(ALK)-positive advanced NSCLC (ALEX study)

Randomised, multicentre, phase III, open-label study of alectinib vs crizotinib in
treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced NSCLC (ALEX study)
1334TiP
Solange Peters,1 Tony Mok,2 Maurice Perol,3 Sai-Hong Ignatius Ou,4 Rafael Rosell,5 Ilze Bara,6 Volkmar Henschel,6 D. Ross Camidge,7 on behalf of the ALEX study investigators
1Lausanne
University Hospital (CHUV), Lausanne, Switzerland; 2State Key Laboratory of Southern China, Hong Kong Cancer Institute, Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China; 3Centre Léon Bérard, Lyon, France;
4University of California Irvine Medical Center, CA, USA; 5Catalan Institute of Oncology, Badalona, Spain; 6F. Hoffmann-La Roche, Basel, Switzerland; 7University of Colorado, Denver, CO, USA
INTRODUCTION AND RATIONALE
STUDY DESIGN AND METHODS
● Non-small-cell lung cancer (NSCLC) is increasingly being characterised into different molecular
subtypes based on mutation profiling, which then allows for individualised therapy. One of the
most established molecular markers is the presence of ALK rearrangements, which are present
in ~5% of cases of advanced NSCLC.1
Phase II data
● The first approved ALK inhibitor, crizotinib, demonstrated strong efficacy versus traditional
chemotherapy in ALK+ NSCLC,2,3 and was approved for use in this population. However, all
patients receiving crizotinib will eventually relapse, often due to secondary ALK mutations or
amplifications (Figure 1),4–6 or progression of central nervous system (CNS) metastases.7–9
● Notably, promising CNS activity was observed in this phase II alectinib study:
Figure 1. Acquired resistance in ALK+ NSCLC treated with crizotinib6
(a)
(b) 1) Emergence of second
oncogenic driver
− of the three patients with no prior CNS radiation, two had PFS of more than 15 months.10
Figure 3. PFS in (a) the intent-to-treat population and (b) patients
with baseline brain metastases in the phase II Japanese study10
2) Emergence of separate
oncogenic driver
Unknown
oncogene/
ALK−
EGFR
9% mut/ALK−
9%
(a)
KRAS
mut/ALK+*
9%
ALK+ and
alternate
oncogene
ALK
ALK CNG
mutation/
9%
CNG
9%
0.6
0.4
PFS (median)
Not reached
1-year PFS rate
83% (95% CI: 68–92)
+ censored,
5
10
10
Patients
*
5
NC
O
N
N
Inside
*Ongoing
0
5
10
15
Duration (months)
Protein kinase domain of ALK
P
ATP
Activation of
signalling
pathways
0
Amino-terminal of EML4
-HCI
CH3
*
History of radiation for brain metastasis
Cell membrane
H C CH3
H 3
N
*
*
*
*
*
*
*
No prior treatment for brain metastasis
Outside
O
20
(b)
Alectinib binds to the tyrosine-kinase domain of ALK, preventing the
binding of ATP and inhibiting autophosphorylation of the ALK receptor
Alectinib
15
Time (months)
Figure 2. Mechanism of action for alectinib
RAS
Proliferation
Phosphate group
P
STAT3
PI3K
Cell survival
Subsequent
therapy
and
survival
follow up
(n≈143)
ECOG PS (0/1 vs 2)
Race (Asian vs non-Asian)
CNS metastases at baseline (yes vs no)
Johnson, et al. ASCO 2013
Shaw, et al. N Engl J Med 2013
Mok, et al. ASCO 2014
Shaw & Engelman. J Clin Oncol 2013
Gainor & Shaw. J Clin Oncol 2013
20
● The first study site was activated in July 2014; the first patient entered the study in August
2014. Initial results are expected in early 2017. PFS will be assessed by investigators at
baseline, week 4, week 8 and every 8 weeks thereafter until progression, death or withdrawal
from the study. PFS will also be corroborated by an independent review committee (IRC).
Statistical considerations
● A primary endpoint of PFS was selected and this was then used to determine the required
sample size for this randomised study, based on the required number of PFS events. The
difference between the two treatment groups will be assessed and tested for the following
hypothesis: the survival distribution function of PFS for the alectinib arm is the same as for the
crizotinib arm, versus the alternative that the two distributions are different.
● At the time that the protocol was being designed, no phase III data were available for crizotinib
in first-line ALK+ NSCLC. Recently, the phase III PROFILE 1014 study reported a median PFS
of 10.9 months for first-line crizotinib.3 This ensured that the ALEX study statistical design does
not require modifications and the determined target hazard ratio (HR) is sufficiently robust to
assess a substantial target magnitude of benefit.
Key inclusion/exclusion criteria
REFERENCES
1.
2.
3.
4.
5.
Crizotinib
250mg BID
● Central randomisation will be performed via an interactive voice or web-based response system
(IxRS) using the stratification factors shown in Figure 4.
95% CI for each probability
0
● Alectinib is a highly selective, CNS-active, oral inhibitor of ALK, which binds to the tyrosinekinase domain of the ALK protein, thereby inhibiting autophosphorylation and controlling the
activation of signalling pathways involved in cell survival and proliferation (Figure 2).
R
1:1
● ALEX (clinicaltrials.gov NCT02075840) is a randomised, active-controlled, multicentre, phase
III, open-label study in patients with treatment-naïve ALK+ advanced NSCLC (Figure 4), to be
conducted in ~180 centres in ~30 countries worldwide.
0.0
Reprinted from Clin Cancer Res, 2012, 18(5), 1472-82, Doebele RC,
Mechanisms of resistance to crizotinib in patients with ALK gene
rearranged non-small cell lung cancer, with permission from AACR
Until PD* or
premature
withdrawal
(e.g. due to
toxicity)
(n≈143)
Study description
N=46
0.2
*One patient with intrinsic resistance is included within this category; CNG = copy number gain
Stratification factors:
Alectinib
600mg BID
*According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
BID = twice daily; ECOG PS = Eastern Cooperative Oncology Group performance status; PD = progressive disease
0.8
Alternate
oncogene
(ALK−)
Eligible patients:
• Advanced or metastatic
ALK+ NSCLC
• Treatment naïve
• ECOG PS 0–2
N≈286
1.0
ALK+
KRAS
mut/ALK−
9%
ALK
mutation
28%
− of the 14 patients with baseline brain metastases, 11 had received prior CNS radiation;
nine of these patients experienced CNS and systemic progression-free survival (PFS) of
more than 12 months (Figure 3b)
PFS probability
ALK+/unknown
mechanism*
18%
● Alectinib demonstrated an objective response rate of 93.5% and a 1-year progression-free rate
of 83% (95% confidence interval (CI): 68–92%) in a phase II trial conducted in 46 crizotinibnaïve Japanese patients with advanced ALK+ NSCLC (Figure 3a).10
Figure 4. ALEX study design
6. Doebele, et al. Clin Cancer Res 2012
7. Chun, et al. Cancer Biol Ther 2012
8. Weickhardt, et al. ASCO 2012
9. Otterson, et al. ASCO 2012
10. Inoue, et al. WCLC 2013
● Patients are eligible for the study if they meet the following criteria:
− aged ≥18 years, with histologically/cytologically confirmed, advanced, recurrent or
metastatic NSCLC and a life expectancy of ≥12 weeks
− ECOG PS of 0–2 and no prior systemic treatment for advanced NSCLC
− adequate haematological and renal function
− available pre-treatment tumour tissue to confirm the presence of ALK rearrangement (by
immunohistochemistry test).
● Key exclusion criteria include prior malignancy within 3 years, active liver disease, any
gastrointestinal disorder that may affect absorption of oral medications, pregnancy/lactation,
history of organ transplant, known sensitivity to any components of the drug formulation, and
baseline QTc >470 ms or symptomatic bradycardia. Prior CNS metastases are permitted if
they are asymptomatic or stable following prior treatment completed ≥14 days before
enrolment.
● The study will be conducted according to the Declaration of Helsinki and good clinical practice
guidelines. All patients must provide written informed consent prior to undergoing any study
procedure.
KEY ENDPOINTS
● Primary endpoint is investigator-assessed PFS (by RECIST v1.1). The targeted
HR for alectinib versus crizotinib is 0.65.
● Secondary endpoints include IRC-assessed PFS, time to CNS progression,
objective response rate and duration of response, overall survival, safety,
pharmacokinetics and quality of life.
● Time to CNS progression will be evaluated in regular scheduled visits using
brain MRI for the first time in a prospective randomised clinical trial in NSCLC
patients
− those with isolated asymptomatic CNS progression will be permitted to
continue treatment beyond that progression until either systemic PD or
symptomatic CNS progression is confirmed by the investigator
− CNS progression and response will be retrospectively assessed by the IRC
using two separate criteria: RECIST and Response Assessment in NeuroOncology (RANO) criteria.
For more information, please contact [email protected]
Support for third-party writing assistance for this poster was provided by F. Hoffmann-La Roche Ltd
39th European Society for Medical Oncology Congress, Madrid, Spain, 26–30 September 2014