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Treatment of ALK- and ROS-1 translocated NSCLC
Massimo Di Maio, MDDepartment of Oncology, University of Torino
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Treatment of ALK- and ROS-1 translocated NSCLC
Massimo Di Maio, MDDepartment of Oncology, University of Torino
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GYRapid success in a short time:
ALK drug development timeline
1994 2007 2011
NPM-ALK discovered in ALCL
EML4-ALK discovered in NSCLC
Crizotinib US FDA approved for ALK+ NSCLC
2014
Ceritinib US FDA approved for ALK+, crizotinib-resistant NSCLC
2010
Crizotinib resistance mechanism reported
Chromosomal translocation is the most common ALK abnormality in cancer
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Characteristics of ALK translocation in advanced NSCLC
• Patients: younger, non smokers, with adenocarcinoma (or adenosquamous carcinoma; rarely SCC)
• Incidence: ~4% in all patients, up to 33% in EGFR-negative never smokers
• Biology: >15 EML4-ALK variants have been identified in NSCLC. Clinical significance of each variant is unknown.
Shaw AT, ASCO; 2010; Kris MG. ASCO 2011; abstract CRA7506.Rodig SJ, Clin Cancer Res; 2009;15Soda M, et al. Nature; 2007;448
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All non-squamous tumors in patients with advanced / recurrent NSCLC should be tested for EGFR mutation and ALK rearrangement.
Also selected squamous tumours (from patients with minimal or remote smoking history) should strongly be considered for testing.
Testing for ALK translocation:a rule for clinical practice
Kerr KM et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for NSCLC.
Ann Oncol 2014 Sep;25(9):1681-90
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Activity of crizotinib in patients with ALK+ NSCLC
Camidge DR et al. Lancet Oncol. 2012 Oct;13(10):1011-9.
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Randomized trial: crizotinib vs chemotherapy as second-line
Shaw AT et al. N Engl J Med 2013;368:2385-2394.
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Crizotinib vs chemotherapy: impact on QoL
Shaw NEJM; June 2013
Shaw AT et al. N Engl J Med.2013 Jun 20;368(25):2385-94.Blackhall F et al. J Thorac Oncol. 2014 Nov;9(11):1625-33.
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Randomized trial: crizotinib vs chemotherapy as first-line
Solomon BJ et al. N Engl J Med 2014;371:2167-2177.
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Adverse events with crizotinib
Shaw AT et al. N Engl J Med.2013 Jun 20;368(25):2385-94.
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Patient-reported impact on activities of daily living
of visual disturbances with crizotinib
Besse B et al. ESMO 2012 [abstract 1268P] Cappuzzo E et al. Lung Cancer 2015; 87: 89-95
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All patients will eventually experience disease progression
Sharma SV, Settleman J. Genes Dev. 2007;21:3214-3231©2007 by Cold Spring Harbor Laboratory Press
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Shaw A T , and Engelman J A JCO 2013;31:1105-1111
Summary of crizotinib resistance mechanisms in ALK+ NSCLC
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Potential strategies at the time of clinical progression
for ALK-translocated NSCLC
• Switch to chemotherapy
• Add chemotherapy
• Continue crizotinib beyond progression• Local therapies
• Different targeted therapy
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Potential strategies at the time of clinical progression
for ALK-translocated NSCLC
• Switch to chemotherapy
• Add chemotherapy
• Continue crizotinib beyond progression• Local therapies
• Different targeted therapy
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Crizotinib superior to standard chemotherapy
PROFILE 1014: Crizotinib vs. Platinum/Pemetrexed
ORR: Crizotinib 74% vs. Chemo 45%
Solomon BJ et al, N Engl J Med 2014;371(23):2167-77.Shaw A et al., N Engl J Med 2013; 368(25):2385-94
PROFILE 1007: Crizotinib vs. Doc / Pem
1st Line therapy 2nd Line therapy
ORR: Crizotinib 65% vs. Chemo 20%
…but, of course, this does not mean that patients should never receive chemotherapy
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Potential strategies at the time of clinical progression
for ALK-translocated NSCLC
• Switch to chemotherapy
• Add chemotherapy
• Continue crizotinib beyond progression• Local therapies
• Different targeted therapy
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Disease
Progression
The role of adding crizotinib to chemotherapy: SWOG 1300
RANDOMIZE
1:1
crizotinib 250 mg PO BID daily
+ pemetrexed
500 mg/m2 IV d1
pemetrexed 500 mg/m2 IV d1
Eligibility•Non-SCC NSCLC patients with ALK+ tumors (FISH)• Systemic progression on crizotinib after clinical benefit (either ORR or SD ≥ 3 mo.)• Start treatment within 3-30d post-criz• Absent/asymptomatic brain metastases• pemetrexed-naïve
Trial PI: CamidgeTranslational Medicine PI: Doebele
N = 108
re-challengecrizotinib
250 PO BID
BIO
PS
Y
Resistance mechanisms and association with benefit
Robert Doebele, 2014
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Potential strategies at the time of clinical progression
for ALK-translocated NSCLC
• Switch to chemotherapy
• Add chemotherapy
• Continue crizotinib beyond progression• Local therapies
• Different targeted therapy
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who continued crizotinib after progression
Camidge DR et al. Lancet Oncol. 2012 Oct;13(10):1011-9.
69/149 patients had PD at the data cut off.
39 continued crizotinib for at least 2 weeks post PD.
12 of them did that for 6 months. Range of post-PD treatment is 21-591 days.
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Although solid evidence supporting the continuation of crizotinib beyond progression is lacking, in some cases (minimal, asymptomatic progression, or oligoprogression manageable by local therapy), treatment continuation beyond progression could be justified.
Weickhardt AJ et al, J Thorac Oncol. 2012 December ; 7(12): 1807–1814.
Gan GN et al, Int J Radiat Oncol Biol Phys. 2014 March 15; 88(4): 892–898.
Crizotinib beyond progression
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Stereotactic Radiotherapy for Extra-CNS Oligoprogressive Disease
in ALK+ Lung Cancer Patients on Crizotinib
Gan GN et al, Int J Radiat Oncol Biol Phys. 2014 March 15; 88(4): 892–898.
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Stereotactic Radiotherapy for Extra-CNS Oligoprogressive Disease
in ALK+ Lung Cancer Patients on Crizotinib
Gan GN et al, Int J Radiat Oncol Biol Phys. 2014 March 15; 88(4): 892–898.
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Feasibility
Efficacy Selection bias
In the absence of randomized trials…
?
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Potential strategies at the time of clinical progression
for oncogene addicted NSCLC
• Switch to chemotherapy
• Add chemotherapy
• Continue EGFR or ALK TKIs beyond progression• Local therapies
• Different targeted therapy
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ALK Inhibitors in clinical development
Awad MM, Shaw AT. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39.
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Response to ceritinib in ALK-translocated advanced NSCLC
Shaw AT et al. N Engl J Med. 2014 Mar 27;370(13):1189-97.
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Ceritinib activity in a crizotinib-resistant patient
Shaw AT et al. N Engl J Med. 2014 Mar 27;370(13):1189-97.
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Progression-free survival for ALK+ NSCLC treated with ceritinib 750 mg/day
Felip E, et al. ECCO/ESMO Madrid 27 September, 2014
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Future scenario:Ceritinib as first-line option?
Di Maio M et al. Int J Oncol 2014 Aug;45(2):509-15.
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Responses to second generation inhibitors in crizotinib-resistant tumors
• Ceritinib (LDK378); phase I– 56% ORR1
– CNS penetration
• Alectinib (CH5424802); phase I/II – 55% ORR2
– CNS penetration
• AP26113; phase I/II– 76% ORR3 – CNS penetration
1Shaw AT et al. N Engl J Med 2014 Mar 27;370(13):1189-97.2Gadgeel SM et al, Lancet Oncol 2014 Sep;15(10):1119-28.
3Camidge R. WCLC 2013. MO0706
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Activity of alectinib against systemic disease and brain metastases in patients with
crizotinib-resistant ALK-rearranged NSCLC
Gadgeel SM et al. Lancet Oncology 2014; 15(10):1119-1128
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Gainor JF, et al.J Thorac Oncol. 2015 Feb;10(2):232-6.
Alectinib in CNS relapses of ALK+ patients previously treated with crizotinib and ceritinib
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In the next future :Head to head comparison
The ALEX study
Alectinib 600mg BID
(n≈143)
Crizotinib 250mg BID
(n≈143)
Until PD*, toxicity,
withdrawal or death
R1:1
Subsequent therapy
and survival follow up
Eligible patients:
• Advanced or metastatic ALK+ NSCLC
• Treatment naïve
• ECOG PS 0–2
N≈286*RECIST v1.1
ClinicalTrials.gov Identifier NCT02075840 (accessed February 7, 2015)
Recruitment Status Recruiting
Estimated Enrollment 286
Study start date August 2014
Estimated Completion Date December 2017
Estimated Primary Completion Date December 2017
Primary endpoint:• PFS
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ALK+ Treatment Algorithm*
*Subject to change (rapidly)
Crizotinib
Oligoprogressive disease?
Yes
NoStudy available?
ceritinib
Oligoprogression?
Alectinibor
AP26113 Local ablative therapy
S1300
Study available?
HSP90 Immunotherapy Chemo
YY
N
Y
N
NY Y
Continue current therapy
Robert Doebele, 2014
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Treatment of ALK- and ROS-1 translocated NSCLC
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ROS1• ROS1 is activated by chromosomal rearrangement in
several human cancers, including NSCLC, cholangio-carcinoma, gastric cancer, ovarian cancer, and glioblastoma multiforme.1-5
• Rearrangement leads to fusion of a ROS1 portion (including the tyrosine kinase domain) with 1 of 12 different partner proteins.6
• ROS1 rearrangements occur in approximately 1% of NSCLC patients.7
• Similarly to ALK, ROS1 rearrangements are more common in patients who have never smoked or have a history of light smoking and in adenocarcinoma.7,8
1. Charest A. Genes Chromosomes Cancer 2003;37:58-71.2. Rikova K. Cell 2007;131:1190-203.3. Gu TL. PLoS One 2011;6(1):e15640.4. Lee J. Cancer 2013;119:1627-35.
5. Birch AH. PLoS One 2011;6(12): e28250.6. Davies KD. Clin Cancer Res 2013;19:4040-5.7. Gainor JF. Oncologist 2013;18:865-75.8. Bergethon K. J Clin Oncol 2012;30:863-70.
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ALK and ROS1 Encode Related Receptor Tyrosine Kinases
Brock TG, Receptors and Tyrosine Kinaseshttp://www.caymanchem.com/app/template/Article.vm/article/2187
Ron
PTK7
ROS1ALK
LTK
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Response of ROS1 Positive Patients to Crizotinib
Bergeron, JCO, 30, 2012.
Baseline 12 weeks
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Shaw AT et al, N Engl J Med 2014;371:1963-71.
• 50 patients• Median age 53 (range 25-77)• Female 56%, never smokers 78%, adenocarcinoma 98%
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Tumor responses to crizotinib in ROS1-rearranged NSCLC
Shaw AT et al, N Engl J Med 2014;371:1963-71.
Overall response rate 72% (6% CR, 66% PR). Median time to response 7.9 weeks (range, 4.3 - 32.0)
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Tumor responses to crizotinib in ROS1-rearranged NSCLC
Shaw AT et al, N Engl J Med 2014;371:1963-71.
Median duration of response:17.6 months (95%CI 14.5 – not reached)
Median progression-free survival:19.2 months (95%CI 14.4 – not reached)
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[…]The study by Shaw et al. proves that it is possible to conduct trials in small subgroups of patients with NSCLC and demonstrate big results.[…]
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• 32 patients, mostly pre-treated • Overall response rate: 80% • Disease control rate: 86.7%. • Median PFS: 9.1 months.
Crizotinib in ROS1-rearranged NSCLC:European retrospective study
Mazieres J et al. J Clin Oncol 2015 Feb 9. [Epub ahead of print]
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Conclusions
• In the majority of patients with ALK and ROS1 rearrangements, durable clinical responses can be obtained with recently developed targeted agents.
• The availability of these drugs highlights the importance of screening for these genetic alterations in patients with advanced NSCLC.
• Improvement in the management of resistance remains the major challenge in the treatment of these patients.
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Thanks for your attention!
Massimo Di MaioDepartment of Oncology, University of Torino
