1. Evidence-Based Treatment for ALK and ROS1 Rearrangement- Positive NSCLC
Alice T. Shaw, MD, PhD
Associate Professor of Medicine
Harvard Medical School
Director, Center for Thoracic Cancers
Paula O'Keefe Endowed Chair in Thoracic Oncology
MGH Cancer Center/Center for Thoracic Cancers
Massachusetts General Hospital
Boston, Massachusetts
NSCLC, non-small-cell lung cancer.

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3. Faculty Disclosure
Alice T. Shaw, MD, PhD, has disclosed that she has received consulting fees from Ariad, Blueprint Medicines, Daiichi Sankyo, EMD Serono, Genentech, Ignyta, Loxo Oncology, Novartis, Pfizer, Roche, and Taiho.
This slide lists the faculty who were involved in the production of these slides.

4. Case 1: Newly Diagnosed Stage IV NSCLC
45-yr-old female never-smoker nurse with no past medical history
Developed fatigue, trace hemoptysis, and wheezing
CT/PET demonstrated a 2.3-cm left hilar mass, bilateral pulmonary nodules, enlarged subcarinal nodes, and multiple liver masses; brain MRI negative
Bronchoscopy and transbronchial biopsy: undifferentiated high-grade NSCLC
Molecular testing: negative for EGFR/KRAS mutations, ALK-positive
NSCLC, non-small-cell lung cancer.

5. ALK Gene Rearrangements
Most common in younger nonsmokers with adenocarcinoma, adenosquamous carcinoma, and rarely SCC
Frequency: 4% overall, 33% in EGFR-negative never-smokers
Several ALK variants identified in NSCLC
Testing
Vysis break apart FISH (> 15% cells with split signal in 50 nuclei scored); ALK IHC also approved
ALK next generation sequencing
3 agents now approved for ALK-positive NSCLC (first line and/or after progression)
NSCLC, non-small-cell lung cancer; SCC, small-cell carcinoma.
Shaw AT, et al. J Clin Oncol. 2009;27: Soda M, et al. Nature. 2007;448:
Slide credit: clinicaloptions.com

6. PROFILE 1014: First-line Crizotinib vs Pemetrexed/Platinum
PROFILE 1014: First-line Crizotinib vs Pemetrexed/Platinum* in Advanced NSCLC
Phase III trial (N = 343) ALK-positive pts with nonsquamous NSCLC and no prior systemic treatment for advanced disease
Crizotinib
(n = 172)
Chemotherapy
(n = 171)
Median PFS, mos
10.9
7.0
HR (95% CI)
0.45 ( )
P value
< .001
ORR, % 74 45
100 80 60 40 20
Crizotinib
PFS (%)
CT, chemotherapy; NSCLC, non-small-cell lung cancer.
Chemotherapy 5 10 15 20 25 30 35
Pts at Risk, n Crizotinib CT
Mos
*Carboplatin or cisplatin.
65 36
38 12
19 2
7 1
1 0
0 0
Slide credit: clinicaloptions.com
Solomon BJ, et al. N Engl J Med. 2014;371:

7. PROFILE 1014: Select AEs of Any Cause With ≥ 5% Difference Between Treatment Groups
AEs (≥ 20%, Either Arm), n (%)
Crizotinib (n = 171)
Chemotherapy (n = 169)
Any Grade
Grade 3/4
Higher frequency (≥ 5% absolute difference) in crizotinib arm
Vision disorder
122 (71)
1 (1)
16 (9)
Diarrhea
105 (61)
4 (2)
22 (13)
Edemac
83 (49)
21 (12)
Vomiting
78 (46)
3 (2)
60 (36)
5 (3)
Constipation
74 (43)
51 (30)
Elevated transaminases
61 (36)
24 (14)
Higher frequency (≥ 5% absolute difference) in chemotherapy arm
Fatigue
49 (29)
65 (38)
Neutropenia
36 (21)
19 (11)
26 (15)
Stomatitis
34 (20)
2 (1)
Asthenia
41 (24)
Anemia
15 (9)
54 (32)
AE, adverse event.
Slide credit: clinicaloptions.com
Solomon BJ, et al. N Engl J Med. 2014;371:

8. J-ALEX: Alectinib vs Crizotinib as First-line Therapy for ALK-Positive NSCLC
Alectinib (n = 103)
Crizotinib (n = 104)
Events, n (%) Median, mos (95% CI) P value HR ( % CI)
25 (24.3) NR (20.3-NR)
58 (55.8) 10.2 ( )
100
< ( ) 80 60 NR
PFS (%) 40
NR, not reached; NSCLC, non-small-cell lung cancer. 20
10.2 mos 1 3 6 9 12 15 18 21 24 27
Pts at Risk, n Alectinib Crizotinib
Mos
93 86
76 65
49 40
36 21
27 14
9 4 1
Slide credit: clinicaloptions.com
Nokihara H, et al. ASCO Abstract 9007.

9. J-ALEX: Safety
AEs (≥ 20%, Either Arm), n (%)
Alectinib (n = 103)
Crizotinib (n = 104)
All Grade
Grade 3/4
Constipation
36 (35.0)
1 (1.0)
46 (44.2)
Nausea
11 (10.7)
77 (74.0)
2 (1.9)
Diarrhea
9 (8.7)
76 (73.1)
Vomiting
6 (5.8)
60 (57.7)
AST increase
32 (30.8)
5 (4.8)
ALT increase
33 (31.7)
13 (12.5)
Visual disturbance
57 (54.8)
Nasopharyngitis
21 (20.4)
24 (23.1)
Dysgeusia
19 (18.4)
54 (51.9)
Pyrexia
10 (9.7)
21 (20.2)
Decreased appetite
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase;.
8.7% alectinib discontinuations due to AE vs 20.2% for crizotinib
29.1% alectinib dose interruptions due to AE vs 74.0% for crizotinib
Slide credit: clinicaloptions.com
Nokihara H, et al. ASCO Abstract 9008.

10. ASCEND-4: First-line Ceritinib Vs Chemotherapy for ALK-Positive NSCLC
Randomized, global, open-label phase III study
Primary endpoint: PFS
Median DoR of 23.9 mos for pts treated with ceritinib
Median PFS of 26.3 mos for pts without brain metastases at screening treated with ceritinib
Efficacy outcome
Ceritinib
(n = 189)
Chemotherapy
(n = 187) HR
P Value
Median PFS, mos
16.6
8.1
0.55
< .001
ORR, %
72.5
26.7 --
OIRR, %
72.7 (n = 22)
27.3 (n = 22)
DoR, duration of response; NSCLC, non-small-cell lung cancer; OIRR, overall intracranial response rate
Slide credit: clinicaloptions.com
De Castro G, et al. WCLC Abstract PL03.07.

11. Case 2: Progressive ALK-Positive NSCLC
66-yr-old female never-smoker diagnosed more than 3 yrs ago with metastatic ALK-rearranged NSCLC
Brain MRI at diagnosis with 2 tiny brain metastases (2-3 mm)
She was started on first-line crizotinib and responded both systemically and intracranially
However, restaging scans after 7 mos demonstrated worsening bone mets and recurrence of the 2 brain metastases
No symptoms of progressive disease
NSCLC, non-small-cell lung cancer.

12. Response to Ceritinib or Alectinib in Previously Treated ALK-Positive NSCLC
100
Ceritinib
Ceritinib (2014) and alectinib (2015) approved for pts with ALK- positive, metastatic NSCLC with disease progression on or who are intolerant to crizotinib 80 60 PD 40
Change From Baseline in SLDs (%) 20 SD
-20
-40
-60
PR + CR
-80
-100
Alectinib
140
120
Systemic best overall response
100
PD (n = 11) SD (n = 18)
PR (n = 35) 80
NSCLC, non-small-cell lung cancer; PD, progressive disease; SD, stable disease; SLDs, sum of the longest diameters. 60
SLD, Maximum Decrease From Baseline (%) 40 20
-20
-40
-60
-80
-100
Pts
Kim DW, et al. Lancet Oncol. 2016;17: Shaw AT, et al. Lancet Oncol. 2016;17: Ou SH, et al. J Clin Oncol. 2016;34:
Slide credit: clinicaloptions.com

13. Second-Generation ALK Inhibitors
Phase
Prior
Cri?
ORR, %
Median PFS,
Mos
Ceritinib
ASCEND-1[1]
ASCEND-2[2]
ASCEND-3[3]
ASCEND-5 [4]
163 83
140
124
231 I II
III
Yes No
56.0
72.0
38.6
63.7
39.1
6.9
18.4
5.7
11.1
5.4
Alectinib
Shaw[5]
Ou[6] 87
138
48.0
50.0
8.1
8.9
Brigatinib[7]
222
45.0 (90 mg QD)
54.0 (180 mg QD)
15.6 (90 mg QD)
NR (180 mg QD)
Cri, ceritinib; NR, not reached.
1. Kim DW, et al. Lancet Oncol. 2016;17: Mok T, et al. ASCO Abstract Felip E, et al. ASCO Abstract Scagliotti G, et al. ESMO Abstract LBA42_PR. 5. Shaw AT, et al. Lancet Oncol. 2016;17: Ou SH, et al. J Clin Oncol. 2016;34: Kim DW, et al. ASCO Abstract 9007.
Slide credit: clinicaloptions.com

14. Key Treatment-Related AEs Associated With ALK Inhibitors
AE, % (All Grades)
Crizotinib[1]
Ceritinib[2,3]
Alectinib[2,4]
Brigatinib[2,5]
Visual disorders
50-60 NR
Liver dysfunction
35-40
15-35
10-25 15
GI effects
40-60
60-85
10-15
25-40
Edema
20-30
15-25
Fatigue
15-30
40-45
25-30
HTN 21
AE, adverse event; GI, gastrointestinal; HTN, hypertension; NR, not reported.
Predominantly grade 1/2
Visual disorders: median onset < 2 wks
GI effects include diarrhea, nausea, and vomiting
1. Rothenstein JM, et al. Curr Oncol.2014;21: Liao BC, et al. Ther Adv Med Oncol. 2015;7: Kim DW, et al. Lancet Oncol. 2016;17: Ou S, et al. J Clin Oncol. 2016;34: Kim DW, et al. ASCO 2016.Abstract 9007.
Slide credit: clinicaloptions.com

15. Second-Generation ALK Inhibitor CNS Activity
100
*No previous ALK inhibitor. 90 80
75.0%
67.0% 70
63.0%*
58.8%*
57.0% 60
Brain ORR (%) 50
39.4%
39.0% 40
36.0%
36.0% 30 20
CNS, central nervous system. 10
(n = 8)
(n = 28)
(n = 33)
(n = 17)
(n = 16)
(n = 35)
(n = 25)
(n = 18)
(n = 18)
Ceritinib
(750 mg/day)
Alectinib
(600 mg BID)
Brigatinib
(90 or 180 mg QD)
Lorlatinib
(Various)
Kim DW, et al. Lancet Oncol. 2016;17: Mok T, et al. ASCO Abstract Felip E, et al. ASCO Abstract Shaw AT, et al. Lancet Oncol. 2016;17: Ou S, et al. J Clin Oncol. 2016;34: Kim DW, et al. ASCO Abstract Solomon BJ, et al. ASCO Abstract 9009.
Slide credit: clinicaloptions.com

16. Resistance to Second-Generation ALK TKIs
Ceritinib
(N = 24)
Alectinib
(N = 17)
Brigatinib
(N = 6) WT WT WT
TKI, tyrosine kinase inhibitor; WT, wild type.
L1196M
G1202R
E1210K
G1202del
ALK WT
G1269A
I1171T/N/S
F1174C
≥ 2 ALK mutations
C1156Y
S1206Y
V1180L
ALK amplification
Slide credit: clinicaloptions.com
Gainor JF, et al. Cancer Discovery. 2016;6:

17. Lorlatinib Inhibits All Known Crizotinib-Resistance Mutations, Including ALK G1202R
Pt 1: ALK+ NSCLC
Previously treated with crizotinib and ceritinib
Local molecular testing after ceritinib with ALK G1202R
Started lorlatinib at 75 mg QD
Dose reduced to 50 mg QD
Ongoing at > 16 mos
Pt 2: ALK+ NSCLC
Previously treated with crizotinib and brigatinib
Local molecular testing after brigatinib with ALK G1202R
Started lorlatinib at 200 mg QD
Dose reduced to 100 mg QD
Ongoing at > 12 mos
NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com
Shaw AT, et al. ASCO Abstract 8018.

18. Summary: ALK-Driven Disease
All nonsquamous NSCLC should be tested for ALK mutations
Pts tend to develop brain metastases
Crizotinib improves response rate and PFS over chemotherapy in first-line and second-line settings
Second-generation ALK inhibitors ceritinib and alectinib are approved for secondary refractory disease or intolerance to crizotinib
Second-generation ALK inhibitors active in CNS disease
Alectinib demonstrated improved response rate and PFS over crizotinib as first-line therapy (J-ALEX)
Many ALK-positive pts may derive benefit from multiple sequential ALK inhibitors
CNS, central nervous system; NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com

19. Case 3: Newly Diagnosed Stage IV NSCLC
66-yr-old female with history of light smoking (a few cigarettes/day x 20 yrs)
She developed cough, dyspnea, and left lower back pain radiating down the left leg
Chest CT revealed a 6-cm left lower lobe mass, innumerable pulmonary nodules, extensive mediastinal lymphadenopathy; PET scan with extensive metastatic disease
CT-guided biopsy of the lung mass: poorly differentiated NSCLC, favor adenocarcinoma
Molecular testing: EGFR wild type, ALK-negative, ROS1- rearrangement positive; PD-L1 IHC 30%
NSCLC, non-small-cell lung cancer.

20. ROS1 Fusion
Most common in younger pts, never-smokers, adenocarcinoma, high-grade histology[1]
Frequency: 1.2% to 1.7% overall[2]
Several variants identified; clinical significance unknown[3]
FIG-, CD74-, SCL34A2-, TPM3-, SDC4-, EZR-, LRIG3, KDELR2-, and CCDC6-
Testing: Vysis break apart FISH (> 15% cells with split signal in 50 nuclei scored)[4-6]
ROS1 NGS, PCR, IHC (not validated)
Crizotinib highly active; FDA approved in March 2016 for ROS1- positive NSCLC[7]
NSCLC, non-small-cell lung cancer.
1. Bergethon K, et al. J Clin Oncol. 2012;30: Davies KD, et al. Clin Cancer Res. 2012;18: Takeuchi K, et al. Nat Med. 2012;18: Gu TL, et al. PLoS One. 2011;6:e Birch AH, et al. PLoS One. 2011;6:e Lee J, et al. Cancer. 2013;119: Shaw AT, et al. ASCO Abstract 7508.
Slide credit: clinicaloptions.com

21. Activity of Crizotinib in Pts With ROS1 Fusions: Best Overall Response
Pts With NSCLC Who Tested Positive for ROS1 Fusion (N = 50)
100 PD
SD PR CR 80 60
72% ORR
Median PFS: 19.2 mos (95% CI: 14.4-NR) 40 20
Change From Baseline (%)
-20
NR, not reached; PD, progressive disease; SD, stable disease.
-40
-60
-80
-100
Slide credit: clinicaloptions.com
Shaw AT, et al. N Engl J Med. 2014;371:

22. Prolonged PFS With Crizotinib in ROS1-Positive NSCLC
1.0
Median PFS: 19.2 mos
0.8
0.6
Probability of PFS
0.4
NSCLC, non-small-cell lung cancer.
0.2 5 10 15 20 25
Mos
FDA approved in 2016 for ROS1-positive NSCLC
Slide credit: clinicaloptions.com
Shaw AT, et al. N Engl J Med. 2014;371:

23. Summary: ROS1-Driven Disease
All nonsquamous NSCLC should be tested for ROS1 mutations
Crizotinib is highly active in patients with ROS1-positive NSCLC
ORR of approximately 70%
Prolonged PFS
Crizotinib is approved by the FDA for pts with ROS1- positive NSCLC and is the guideline recommended first- line therapy option in this setting
NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com

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