) in Barcelona Auditorium.
2. Abstract 1298O_PR “Alectinib vs crizotinib in treatment-naïve ALK+ NSCLC: CNS efficacy results from the ALEX study”, will be presented by Dr Silvia Novello during the Proffered Paper Session ‘NSCLC, metastatic 2’ on Monday, 11 September 2017, 09:30 to 10:30 (CEST) in Barcelona Auditorium.
3. N Engl J Med. 2017 Jun 6. doi: 10.1056/NEJMoa1704795. [Epub ahead of print]

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Abstract 1299O_PR

Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated alk+ non-small-cell lung cancer (NSCLC)

J. Wolf¹, J. Mazieres², I.-J. Oh³, J. de Castro⁴, M.R. Migliorino⁵, A. Helland⁶, R. Dziadziuszko⁷, F. Griesinger⁸, A. Kotb⁹, A. Zeiter⁹, A. Cardona¹⁰, B. Balas⁹, H. Johannsdottir⁹, A. Das-Gupta⁹, S. Novello^11
1Medical Oncology, Center for Integrated Oncology, University Hospital of Cologne, Cologne/GERMANY, ²Thoracic Oncology Department, Toulouse University Hospital, Toulouse/FRANCE, ³Lung Cancer Clinic, Chonnam National University Medical School & Chonnam National University Hwasun Hospital, Hwasun/KOREA, REPUBLIC OF, ⁴Department Of Medical Oncology, University Hospital, Madrid/SPAIN, ⁵Oncology, A.O. San Camillo Forlanini, Rome/ITALY, ⁶Department Of Cancer Genetics And Department Of Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo/NORWAY, ⁷Department Of Oncology And Radiotherapy, Medical University of Gdansk, Gdansk/POLAND, ⁸Department Of Hematology And Oncology, Pius Hospital, OIdenburg/GERMANY, ⁹Oncology, F. Hoffmann-La Roche Ltd., Basel/SWITZERLAND, ¹⁰Pdma Biometrics, F. Hoffmann-La Roche Ltd., Basel/SWITZERLAND, ¹¹Department Of Oncology, University of Turin, S. Luigi Hospital, Torino/ITALY

Background: ALK+ NSCLC current standard of care is crizotinib. However, many pts experience progressive disease (PD) within a year, often in the central nervous system (CNS). Alectinib (ALC) has shown systemic and CNS efficacy in phase II trials of previously treated ALK+ NSCLC after crizotinib failure. The phase III ALUR study (NCT02604342) investigated efficacy and safety of ALC vs standard relapse chemotherapy (CT) in ALK+ NSCLC previously treated with platinum-based doublet CT and crizotinib.

Methods: Pts aged ≥18 years with previously treated ALK+ NSCLC were randomised 2:1 to ALC (600mg twice daily) or CT (pemetrexed 500mg/m² q3w or docetaxel 75mg/m² q3w) until PD, death or withdrawal. Crossover from CT to ALC was permitted after PD. Primary outcome was progression-free survival (PFS) by investigator (INV) assessment. Secondary outcomes included PFS by Independent Review Committee (IRC), overall response rate (ORR) and CNS ORR (CORR) by IRC, disease control rate (DCR), duration of response (DOR) and safety.

Results: 107 pts were randomised (ALC n=72; CT n=35); 104 received ≥1 dose of study drug (ALC n=70; CT n=34). At data cut-off (26.01.17) median follow-up: 6.5 months ALC, 5.8 months CT. Median treatment duration: 20.1 weeks ALC, 6.0 weeks CT. Median PFS by INV was 9.6 months (95% CI 6.9–12.2) ALC, 1.4 months (95% CI 1.3–1.6) CT (HR 0.15, 95% CI 0.08–0.29; p<0.001); median PFS by IRC was 7.1 months ALC vs 1.6 months CT (HR 0.32, 95% CI 0.17–0.59, p<0.001). ORR by IRC was 36.1% ALC, 11.4% CT (difference 24.7%, 95% CI 0.05–0.43); CORR in pts with measurable disease was 54.2% ALC, 0% CT (difference 54.2%, 95% CI 0.23–0.78). DCR was 80.6% ALC, 28.6% CT (difference 52%, 95% CI 0.33–0.69). Median DOR was 9.3 months ALC (95% CI 6.9–not estimable [NE]) and 2.7 months CT (95% CI NE). Adverse events (AEs; all grades) occurred in 77.1% ALC and 85.3% CT, with grade 3–5 AEs in 27.1% and 41.2%, respectively. There was one fatal AE in the CT arm. AEs leading to discontinuation or dose reduction occurred in 10% ALC and 20.6% CT arm.

Conclusions: ALC significantly improved systemic and CNS efficacy, including PFS and ORR, vs CT for previously treated ALK+ NSCLC, with a favourable safety profile vs CT.

Keywords: alectinib, chemotherapy, ALK+, NSCLC

Funding: F. Hoffmann-La Roche Ltd.

Disclosure: J. Wolf: Advisory boards and lecture fees: AstraZeneca, BMS, Boehringer-Ingelheim, Clovis, Lilly, MSD, Novartis, Pfizer, Roche. Research support: BMS, MSD, Novartis, Pfizer, Roche.
J. Mazieres: Honoraria from Novartis, Roche, Pfizer, BMS, MSD.
J. de Castro: Membership on an advisory board: Astra-Zeneca, Boehringer, MSD, Novartis, Pfizer, Roche.
M.R. Migliorino: Honoraria and Advisory board: Bristol Mayer Squibb, Boehringer Ingelheim, MSD, Astra Zeneca.
R. Dziadziuszko: Travel accommodation: Roche. Honoraria: Novartis, Tesaro, Clovis. Honoraria and speakers bureau: Pfizer, Honoraria and consulting role: Boehringer-Ingelheim, Astra-Zeneca, Ignyta
F. Griesinger: Advisory Board and corporate sponsored research: Roche, Astra Zeneca, Lilly, BMS, MSD, Celgene, Boehringer, Pfizer, Novartis.
A. Kotb, A. Cardona, B. Balas, H. Johannsdottir, A. Das-Gupta: Employee of F. Hoffmann-La Roche Ltd.
A. Zeiter: Employee of F. Hoffmann-La Roche Ltd. with stock ownership.
S. Novello: Speaker Bureau: Eli Lilly, BMS, MSD, Astra Zeneca, Roche.
All other authors have declared no conflicts of interest.

Abstract 1298O_PR

Alectinib vs crizotinib in treatment-naïve ALK+ NSCLC: CNS efficacy results from the ALEX study

S. Gadgeel¹, S. Peters², T. Mok³, A.T. Shaw⁴, D.-W. Kim⁵, S.-H.I. Ou⁶, M. Perol⁷, R. Dziadziuszko⁸, J.S. Ahn⁹, R. Rosell¹⁰, A. Zeaiter¹¹, E. Mitry¹¹, E. Nueesch¹¹, B. Balas¹¹, R. Camidge^12
1Medical Oncoloy, University of Michigan, Ann Arbor/UNITED STATES OF AMERICA, ²Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne/SWITZERLAND, ³State Key Laboratory Of South China, Chinese University of Hong Kong, New Territories/HONG KONG PRC, ⁴Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston/UNITED STATES OF AMERICA, ⁵Oncology, Seoul National University Hospital, Seoul/KOREA, REPUBLIC OF, ⁶Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange/UNITED STATES OF AMERICA, ⁷Oncologie, Centre Léon Bérard, Lyon/FRANCE, ⁸Department Of Oncology And Radiotherapy, Medical University of Gdansk, Gdansk/POLAND, ⁹Division Of Hematology-oncology, Departments Of Internal Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul/KOREA, REPUBLIC OF, ¹⁰Medical Oncology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, Badalona/SPAIN, ¹¹Oncology, F. Hoffmann-La Roche Ltd., Basel/SWITZERLAND, ¹²Cancer Center, University of Colorado, Aurora/UNITED STATES OF AMERICA

Background: ALEX phase III study (NCT02075840) of alectinib (ALC) vs crizotinib (CRZ) in treatment-naïve advanced ALK+ NSCLC, met its primary endpoint of improved progression-free survival (PFS). Pts with asymptomatic brain mets at baseline (BL), treated with radiotherapy (RT) or not, were eligible. We present comprehensive CNS efficacy data.

Methods: Pts aged ≥18 years were randomized 1:1 to ALC 600mg or CRZ 250mg (both twice daily) until disease progression (PD), toxicity, withdrawal or death. CNS MRIs were done at BL and every 8 wks in all pts. An Independent Review Committee (IRC) assessed CNS endpoints (RECIST v1.1 and RANO). Endpoints (analysed by subgroup: pts with/without BL CNS disease; pts with/without prior RT) included patterns of PD, CNS objective response rates (CORR), CNS PD and PFS.

Results: Overall, 303 pts were randomised (ALC n=152; CRZ n=151); 122 had BL CNS mets by IRC (ALC n=64 [42%]; CRZ n=58 [38%]), of whom 43 had IRC-assessed measurable lesions (ALC n=21; CRZ n=22); 47/122 pts had received prior RT (ALC n=26 [62% WBRT]; CRZ n=21 [71% WBRT]). Subgroup analyses of PFS and CNS PD are in Table 1. In the CRZ arm first PD was more common in CNS than in non-CNS sites in pts with (CNS PD 57% vs non-CNS PD 24%) and without (CNS PD 38% vs non-CNS PD 20%) CNS mets at BL. In the ALC arm first PD was more common in non-CNS sites in pts without CNS mets at BL (CNS PD 6.8% vs non-CNS PD 28%); first PD in CNS and non-CNS was similar in pts with CNS mets at BL (CNS PD 19% vs non-CNS PD 17%). CORR (RECIST) in pts with measurable CNS mets at BL was ALC 85.7% vs CRZ 71.4% for pts with prior RT and ALC 78.6% vs CRZ 40.0% for pts without RT. In pts with measurable and non-measurable CNS mets at BL, CORR was ALC 36.0% vs CRZ 28.6% for pts with prior RT, and ALC 74.4% vs CRZ 24.3% for those without. Data by RANO criteria will be presented.

Conclusions: ALC showed significantly superior CNS activity vs CRZ in previously untreated advanced ALK+ NSCLC, irrespective of prior RT, and had a protective effect in the CNS. 

Table 1. Subgroup analysis of PFS and CNS PD§

Clinical trial identification: NCT02075840

Keywords: ALK+, NSCLC, CNS, alectinib

Funding: F. Hoffmann-La Roche Ltd.

Disclosure: S. Gadgeel: Consulting fees from Boehringer Ingelheim, ARIAD, Novartis, Genentech, Pfizer and AstraZeneca during the conduct of the study.
S. Peters: Dr. Peters reports grants and personal fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, Roche, Guardant health, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Morphotek, Pfizer, Regeneron and Takeda.
T. Mok: Personal fees: AZ, MSD, Novartis, BI, Pfizer, Roche/Genentech, BMS, Eli Lilly, Eisai, SFJ, Clovis, Taiho, Merck Serono, Celgene, OncoGenex Technologies, ACEA Biosciences, Vertex, Ignyta, Cirina, GeneDecode., Ariad/Tekeda. Stock ownership: Sanomics.
A.T. Shaw: Dr. Shaw reports personal fees from Genentech/Roche, Pfizer, Novartis, Genentech/Roche, Ariad, Ignyta, Daiichi-Sankyo, Taiho, Blueprint Medicines, Loxo, EMD Serono and Foundation Medicine.
S.I. Ou: Personal fees from Pfizer, Roche, Astra Zeneca, ARIAD, Ignyta and Foundation Medicine.
M. Perol: Personal fees from Roche, Lilly, BMS, Novartis, Astra-Zeneca, Boehringer-Ingelheim, Clovis Oncology, Merck, Pfizer, Pierre Fabre, Amgen.
R. Dziadziuszko: Personal fees from Roche, Novartis, Tesaro, Clovis, Pfizer, Boehringer-Ingelheim, Ignyta and Astra-Zeneca.
J.S. Ahn: Personal fees from BMS, Eisai, Janssen, Roche, Menarini and Boehringer Ingelheim.
A. Zeaiter, E. Mitry, E. Nueesch: Full-time employee at F. Hoffmann-La Roche Ltd.
B. Balas: Full-time employee at F. Hoffmann-La Roche Ltd with stock ownership.
R. Camidge: Personal fees from Roche Genetech, Genoptix, G1 Therapeutics, Orion, Clovis, Ariad, Novartis, Celgene, Array, Abbvie and Eli Lilly.
All other authors have declared no conflicts of interest.