is nsclc becoming a chronic disease?is nsclc becoming a chronic disease? paul a. bunn, jr, md...
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Is NSCLC Becoming a Chronic Disease?
Paul A. Bunn, Jr, MDDistinguished Professor and Dudley Chair
University of Colorado Cancer CenterAurora, Colorado, United States
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Q1: Which of the following statements regarding EGFR-mutant or ALK-rearranged NSCLC is FALSE?
1. To determine EGFR and ALK status for initial treatment selection, primary tumors or metastatic lesions are equally suitable for molecular testing
2. Deletions in exon 19 and the point mutation of L858R constitute about 90% of all EGFR-activating mutations
3. ORR to first/second generation EGFR TKIs is 60%-70%, but most of the patients progress after 10-13 months of therapy
4. Afatinib compared to chemotherapy significantly improved survival in patients with tumors harboring exon 19 del or L858R mutation
5. The CNS is the most common site of progression in patients with ALK-rearranged NSCLC treated with crizotinib
NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase;ORR, overall response rate; TKI, tyrosine kinase inhibitor; CNS, central nervous system
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Q2: Do you think that for patients diagnosed with metastatic lung adenocarcinoma, testing for EGFR mutations and ALKrearrangements should be performed as part of multiplex next-generation sequencing?
1. Yes2. No; based on currently approved treatment options we
should use recommended companion diagnostic assays
3. Uncertain
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Is NSCLC Becoming a Chronic Disease?Timeline of Historical Milestones in NSCLC Management
Thomas A, et al. Nat Rev Clin Oncol. 2015 May 12 [Epub ahead of print].
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Lindeman NI, et al. J Mol Diagn. 2013;15(4):415-453; Leighl NB et al. J Clin Oncol. 2014 Nov 10;32(32):3673-3679.
Testing for EGFR Mutations and ALKRearrangements Is Now Routine
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2015 Treatment AlgorithmNonsquamous
DriverNonsquamous
No DriverSquamous LCNE
PS 0-3 PS 0-2 PS 0-2 PS 0-21st Line EGFR +
Gefitinib, Erlotinib, AfatinibPlatinum doublet (Pem,Taxane) ±Bevacizumab
Platinum doublet (Gem, Taxane) ±Necitumumab
Etop+ Platinum
ALK/ROS1+CrizotinibBRAF+ Debrafenib/TrametinibRET, MET, HER2, NTRAK+ specific TKI
Maintenance Continue TKI Bev, Pem, ErlotinibOr none
None? Doce, Gem, Erlotinib
None
2nd/3rd Line 2nd/3rd-generation TKI then chemotherapy
NivolumabDoce ± RamucirumabErlotinib
Nivolumab,Doce ± RamErlotinib
CAV, Irinotecan, Taxane, Gem
Determine Performance Status, Histology, and Presence of Driver Mutations
LCNE, Large cell neuroendocrine (LCNE) carcinomas; TKI, tyrosine kinase inhibitor; Pem, pemetrexed; Gem, gemcitabine; Etop, etoposide; Doce, docetaxel; Ram, ramucirumab
Approved in 2015 Not yet approved
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Randomized Trials of EGFR TKI vs Chemotherapy in 1st-Line Therapy
Study ORR,TKI vs CT
PFS,mo
HR
EURTAC1 58% vs 15% 9.7 vs 5.2 0.37OPTIMAL2 83% vs 36% 13.7 vs 4.6 0.16NEJ 0023 74% vs 31% 10.8 vs 5.4 0.32WJTOG 34054 62% vs 32% 9.2 vs 6.3 0.49IPASS5 71% vs 47% 9.8 vs 6.4 0.48LUX LUNG 36 56% vs 23% 11.1 vs 6.9 0.58
LUX LUNG 67 67% vs 23% 11.0 vs 5.6 NR
There are no survival differences in any of the trials presumably because of crossover effects.1. Rosell R, et al. Lancet Oncol. 2012;13(3): 239-246; 2. Zhou C, et al. Lancet Oncol. 2011;12(8):735-742; 3. Maemondo M, et al. N Engl J Med. 2010;362(25):2380-2388; 4. Mitsudomi T, et al. Lancet Oncol. 2010;11(2):121-128; 5. Mok TS, et al. N Engl J Med. 2009;361(10):947-957; 6. Sequist LV, et al. J Clin Oncol. 2013;31(27):3327-3334; 7. Wu YL, et al. Lancet Oncol. 2014;15(2):213-222.
Erlotinib Gefitinib Afatinib
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LUX-Lung 3 and 6 Exploratory Combined OS Analysis: Del19 and L858R
Yang JC, et al. Lancet Oncol. 2015;16(2): 141-151.
Del19
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• Is afatinib better than gefitinib in patients with EGFR mutation?
Advanced NSCLC• Adenocarcinoma• EGFR mut+• First-line treatment• PS 0-1
RANDOMIZE
Afatinib 40 mg qd
Gefitinib 250 mg qd
1
1
N = 264 patients
Sample size increased
to 319
Second- or First-Generation TKI?LUX Lung 7 Randomized Phase IIb Study
National Institutes of Health. www.clinicaltrials.gov/ct2/show/NCT01466660. Accessed 10 August 2015.
Accrual completed!
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RECIST Criteria for Progressiona Signal to Stop the EGFR TKI?
Mok T. Presented at: 11th Annual Targeted Therapies of the Treatment of Lung Cancer; February 23-26, 2011: Santa Monica, California.
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Trials Treating Beyond RECIST ProgressionSu
rviv
al P
roba
bilit
y
Progression-Free Survival Time, Months
1.0
0
0.8
0.6
0.4
0.2
0.010 20 30
PFS1PFS2
11.0 months 14.1 months
Study N PFS1, months PFS2, months
Colorado 25 10 6.2MSKCC 18 19 10
Park K, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 1223O.
Weickhardt AJ, et al. J Clin Oncol. 2012;30(suppl): Abstract 7526; Yu HA, et al. J Clin Oncol. 2012;30(suppl): Abstract 7527.
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RADIANT Trial: DFS and OS for EGFR M+ Subset
DFS OS
Shepard F, et al. J Clin Oncol. 2015;33(suppl): Abstract 7539.
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• ALK (anaplastic lymphoma kinase) is a receptor tyrosine kinase activated by chromosomal rearrangement in NSCLC, leading to constitutive kinase activation and oncogene addiction.
• ALK rearrangements are identified in 3%-7% of lung adenocarcinomas, commonly from younger never-smoking patients, identified by FISH, IHC, or Nex Gen sequencing (NGS). Crizotinib is a potent ALK inhibitor.
ALK Rearrangement in NSCLC
KinaseIC50 (nM)
mean* Selectivity
ratioc-MET 8 –ALK 40-60 5-8X
ROS1 60 7X
ALK EML4
ALK
EML4
EML4
ALK5 5
53
Camidge DR. Clin Cancer Res. 2010;16(22):5581-5590.
3 3
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PROFILE 10011
(N = 143)
PROFILE10052
(N = 259)
PROFILE 10073
(N = 172)
PROFILE10144
(N = 172)Phase 1 2 3 3
Line of therapy Any line 2nd line and beyond
2nd line 1st line
ORR 61% 60% 65% 74%PFS, median (months)
9.7 8.1 7.7 10.9
Survival probability at 12 months
75% NA 70% NA
1. Camidge DR, et al. Lancet Oncol. 2012;13(10):1011-1019. 2. Kim D-W, et al. J Clin Oncol. 2012;30(15S): Abstract 7533. 3. Shaw AT, et al. N Engl J Med. 2013;368(25):2385-2394. 4. Mok T, et al. N Engl J Med , 2014; 371 (23):2167-2177
Crizotinib Studies in ALK-Positive NSCLC
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Previously Untreatedfor Brain Metastasis
(n = 109)
Previously Treated for Brain Metastasis
(n = 166)
No Brain Metastasis Detected(n = 613)
n Outcome n Outcome n Outcome
Target lesions only 4 9% 8 13% 52 21%
Non-target lesions or new lesions (n = 43) (n = 54) (n = 201)
Intracranial (IC)/Brain 30 70% 39 72% 51 25%
Lung 3 7% 6 11% 25 12%
Bone 4 9% 8 15% 25 12%
Liver 2 5% 3 6% 47 23%
Other sites not included in this table
The Brain Is the Most Common Site of Relapse on Crizotinib
Costa DB, et al. J Torac Oncol. 2013;8(Suppl 2): Abstract MO07.02.
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Status ORRPFS,
monthsDR,
monthsCNS Activity
RR
Ceritinib1
(LDK378)Novartis
Approved55%
(N = 163)6.9 7.4
Yes(50%)
Alectinib2
(CH5424802)Roche
Breakthrough therapy
designationPhase II/III
50%(N = 122)
8.9 11.2 Yes
(57%)
Brigatinib3
(AP26113)Ariad
Phase I/II71%
(N = 70)13.4 9.3
Yes(53%)
PF-064639224
Pfizer Phase I/II44%
(N = 34)Most >1 TKI
NR NRYes
(36%)
Next Generation ALK Inhibitors in Crizotinib Resistance
1. Kim D-W, et al. J Clin Oncol 2014;32(5S): Abstract 8003; 2. Ou S-H, et al. J Clin Oncol 2015;33(Suppl): Abstract 8008; 3. Camidge DR, et al. J Clin Oncol 2015;33(Suppl): Abstract 8062; 4. Shaw AT, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8018.
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Crizotinib in ROS1-Rearranged NSCLC
Shaw AT, et al. N Engl J Med , 2014; 371 (21):1963-1971.
PFS
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Crizotinib in MET-Positive NSCLC Low MET,
n = 2Intermediate MET, n = 6
High MET,n = 6
ORR, % (95% CI)b 0 (0–84) 17 (0–64) 67 (22–96)
Best response, n (%)Complete responsePartial responseStable diseaseObjective progression
000
2 (100)
01 (17)4 (67)1 (17)
1 (17)3 (50)1 (17)1 (17)
Median duration of response, weeks (range)c
– 16 73.6(24.1–128.0)
Duration of stable disease, n (%)d
0–<3 months3–<6 months
––
3 (75)1 (25)
01 (100)
ORR, objective response rate
aRECIST v1.0, based on investigator assessmentbComplete response + partial response; CI based on exact F distributioncDescriptive statistics are presented based on all respondersdAmong patients with stable disease as best overall response
Camidge DR, et al. J Clin Oncol. 2014;32(5S): Abstract 8001.
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Early Results With Other Targeted TherapyDriver Alteration Therapy ORR mPFS, months
ALK (1st line) Alectinib 94%** 28**ROS1 (any line) Crizotinib 60% 19.2MET* (any line) Crizotinib 67% 17MET exon14 splice Crizotinib and Cabozantinib 4/5 NR
BRAF (2nd line) Dabrafenib 32% 5.5BRAF (2nd line) Dabrafenib + Trametinib 63% NRHER2 (any line) Dacomitinib 3/26 = 12% 3HER2 (2nd line) Neratinib + Torisel 1/6 NRRET Cabozantinib, Alectinib 2/3 NRRET Many NR NRTRK LOXO101, RXDX101 NA NA
*High MET expression; **First-line Japanese study
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Kris MG, et al. JAMA. 2014;311(19):1998-2006.
Using Multiplexed Assays of Oncogenic Drivers in Lung Cancer to Select Targeted Drugs
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Driver detected –Targeted Rx
Survival by Subgroup
Using Multiplexed Assays of Oncogenic Drivers in Lung Cancer to Select Targeted Drugs
Driver detected –No targeted Rx
No driver
Kris MG, et al. JAMA. 2014;311(19):1998-2006.
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Brahmer J et al. N Engl J Med 2015;373(2):123-135.
Nivolumab vs Docetaxel in 2nd-Line SqCLC: Overall Survival
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Q3: What treatment would you recommend for a 41yo otherwise healthy woman, never smoker, who is diagnosed with symptomatic EGFR mutation−positive (L858R) stage IV lung adenocarcinoma (FDG avidity in left upper lobe, left hilum, ipsilateral mediastinal lymph nodes, and left pleura)? Her PS is 0.
1. First-generation TKI ( eg, erlotinib, gefitinib)2. Second-generation TKI (eg, afatinib)3. Erlotinib + bevacizumab4. Chemotherapy→ erlotinib5. Clinical trial with third-generation TKI