1. Treatment of ALK- and ROS-1 translocated NSCLC
Massimo Di Maio, MD
Department of Oncology, University of Torino

2. Treatment of ALK- and ROS-1 translocated NSCLC
Massimo Di Maio, MD
Department of Oncology, University of Torino

3. Rapid success in a short time: ALK drug development timeline
Chromosomal translocation is the most common ALK abnormality in cancer
EML4-ALK discovered in NSCLC
Crizotinib resistance mechanism reported
Crizotinib US FDA approved for ALK+ NSCLC
Ceritinib US FDA approved for
ALK+, crizotinib-resistant NSCLC
NPM-ALK discovered in ALCL
1994
2007
2010
2011
2014

4. 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;15
Soda M, et al. Nature; 2007;448

5. Testing for ALK translocation: a rule for clinical practice
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.
Kerr KM et al. Second ESMO consensus conference on lung cancer:
pathology and molecular biomarkers for NSCLC.
Ann Oncol 2014 Sep;25(9):

6. Activity of crizotinib in patients with ALK+ NSCLC
Camidge DR et al. Lancet Oncol Oct;13(10):

7. Randomized trial: crizotinib vs chemotherapy as second-line
Shaw AT et al. N Engl J Med 2013;368:

8. Crizotinib vs chemotherapy: impact on QoL
Shaw NEJM; June 2013
Shaw AT et al. N Engl J Med.2013 Jun 20;368(25):
Blackhall F et al. J Thorac Oncol Nov;9(11):

9. Solomon BJ et al. N Engl J Med 2014;371:2167-2177.
Randomized trial: crizotinib vs chemotherapy as first-line
Solomon BJ et al. N Engl J Med 2014;371:

10. Adverse events with crizotinib
Shaw AT et al. N Engl J Med.2013 Jun 20;368(25):

11. 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

12. All patients will eventually experience disease progression
Sharma SV, Settleman J. Genes Dev. 2007;21:
©2007 by Cold Spring Harbor Laboratory Press

13. Summary of crizotinib resistance mechanisms in ALK+ NSCLC
Shaw A T , and Engelman J A JCO 2013;31:

15. 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

16. 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

17. Crizotinib superior to standard chemotherapy
1st Line therapy
2nd Line therapy
PROFILE 1014: Crizotinib vs. Platinum/Pemetrexed
PROFILE 1007: Crizotinib vs. Doc / Pem
ORR: Crizotinib 74% vs. Chemo 45%
ORR: Crizotinib 65% vs. Chemo 20%
…but, of course, this does not mean that patients should never receive chemotherapy
Solomon BJ et al, N Engl J Med 2014;371(23):
Shaw A et al., N Engl J Med 2013; 368(25):

18. 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

19. The role of adding crizotinib to chemotherapy: SWOG 1300
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
R A N D O M I Z E
1:1
crizotinib 250 mg
PO BID daily +
pemetrexed
500 mg/m2 IV d1
re-challenge
crizotinib
250 PO BID
Disease
Progression
N = 108
BIOPSY
Resistance mechanisms and association with benefit
Trial PI: Camidge
Translational Medicine PI: Doebele
Robert Doebele, 2014

20. 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

21. Duration of initial response in patients who continued crizotinib after progression
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 days.
Camidge DR et al. Lancet Oncol Oct;13(10):

22. Crizotinib beyond progression
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 December ; 7(12): 1807–1814.
Gan GN et al, Int J Radiat Oncol Biol Phys March 15; 88(4): 892–898.

23. Stereotactic Radiotherapy for Extra-CNS Oligoprogressive Disease in ALK+ Lung Cancer Patients on Crizotinib
Gan GN et al, Int J Radiat Oncol Biol Phys March 15; 88(4): 892–898.

24. Stereotactic Radiotherapy for Extra-CNS Oligoprogressive Disease in ALK+ Lung Cancer Patients on Crizotinib
Gan GN et al, Int J Radiat Oncol Biol Phys March 15; 88(4): 892–898.

25. In the absence of randomized trials…
Feasibility ?
Efficacy
Selection bias

26. 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

27. ALK Inhibitors in clinical development
Awad MM, Shaw AT. Clin Adv Hematol Oncol Jul;12(7):

28. Response to ceritinib in ALK-translocated advanced NSCLC
Shaw AT et al. N Engl J Med Mar 27;370(13):

29. Ceritinib activity in a crizotinib-resistant patient
Shaw AT et al. N Engl J Med Mar 27;370(13):

30. Progression-free survival for ALK+ NSCLC treated with ceritinib 750 mg/day
Felip E, et al. ECCO/ESMO Madrid 27 September, 2014

31. Future scenario: Ceritinib as first-line option?
Di Maio M et al. Int J Oncol 2014 Aug;45(2):

32. Responses to second generation inhibitors in crizotinib-resistant tumors
Ceritinib (LDK378); phase I
56% ORR1
CNS penetration
Alectinib (CH ); phase I/II
55% ORR2
AP26113; phase I/II
76% ORR3
1Shaw AT et al. N Engl J Med 2014 Mar 27;370(13):
2Gadgeel SM et al, Lancet Oncol 2014 Sep;15(10):
3Camidge R. WCLC MO0706

33. Gadgeel SM et al. Lancet Oncology 2014; 15(10):1119-1128
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):

34. Alectinib in CNS relapses of ALK+ patients previously treated with crizotinib and ceritinib
Gainor JF, et al.
J Thorac Oncol Feb;10(2):232-6.

35. In the next future : Head to head comparison The ALEX study
Alectinib 600mg BID
(n≈143)
Eligible patients:
Advanced or metastatic ALK+ NSCLC
Treatment naïve
ECOG PS 0–2
N≈286
Until PD*, toxicity, withdrawal or death
Subsequent therapy and survival follow up
R 1:1
Crizotinib 250mg BID
(n≈143)
*RECIST v1.1
Primary endpoint:
PFS
Recruitment Status
Recruiting
Estimated Enrollment 
286
Study start date
August 2014
Estimated Completion Date
December 2017
Estimated Primary Completion Date
December 2017
ClinicalTrials.gov Identifier NCT (accessed February 7, 2015)

36. ALK+ Treatment Algorithm*
Crizotinib
Oligoprogressive disease?
Study available? No Y Y N
Yes
Alectinib or
AP26113
S1300
ceritinib
Local ablative
therapy Y
Oligoprogression? N
Study available?
Continue current therapy Y Y N
HSP90
Immunotherapy
Chemo
*Subject to change (rapidly)
Robert Doebele, 2014

37. Treatment of ALK- and ROS-1 translocated NSCLC

38. 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
Charest A. Genes Chromosomes Cancer 2003;37:58-71.
Rikova K. Cell 2007;131:
Gu TL. PLoS One 2011;6(1):e15640.
Lee J. Cancer 2013;119:
Birch AH. PLoS One 2011;6(12): e28250.
Davies KD. Clin Cancer Res 2013;19:
Gainor JF. Oncologist 2013;18:
Bergethon K. J Clin Oncol 2012;30:

39. ALK and ROS1 Encode Related Receptor Tyrosine Kinases
Ron
ROS1
ALK
LTK
PTK7
Brock TG, Receptors and Tyrosine Kinases

40. Response of ROS1 Positive Patients to Crizotinib
Baseline
12 weeks
Bergeron, JCO, 30, 2012.

41. Female 56%, never smokers 78%, adenocarcinoma 98%
50 patients
Median age 53 (range 25-77)
Female 56%, never smokers 78%, adenocarcinoma 98%
Shaw AT et al, N Engl J Med 2014;371:

42. Tumor responses to crizotinib in ROS1-rearranged NSCLC
Overall response rate 72% (6% CR, 66% PR).
Median time to response 7.9 weeks (range, )
Shaw AT et al, N Engl J Med 2014;371:

43. Tumor responses to crizotinib in ROS1-rearranged NSCLC
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)
Shaw AT et al, N Engl J Med 2014;371:

44. […]
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.

45. Crizotinib in ROS1-rearranged NSCLC: European retrospective study
32 patients, mostly pre-treated
Overall response rate: 80%
Disease control rate: 86.7%.
Median PFS: 9.1 months.
Mazieres J et al. J Clin Oncol 2015 Feb 9. [Epub ahead of print]

46. 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.

47. Thanks for your attention!
Massimo Di Maio
Department of Oncology, University of Torino