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Targeted therapy and immunotherapy in lung cancer
1. Targeted Therapy and
Immunotherapy in Lung Cancer
Dr Alok Gupta
MD, DM,
Consultant Medical Oncologist
Max Super Speciality Hospital, Saket
Ex-Asst. Professor, AIIMS, New Delhi
2. Lung Cancer Remains Major Global Health Burden
ī§ One of the most common cancers and leading cause of
cancer deaths[1,2]
ī§ 5-yr survival rates[3]
ī§ Overall: 18%
ī§ Metastatic: 4%
ī§ 5 new agents received FDA approval in 2015/2016
ī§ Osimertinib, necitumumab, nivolumab, pembrolizumab, alectinib
1. GLOBOSCAN Cancer Fact Sheets. 2012.
2. Siegel RL, et al. CA Cancer J Clin. 2016;66:7-30.
3. National Cancer Institute. Surveillance, Epidemiology, and End Results
program.
3. Therapeutic Decision Making
Histologic
Subtyping
Genotyping for
Predictive Biomarkers
These factors are interlinked and not independent
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Interlinking Themes in Therapeutic Decision Making
for Advanced NSCLC: How we treat?
8. Selection for Molecular Testing in NSCLC
ī§ All pts with an adenocarcinoma
component should be tested[1,2]
ī§ Pure SCC diagnosis is appropriate for
EGFR mutation and ALK testing in some
clinical settings[1]
ī§ Young, never, or light smoker
ī§ Small biopsy specimens
ī§ Next-generation sequencing may be
used to detect a broader array of
mutations and gene rearrangements[3]
ī§ Broad molecular testing is encouraged to
detect a wider range of mutations,
including BRAF V600E mutations[3]
1. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-859.
2. DâAngelo SP, et al. J Clin Oncol. 2011;29:2066-2070.
3. NCCN. Clinical practice guidelines in oncology: non-small-cell lung cancer. v4.2016.
Pack-Yrs[2] EGFR
Mutation,
%
95% CI
Never 52 48-56
1-5 34 25-43
6-10 34 26-44
11-15 18 11-26
16-25 11 7-16
26-50 8 6-11
51-75 9 5-13
> 75 4 2-8
10. Stewart EL, et al. Transl Lung Cancer Res. 2015;4:67-81.
Chan BA, et al. Transl Lung Cancer Res. 2015;4:36-54.
EGFR Mutations: Context
ī§ Found in approximately 10% to 30% of pts with NSCLC
ī§ More common in neversmokers, adenocarcinomas, females,
Asians
ī§ Associated with response to first-, second-, and third-
generation TKIs
ī§ Predominantly located in EGFR exons 18-21
ī§ 85% of EGFR mutations are either deletions in exon 19 or a
single-point mutation in exon 21 (L858R)
ī§ The specific EGFR mutation identified is important
ī§ There are sensitive mutations, primary resistance mutations
(often exon 20), and acquired resistance mutations (T790M)
11. EGFR Mutations in NSCLC
Herbst RS, et al. N Engl J Med. 2008;359:1367-1380.
Sequist LV, et al. J Clin Oncol. 2007;25:587-595
9%
exon 20
variants
3%
codon 719
variants
2%
other
variants
40%
L858R
substitution
46%
exon 19
deletions
12. First-line Treatment With EGFR TKIs vs Chemotherapy in EGFR-
Mutated NSCLC
Study Treatment N Median PFS, Mos Median OS, Mos
Maemondo[1] Gefitinib vs carboplatin/
paclitaxel
230
10.8 vs 5.4
(P < .001)
30.5 vs 23.6
(P = .31)
Mitsudomi[2,3] Gefitinib vs
cisplatin/docetaxel
172
9.2 vs 6.3
(P < .0001)
35.5 vs 38.8
(HR: 1.19)
OPTIMAL[4,5] Erlotinib vs
carboplatin/gemcitabine
165
13.1 vs 4.6
(P < .0001)
22.8 vs 27.2
(HR: 1.19)
EURTAC[6]
Erlotinib vs
platinum-based
chemotherapy
174
9.7 vs 5.2
(P < .0001)
19.3 vs 19.5
(P = .87)
LUX-Lung 3[7,8] Afatanib vs
cisplatin/pemetrexed
345
11.1 vs 6.9
(P = .001)
28.2 vs 28.2
(P = .39)
LUX-Lung 6[8,9] Afatinib vs
cisplatin/gemcitabine
364
11.0 vs 5.6
(P < .0001)
23.1 vs 23.5
(P = .61)
13. Mok TS, et al. N Engl J Med. 2009;361:247-257.
IPASS: First-line Gefitinib vs Paclitaxel/
Carboplatin in Stage IIIB/IV NSCLC
ī§ Open-label phase III trial
ī§ Primary endpoint: PFS
ī§ Secondary endpoints: OS, ORR, quality of life, symptom
reduction, safety
ī§ Study conducted in Asian countries
Previously untreated pts
with stage IIIB/IV
NSCLC,
adenocarcinoma, never
or ex-light smokers,
WHO PS 0-2
(N = 1217)
Up to six
3-wk cycles
Gefitinib 250 mg/day PO
(n = 609)
Paclitaxel 200 mg/m2 IV on Day 1 +
Carboplatin AUC 5-6 mg/mL/min IV on Day 1
(n = 608)
14. Gefitinib vs Paclitaxel/Carboplatin in
Advanced NSCLC: PFS by EGFR Status
ī§ PFS: gefitinib superior to carboplatin/paclitaxel in ITT population
â HR for progression/death: 0.74 (95% CI: 0.65-0.85; P < .001)
ī§ EGFR mutations strongly predicted PFS (and tumor response) to
first-line gefitinib vs carboplatin/paclitaxel
Mok TS, et al. N Engl J Med. 2009;361:947-957.
EGFR Mutation Positive
HR: 0.48
(95% CI: 0.36-0.64; P < .001)
ProbabilityofPFS
Mos Since Randomization
1.0
0.8
0.6
0.4
0.2
0
0 4 8 12 16 20 24
EGFR Mutation Negative
HR: 2.85
(95% CI: 2.05-3.98; P < .001)
ProbabilityofPFS
Mos Since Randomization
1.0
0.8
0.6
0.4
0.2
0
0 4 8 12 16 20 24
Gefitinib
Pac/carbo
Gefitinib
Pac/carbo
15. ī§ Primary endpoint: PFS (interim analysis planned at 88 events)
ī§ Secondary endpoints: ORR, OS, location of progression, safety,
EGFR-mutation analysis, QoL
EURTAC: Erlotinib vs Chemo in EGFR
MutationâPositive, Stage IIIB/IV NSCLC
Pts with no prior
chemotherapy, stage
IIIB/IV NSCLC,
mutated EGFR,*
ECOG PS 0-2
(N = 174â )
PD
PD
Erlotinib 150 mg/day
(n = 86)
Platinum DoubletâĄ
Q3W x 4 cycles
(n = 87)
Stratified by mutation type,*
ECOG PS (0 vs 1 vs 2)
*Exon 19 deletion or exon 21 L858R mutation. â 1227 pts screened; 174 pts with mutated EGFR enrolled;
1 pt withdrawn. âĄCisplatin 75 mg/m2 Day 1/docetaxel 75 mg/m2 Day 1; cisplatin 75 mg/m2 Day 1/
gemcitabine 1250 mg/m2 Days 1, 8; carboplatin AUC = 6 Day 1/docetaxel 75 mg/m2 Day 1; carboplatin
AUC = 5 Day 1/gemcitabine 1000 mg/m2 Days 1, 8.
Rosell R, et al. Lancet Oncol. 2012;13:239-246.
ī§ Randomized, open-label phase III trial
16. PFS in ITT Population
ProbabilityofPS
Erl (n = 86)
Chemotherapy (n = 87)
HR: 0.37 (95% CI: 0.25-0.54;
log-rank P < .0001)
Mos
0 3 6 9 12 15 18 21 24 27 30 33
Pts at Risk, n
Erl 86 63 54 32 21 17 9 7 4 2 2 0
Chemo 87 49 20 8 5 4 3 1 0 0 0 0
1.0
0.8
0.6
0.4
0.2
0
9.75.2
Rosell R, et al. Lancet Oncol. 2012;13:239-246.
17. LUX-Lung 3: Afatinib vs Chemo Improves
PFS in TKI-Naive EGFR-Mutated NSCLC
ī§ Phase III study of afatinib vs cisplatin-pemetrexed in EGFR-mutant
NSCLC adenocarcinoma (N = 345)
Sequist et al, JCO, 2013Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.
Median PFS by del(19) and L858R EGFR Mutation Status
1.0
0.8
0.6
0.4
0.2
0
ProbabilityofPFS
0 3 6 9 12 15 18 21 24 27
Mos
Afatinib
Cisplatin/pemetrexed
(HR: 0.47; 95% CI: 0.34-0.65; P < .001)
Events, n (%)
Median, mos
130 (64)
13.6
61 (59)
6.9
Afatinib
(n = 204)
Cisplatin/Pemetrexed
(n = 104)
18. EGFR TKIs in EGFR-Mutant Metastatic
Lung Adenocarcinoma: 5-Yr PFS and OS
ī§ Pts (N = 137) treated with erlotinib or gefitnib were included
Lin JJ, et al. J Thorac Oncol. 2016;11:556-565.
PFS OS
ProbabilityofPFS
1.0
0.8
0.6
0.4
0.2
0
0 10 20 30 40 50 60
Mos From TKI Initiation
Median PFS: 12.1 mos
ProbabilityofOS
1.0
0.8
0.6
0.4
0.2
0
0 20 40 60 80
Mos From Treatment Initiation
Median OS: 30.9 mos
19. 5-Yr OS in EGFR-Mutated NSCLC Treated
With Either Erlotinib or Gefitinib
ī§ Prolonged survival associated with exon 19 vs exon 18 or
21 deletions
Lin JJ, et al. J Thorac Oncol. 2016;11:556-565.
1.0
0.8
0.6
0.4
0.2
0
ProbabilityofOS
0 20 40 60 80
Mos From Treatment Initiation
HR: 0.55 (P = .001)
Median OS: 23.9, 33.6, 27.0
Exon 18 (n = 4)
Exon 19 (n = 76)
Exon 21 (n = 21)
No extrathoracic mets (n = 79)
Extrathoracic mets (n = 58)
HR: 0.52 (P = .001)
Median OS: 26.7, 41.4
1.0
0.8
0.6
0.4
0.2
0ProbabilityofOS
Mos From Treatment Initiation
0 20 40 60 80
20. Improved QoL With First-line EGFR TKI for EGFR
MutationâPositive NSCLC
ī§ IPASS[1]: Gefitinib vs platinum-based doublet chemotherapy showed
improvement with FACT-L
ī§ NEJ002[2]: Gefitinib vs platinum-based doublet chemotherapy showed
improvement assessed with Care Notebook
ī§ First Signal: Gefitinib vs platinum-based doublet chemotherapy showed
improvement assessed with EORTC QoL C30 and Lung Cancer-13
questionnaires
ī§ OPTIMAL[4]: Erlotinib vs platinum-based doublet chemotherapy showed
improvement in FACT-L and LCS scores
ī§ Lux-Lung-3[5]: Afatinib vs platinum-based doublet chemotherapy
showed statistically significant delay in time to deterioration of cough,
dyspnea; improvement in dyspnea scores, and cognitive, and physical
role functions assessed by EORTC QoL C30 and Lung Cancer-13
questionnaires1. Thongprasert S, et al. J Thorac Oncol. 2011;6:1872-1180. 2. Oizumi S, et al. Oncologist.
2012;17:863-870. 3. Han JY, et al. J Clin Oncol. 2012;30:1122-1128. 4. Chen G, et al. Ann
Oncol. 2013;24:1615-1622. 5. Yang JC, J Clin Oncol. 2013;31:3342-3350.
21. 60
Phase III WJOG 5108L Study: Erlotinib vs
Gefitinib in Previously Treated NSCLC
ī§ Eligible pts had stage IIIB/IV or recurrent adenocarcinoma and
previous chemotherapy; EGFR TKI naive
Urata Y, et al. J Clin Oncol. 2016;[Epub ahead of print].
EGFR MutationâPositive
100
80
40
20
0
0 484236302418126
Mos
PFS(%)
198
203
0
0
3
0
5
1
11
4
17
15
31
38
74
72
143
136
No. at risk
Erlotinib
Gefitinib
Erlotinib
Gefitinib
10.0 (95% CI; 8.5-11.2)
8.3 (95% CI;7.2-9.7)
HR 1.093 (95% CI; 0.879-1.358) P = .424
Median (mos)
22. LUX-Lung 7: PFS With First-line Afatinib
vs Gefitinib in EGFR-Mutated NSCLC
ī§ PFS significantly longer with afatinib vs gefitinib
â Afatinib benefit observed for most subgroups except light exsmokers (smoked < 15
pack-yrs, stopped > 1 yr prior to diagnosis)
*Estimated using exploratory Kaplan-Meier analyses.
Park K, et al. Lancet Oncol. 2016;17:577-589.
Afatinib (n = 160)
Gefitinib (n = 159)
HR: 0.73 (95% CI: 0.57-0.95; P = .017)
Median PFS,
Mos (95% CI)
11.0 (10.6-12.9)
10.9 (9.1-11.5)
12-Mo PFS*,
% (95% CI)
47.4 (39.2-55.2)
41.3 (33.0-49.5)
24-Mo PFS*,
% (95% CI)
17.6 (11.7-24.6)
7.6 (3.5-13.8)
100
80
60
40
20
0
0 6 12 18 24 30 36 42
Mos
Pts(%)
23. Toxicity of EGFR TKIs in NSCLC
ī§ Gefitinib and erlotinib have comparable toxicity
ī§ Afatinib associated with more severe toxicity than gefitinib
or erlotinib
EGFR TKI
ī§ Study
Treatment-Related AEs, %
Diarrhea Rash Paronychia Stomatitis
Gr 1/2 Gr 3/4 Gr 1/2 Gr 3/4 Gr 1/2 Gr 3/4 Gr 1/2 Gr 3/4
Gefitinib
ī§ Mitsudomi
ī§ Maemondo
47
38
1.1
0.9
72
75
2.3
5.3
27
NR
1.2
2.6
19
11
0
0
Erlotinib
ī§ OPTIMAL
ī§ EURTAC
21
44
1
5
48
56
2
12
3
NR
0
NR
10
NR
1
NR
Afatinib
ī§ LUX-Lung 3
ī§ LUX-Lung 6
80
81
14.4
5.4
72
65
16.2
14.6
45
32
11.4
0
63
45
8.7
5.4
Burotto M, et al. Oncologist. 2015;20:400-410.
24. Disease Progression on EGFR TKI in
NSCLC With EGFR Sensitizing Mutations
PD: Clinical characteristics
ī§ Rapid global progression
ī§ Slow growth globally
ī§ Growth in several areas, but not all
PD: Molecular characteristics
ī§ Unknown (other pathways)
ī§ EGFR T790M (exon 20)
ī§ MET amplification
ī§ PIK3CA
Camidge DR, et al. Nat Rev Clin Oncol. 2014;11:473-481.
T790M
~ 40% to 55%
T790M +
EGFR amp
~ 10%
Other
EGFR mut
1% to 2%
SCLC
with
PI3K
~ 4%
SCLC
~ 6%
PIK3CA
~ 1% to 2%
MET amp
~ 5%
BRAF
~ 1%
HER2 amp
~ 8% to 13%
EMT
~ 1% to 2%
Unknown
~ 15% to 20%
25. IMPRESS: Cis/Pem Âą Gefitinib in Stage
IIIb/IV NSCLC With EGFR Mut and PD
ī§ Primary endpoint: PFS
ī§ Secondary endpoints: OS, ORR, DCR, safety/tolerability, QoL
ī§ Exploratory endpoints: biomarkers
ī§ Randomization did not include stratification factors; analyses adjusted
for age (< vs âĨ 65 yrs) and prior gefitinib response (SD vs PR/CR)
Soria JC, et al. Lancet Oncol. 2015;16:990-998.
Cisplatin 75 mg/m2 +
Pemetrexed 500 mg/m2 (⤠6 cycles) +
Gefitinib 250 mg
(n = 133)
Cisplatin 75 mg/m2 +
Pemetrexed 500 mg/m2 (⤠6 cycles) +
Placebo 250 mg
(n = 132)
Pts with stage IIIb/IV
NSCLC, EGFR mutations,
chemo naive, response
âĨ 4 mos with first-line
gefitinib, PD < 4 wks prior to
randomization
(N = 265)
Phase III trial
26. Gefitinib (n = 133)
Placebo (n = 132)
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14
ProbabilityofPFS
Mos Since RandomizationPts at Risk, n
Gefitinib
Placebo
133
132
110
100
88
85
40
39
25
17
12
5
6
4
0
0
IMPRESS: Cis/Pem Âą Gefitinib in Stage
IIIb/IV NSCLC With EGFR Mut and PD: PFS
Soria JC, et al. Lancet Oncol. 2015;16:990-998.
Outcome
Gefitinib
(n = 133)
Placebo
(n = 132)
HR
Median PFS, mos 5.4 5.4 0.86*
(P = .27)ī§ Events, % 74 81
Median OS, mos 14.8 17.2
1.62
(P = .03)
*HR < 1 implies lower risk of progression with gefitinib.
27. Third Generation EGFR TKIs
Agent N RR, %
T790M-
RR, %
T790M+
PFS,
mos
Toxicity
Osimertinib[1] 253 21 61 ~ 8.2 Diarrhea
Rociletinib[2,3] 130 29
(17)
59
(45)
13.1
(6.1)
Hyperglycemia
Olmutinib[4] 62 NR 55 NR Dyspnea/rash
EGF816[5] 53 ī 60 NR Rash
ASP8273[6] 47 ~ 33 61 NR Hyponatremia/
diarrhea
1. Jänne PA, et al. N Engl J Med. 2015;372:1689-1699. 2. Sequist LV, et al.
N Engl J Med. 2015;372:1700-1709. 3. Sequist LV, et al. N Engl J Med.
2016;374:2296-2297. 4. Park K, et al. ASCO 2015. Abstract 8084. 5. Tan
DS, et al. ASCO 2015. Abstract 8013. 6. Goto Y, et al. ASCO 2015. Abstract
8014.
28. 3 Generations of EGFR TKIs
Gefitinib
EGFRm
T790M
Wt
Afatinib Osimertinib
EGFRm EGFRm
T790M
T790M
Wt
Wt
1x
10x
100x
RelativeIC50
Li D, et al. Oncogene. 2008;27:4702-4711. Ranson M, et al. WCLC 2013.
Abstract MO21.12. Moyer JD, et al. Cancer Res. 1997;57:4838-4848.
Kancha RK, et al. Clin Cancer Res. 2009;15:460-467.
Erlotinib
T790M
EGFRm
Wt
29. Osimertinib (AZD9291): Novel EGFR TKI in
EGFR-Mutated NSCLC
ī§ Osimertinib FDA approved (November 2015) for advanced
EGFR T790Mâpositive NSCLC after PD on prior EGFR TKI
â Approval based on AURA and AURA2 single-arm phase II studies
of osimertinib in advanced/metastatic NSCLC with EGFR T790M
â Companion diagnostic test for EGFR mutation also approved
AURA[1]
(N = 201)
AURA2[2]
(N = 210)
ORR, % 61 71 (including 2 CRs)
Disease control rate, % -- 92 at 6 wks
Median PFS, mos Not reached 8.6
Median DOR, mos Not reached 7.8
1. Yang JC, et al. WCLC 2015. Abstract 943.
2. Mitsudomi T, et al. WCLC 2015. Abstract 1406.
30. AURA: Osimertinib Efficacy by EGFR
T790M Status
ī§ Phase I/II trial for pts with EGFR-positive NSCLC with
progression after previous treatment with EGFR TKIs
Median PFS: 2.8 mos Median PFS: 9.6 mos
Jänne PA, et al. N Engl J Med. 2015;372:1689-1699.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
ProbabilityofPFS
T790M positive
T790M negative
Mos
0 3 6 9 12
31. Summary of EGFR MutationâDriven NSCLC
ī§ EGFR sensitizing mutations predict higher response rate, PFS, and
QoL if treated with EGFR TKI first line
ī§ Several approved EGFR TKIs
ī§ Only 2 have been compared head to head
ī§ Specific EGFR mutation is important to know since some predict
resistance to EGFR TKIs (eg. exon 20 insertions)
ī§ Upon progression, postprogression biopsy is important to establish
the mechanism of resistance
ī§ Liquid biopsy is an option
ī§ Osimertinib approved for pts with T790M+ disease
ī§ Other third-generation EGFR TKIs are being investigated
32. ALK Gene Rearrangements
ī§ Most common in younger nonsmokers with adenocarcinoma,
adenosquamous carcinoma, and rarely SCC
ī§ Frequency: 4% overall, 33% in EGFR-negative never-smokers
ī§ Several ALK variants identified in NSCLC
ī§ Testing
ī§ Vysis break apart FISH (> 15% cells with split signal in 50 nuclei
scored); ALK IHC also approved
ī§ ALK next generation sequencing
ī§ 3 agents now approved for ALK-positive NSCLC (first line and/or
after progression)
Shaw AT, et al. J Clin Oncol. 2009;27:4247-4253.
Soda M, et al. Nature. 2007;448:561-566.
33. Crizotinib
(n = 172)
Chemotherapy
(n = 171)
Median PFS, mos 10.9 7.0
HR (95% CI) 0.45 (0.35-0.60)
P value < .001
ORR, % 74 45
P value < .001
PROFILE 1014: First-line Crizotinib vs
Pemetrexed/Platinum* in Advanced NSCLC
ī§ Phase III trial (N = 343) ALK-positive pts with nonsquamous NSCLC
and no prior systemic treatment for advanced disease
Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177.
*Carboplatin or cisplatin.
100
80
60
40
0
20
0 5 10 15 20 25 30 35
PFS(%)
172
171
120
105
65
36
38
12
19
2
7
1
1
0
0
0
Crizotinib
Chemotherapy
Mos
Pts at
Risk, n
Crizotinib
CT
34. Second-Generation ALK Inhibitors
N Phase Prior
Cri?
ORR, % Median PFS,
Mos
Ceritinib
ī§ ASCEND-1[1]
ī§ ASCEND-2[2]
ī§ ASCEND-3[3]
ī§ ASCEND-5 [4]
163
83
140
124
231
I
I
II
II
III
Yes
No
Yes
No
Yes
56.0
72.0
38.6
63.7
39.1
6.9
18.4
5.7
11.1
5.4
Alectinib
ī§ Shaw[5]
ī§ Ou[6]
87
138
II
II
Yes
Yes
48.0
50.0
8.1
8.9
Brigatinib[7] 222 II Yes
45.0 (90 mg QD)
54.0 (180 mg QD)
15.6 (90 mg QD)
NR (180 mg QD)
1. Kim DW, et al. Lancet Oncol. 2016;17:452-63. 2. Mok T, et al. ASCO 2015. Abstract 8059.
3. Felip E, et al. ASCO 2015. Abstract 8060. 4. Scagliotti G, et al. ESMO 2016. Abstract
LBA42_PR. 5. Shaw AT, et al. Lancet Oncol. 2016;17:234-242. 6. Ou SH, et al.
J Clin Oncol. 2016;34:661-668. 7. Kim DW, et al. ASCO 2016. Abstract 9007.
35. Response to Ceritinib or Alectinib in
Previously Treated ALK-Positive NSCLC
ī§ Ceritinib
(2014) and
alectinib
(2015)
approved for
pts with ALK-
positive,
metastatic
NSCLC with
disease
progression on
or who are
intolerant to
crizotinib
Kim DW, et al. Lancet Oncol. 2016;17:452-63. Shaw AT, et al. Lancet Oncol.
2016;17:234-242. Ou SH, et al. J Clin Oncol. 2016;34:661-668. Slide credit: clinicaloptions.com
Pts
Alectinib
SLD,MaximumDecrease
FromBaseline(%)
140
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
Systemic best overall response
PD (n = 11)
SD (n = 18)
PR (n = 35)
Ceritinib
ChangeFromBaseline
inSLDs(%)
100
80
60
40
20
0
-20
-40
-60
-80
-100
PD
SD
PR + CR
36. Lorlatinib Inhibits All Known Crizotinib-
Resistance Mutations, Including ALK G1202R
Pt 1: ALK+ NSCLC
ī§ Previously treated with crizotinib
and ceritinib
ī§ Local molecular testing after
ceritinib with ALK G1202R
ī§ Started lorlatinib at 75 mg QD
ī§ Dose reduced to 50 mg QD
ī§ Ongoing at > 16 mos
Pt 2: ALK+ NSCLC
ī§ Previously treated with crizotinib
and brigatinib
ī§ Local molecular testing after
brigatinib with ALK G1202R
ī§ Started lorlatinib at 200 mg QD
ī§ Dose reduced to 100 mg QD
ī§ Ongoing at > 12 mos
Shaw AT, et al. ASCO 2015. Abstract 8018.
38. Summary: ALK-Driven Disease
ī§ All nonsquamous NSCLC should be tested for ALK mutations
ī§ Pts tend to develop brain metastases
ī§ Crizotinib improves response rate and PFS over
chemotherapy in first-line and second-line settings
ī§ Second-generation ALK inhibitors ceritinib and alectinib are
approved for secondary refractory disease or intolerance to
crizotinib
ī§ Second-generation ALK inhibitors active in CNS disease
ī§ Alectinib demonstrated improved response rate and PFS over
crizotinib as first-line therapy (J-ALEX)
ī§ Many ALK-positive pts may derive benefit from multiple
sequential ALK inhibitors
39. ROS1 Fusion
ī§ Most common in younger pts, never-smokers,
adenocarcinoma, high-grade histology[1]
ī§ Frequency: 1.2% to 1.7% overall[2]
ī§ Several variants identified; clinical significance
unknown[3]
ī§ FIG-, CD74-, SCL34A2-, TPM3-, SDC4-, EZR-, LRIG3,
KDELR2-, and CCDC6-
ī§ Testing: Vysis break apart FISH (> 15% cells with split
signal in 50 nuclei scored)[4-6]
ī§ ROS1 NGS, PCR, IHC (not validated)
ī§ Crizotinib highly active; FDA approved in March 2016
for ROS1-positive NSCLC[7]
40. Activity of Crizotinib in Pts With ROS1
Fusions: Best Overall Response
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeFromBaseline(%)
PD
SD
PR
CR
Pts With NSCLC Who Tested Positive for ROS1 Fusion (N = 50)
Slide credit: clinicaloptions.com
100
72% ORR
Median PFS: 19.2 mos
(95% CI: 14.4-NR)
Shaw AT, et al. N Engl J Med. 2014;371:1963-1971.
41. 1.0
Prolonged PFS With Crizotinib in ROS1-
Positive NSCLC
0
ProbabilityofPFS
0 5 10 15 20 25
Mos
FDA approved in 2016 for ROS1-positive NSCLC
0.8
0.6
0.4
0.2
Median PFS: 19.2 mos
Shaw AT, et al. N Engl J Med. 2014;371:1963-1971. Slide credit: clinicaloptions.com
42. Summary: ROS1-Driven Disease
ī§ All nonsquamous NSCLC should be tested for ROS1
mutations
ī§ Crizotinib is highly active in patients with ROS1-positive
NSCLC
ī§ ORR of approximately 70%
ī§ Prolonged PFS
ī§ Crizotinib is approved by the FDA for pts with ROS1-
positive NSCLC and is the guideline recommended first-
line therapy option in this setting
43. MET Exon 14 Mutations in NSCLC
ī§ Associated with advanced age (older than KRAS
or EGFR mutations)
ī§ In one series, 68% were female and 36%
nonsmokers; majority had adenocarcinoma or
adenocarcinoma with pleomorphic or
sarcomatoid histology
ī§ Frequency: 3% overall; 26% in sarcomatoid
pulmonary carcinoma
ī§ Testing: PCR or NGS
ī§ Therapy: MET inhibitors
45. BRAF-Mutant NSCLC
ī§ More common in current and former smokers,
females
ī§ Primarily in adenocarcinoma; other histologies
rarely described
ī§ Frequency: 2% to 4%
ī§ BRAF V600E mutations account for 50% of all BRAF
mutations (lower than incidence in melanoma)
ī§ Testing: PCR
ī§ Therapy: BRAF inhibitors, single agent or in
combination with a MEK inhibitor
46. Dabrafenib + Trametinib: Best Confirmed Response
in īŗ Second Line
ī§ Clinically meaningful antitumor activity with a higher ORR when compared indirectly with dabrafenib
monotherapy in BRAF V600Eâmutated NSCLC
ī§ ORR 63% and DCR 75% for dabrafenib plus trametinib
ī§ ORR 33% and DCR 56% for dabrafenib as monotherapy
40
20
0
-20
-40
-60
-80
-100
MaximumReductionFrom
BaselineMeasurement(%)
Best confirmed response
CR
PR
SD
PD
Not evaluable
Pt
47. RET Fusion
ī§ Most common in adenocarcinoma and adenosquamous
carcinoma, never or former smokers, poorly differentiated
tumors, earlier LN metastases[1,2]
ī§ Frequency: 1.4% overall; increasing in nonsmokers without
other mutations[2,4]
ī§ Several variants identified in NSCLC[4]
ī§ Testing
ī§ Vysis break apart FISH (> 15% cells with split signal in 50 nuclei scored)
ī§ RET PCR (NGS)
ī§ Multikinase inhibitors with RET activity: vandetinib, sorafenib,
sunitinib, cabozantinib
48. Median PFS: 7 mos
Median DoR: 8 mos (range: 5.5-26)
Drilon AE, et al. ASCO 2015. Abstract 8007.
Cabozantinib in RET-Rearranged NSCLC: Response
30
0
-30
-60
-90
Confirmed PR
SD
Best Response % (n)
PR 44 (7/16)
Confirmed
unconfirmed
38 (6/16)
6 (1/16)
SD 56 (9/16)
ORR 38% (95% CI: 15-65)
ORR12 wks 36% (95% CI: 13-65)
(5 PRs of 14 evaluable at 12 wks)
ChangeFromBaseline(%)
49. Neurotrophic Tyrosine Kinase (NTRK) and
Tropomysin-Related Kinases A, B, C
ī§ TrkA, TrkB, and TrkC: receptor tyrosine kinases
encoded by NTRK1, NTRK2, NTRK3 genes
ī§ Implicated in neuronal development
ī§ Mutations or fusions in TK domain lead to
constitutive activation
ī§ Several fusions described in lung cancer primarily
involving NTRK1 and NTRK2
Barbacid M. J Neurobiol. 1994;25:1386-1403. Vaishnavi A, et al. Nature Med.
2013;19:1469-1472. Farago J, et al. J Thorac Oncol. 2015;10:1670-1674.
50. Baseline
Day 26:
-47% response
Day 155:
-77% response
Clinical Response to Entrectinib
NTRK1-Rearranged NSCLC
Farago J, et al. J Thorac Oncol. 2015;10:1670-1674.
51. Conclusions for targeted therapy
ī§ For pts with stage IV NSCLC and adenocarcinoma
component, molecular testing is the standard of care
ī§ FDA-targeted agent approvals for treatment of
metastatic NSCLC
ī§ ALK rearrangement: crizotinib, ceritinib, alectinib
ī§ EGFR mutation: afatinib, erlotinib, gefitinib, osimertinib
ī§ ROS1 rearrangement: crizotinib
ī§ Encourage broad molecular testing for pts without ALK,
EGFR, or ROS1 mutations
53. Immune System Function and Response
ī§ Nonspecific
ī§ First line of defense
ī§ WBCs (natural
killer cells, neutrophils)
ī§ Activation of adaptive
immunity
ī§ Specific target recognition
ī§ Slower to develop
ī§ Ab or cell mediated
ī§ Memory for faster, stronger
subsequent responses
Innate Immunity Adaptive Immunity
Identify and destroy foreign or abnormal cells in the body
Dranoff G. Nat Rev Cancer. 2004;4:11-22.
54. Adaptive Immune System: T Cells
ī§ 4 main types of T cells
ī§ Helper T cells (CD4+)
ī§ Cytotoxic T cells (CD8+)
ī§ Suppressor T cells (CD4+ Foxp3+ CD25+ Tregs)
ī§ Memory T cells (CD4+ and CD8+ cells)
55. T-Cell Response: First Signal
Adapted from: Snyder A, et al. Curr Opin Genet Dev. 2015;30:7-16.
Tumor
CD8+ T cell
T-cell receptor
Class I MHC
Tumor
antigen
CD4+ T cell
Antigen-
presenting cell
Tumor
antigen
T-cell receptor
Class II MHC
56. The Cancer Immunity Cycle
1
2
3
4
5
6
Release of cancer
cell antigens
(cancer cells)
Antigen
presentation
(DCs, APCs)
Priming and
activation
(DCs, T cells)
Trafficking
to tumors
(CTLs)
Tumor
infiltration
(CTLs,
endothelial cells)
Recognition
(CTLs, cancer cells)
Killing of cancer cells
(CTLs, cancer cells)
7
ÎąCTLA-4
ÎąPD-1
Reprinted from Immunity 39(1). Chen DS, et al. Oncology meets immunology: the cancer-immunity cycle. p. 1-10.
Copyright 2013, with permission from Elsevier.
57. Focus on Actionable Immune Synapse
Ribas A. N Engl J Med. 2012;366:2517-2519.
Spranger S, et al. J Immunother Cancer. 2013;1:16.
Effector Phase
Tumor Microenvironment
PD-1 Pathway
Tumor
PD-L1
PD-L2
PD-1
Cytotoxic
T cell
MHC
TCR Antigen
58. History of Cancer Immunotherapy:
Key Milestones
IFN-Îą as adjuvant
therapy for melanoma[2]
Immune component
to spontaneous
regressions in
melanoma
Adoptive T-cell
immunotherapy
IL-2 approved
for RCC and
melanoma (US)[3,4]
First immunotherapy
approved for prostate
cancer (sipuleucel-T)[8]
First checkpoint
inhibitor (ipilimumab)
approved for advanced
melanoma[9]
2000s
First tumor-associated antigen
cloned (MAGE-1)
BCG
approved
for bladder
cancer
Discovery of checkpoint
inhibitors[5-7]
Discovery of
dendritic cell[1]
Tumor-specific
monoclonal Abs
Pembrolizumab and
nivolumab approved for
advanced melanoma[10,11]
1970s 1980s 1990s 2011 2014 2015
Nivolumab
approved for
NSCLC[12,13]
Pembrolizumab
approved for
PD-L1+ NSCLC[14]
Nivolumab
approved
for RCC[15]
References in slidenotes.
2016
Atezolizumab
granted
Priority Review for
PD-L1+ NSCLC
Atezolizumab approved
for advanced urothelial
carcinoma[16]
Nivolumab
approved
for HL[17]
63. CheckMate-057: Nivolumab vs Docetaxel
in R/R Nonsquamous NSCLC
ī§ FDA expanded approval (10/15) of nivolumab to nonsquamous NSCLC
PD on/after platinum-based chemo with data from CheckMate-057
ī§ Primary endpoint: OS
ī§ Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL
Borghaei H, et al. N Engl J Med. 2015;373:1627-1639.
Pts with stage IIIB/IV
nonsquamous NSCLC and
ECOG PS 0-1 who failed 1
prior platinum doublet
chemotherapy Âą TKI therapy
(N = 582)
Nivolumab 3 mg/kg IV Q2W
(n = 292)
Docetaxel 75 mg/m2 IV Q3W
(n = 290)
Until disease
progression or
unacceptable
toxicity
Stratified by previous maintenance
therapy (yes vs no) and line of
therapy (second vs third line)
64. Median OS, Mos
Nivo 10.4
Doc 10.1
Median OS, Mos
Nivo 17.2
Doc 9.0
Median OS, Mos
Nivo 9.9
Doc 10.3
Median OS, Mos
Nivo 19.4
Doc 8.0
Median OS, Mos
Nivo 18.2
Doc 8.1
Median OS, Mos
Nivo 9.7
Doc 10.1
Nivo
Doc
Nivo
Doc
100
90
80
70
60
50
40
30
10
0
20
Mos
24211815129630 27
Mos
24211815129630 27
âĨ 5% PD-L1 Expression Level
< 5% PD-L1 Expression Level
âĨ 1% PD-L1 Expression Level
HR: 0.59 (95% CI: 0.43-0.82)
< 1% PD-L1 Expression Level
OS(%)
HR: 0.90 (95% CI: 0.66-1.24)
HR: 0.43 (95% CI: 0.30-0.63)
HR: 1.01 (95% CI: 0.77-1.34)
OS(%)
Mos
âĨ 10% PD-L1 Expression Level
< 10% PD-L1 Expression Level
HR: 0.40 (95% CI: 0.26-0.59)
HR: 1.00 (95% CI: 0.76-1.31)
24211815129630 27
24211815129630 27
24211815129630 2724211815129630 27
100
90
80
70
60
50
40
30
10
0
20
Paz-Ares L, et al. ASCO 2015. Abstract LBA109.
CheckMate-057: OS With Nivolumab in
Nonsquamous NSCLC by PD-L1 Expression
65. CheckMate 057: Effect of Nivo on OS in
Predefined Subgroups
0
Nivolumab Docetaxel
1 2All randomized pts (Nivo, n = 292; Doc, n = 290). HR was not
computed for other subsets with fewer than 10 pts per treatment group.
Borghaei H, et al. N Engl J Med. 2015;373:1627-1639.
Unstratified HR (95% CI)
0.75 (0.62-0.91)
0.81 (0.62-1.04)
0.63 (0.45-0.89)
0.90 (0.43-1.87)
0.73 (0.56-0.96)
0.78 (0.58-1.04)
0.64 (0.44-0.93)
0.80 (0.63-1.00)
0.70 (0.56-0.86)
1.02 (0.64-1.61)
1.18 (0.69-2.00)
0.66 (0.51-0.86)
0.74 (0.51-1.06)
N
582
339
200
43
319
263
179
402
458
118
82
340
160
Subgroup
Overall
Age categorization (yrs)
< 65
âĨ 65 and < 75
âĨ 75
Sex
Male
Female
Baseline ECOG PS
0
1
Smoking status
Current/former smoker
Never-smoker
EGFR mutation status
Positive
Not detected
Not reported
66. CheckMate 017: Nivolumab vs Docetaxel
in Previously Treated Squamous NSCLC
ī§ International, open-label, randomized phase III trial
ī§ Primary endpoint: OS
ī§ Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression,
safety, QoL
Brahmer J, et al. N Engl J Med. 2015;373:123-135.
Stage IIIB/IV squamous NSCLC
with failure of 1 previous
platinum-containing regimen;
ECOG PS 0-1;
pretreatment (archival or recent)
tumor sample required for
PD-L1 analysis
(N = 272)
Nivolumab 3 mg/kg IV Q2W
(n = 135)
Docetaxel 75 mg/m2 IV Q3W
(n = 137)
Until disease
progression or
unacceptable
toxicity
67. CheckMate 017: OS
ī§ Minimum follow-up for survival: 18 mos
0614253751576986113135 0Nivolumab
Pts at Risk, n
037111722334669104137Docetaxel 1
Docetaxel18-mo OS rate: 13%
OS(%)
Mos
Nivolumab
18-mo OS rate: 28%
100
90
80
70
60
50
40
30
10
0
20
332724211815129630 30
12-mo OS rate: 42%
12-mo OS rate: 24%
Reckamp K, et al. WCLC 2015. ORAL02.01.
Nivolumab (n = 135)
Docetaxel (n = 137)
HR: 0.62 (95% CI: 0.48-0.81; P = .0004)
Median OS,
Mos (95% CI)
9.2 (7.33-12.62)
6.0 (5.29-7.39)
Events,
n
103
122
68. KEYNOTE-010: Pembrolizumab vs Docetaxel in
Previously Treated PD-L1+ NSCLC
ī§ Primary endpoints*: PFS, OS
ī§ Secondary endpoints: ORR, DoR, safety
Pts with advanced NSCLC PD
after âĨ 2 cycles of platinum-
doublet chemotherapy,
PD-L1 TPS âĨ 1%, ECOG PS 0-1,
no brain metastases
(N = 1034)
Pembrolizumab 2 mg/kg Q3W
for 24 mos
(n = 345)
Docetaxel 75 mg/m2 Q3W
per local guidelines
(n = 343)
Pembrolizumab 10 mg/kg Q3W
for 24 mos
(n = 346)
Stratified by ECOG PS (0 vs 1),
region (east Asia vs not), PD-L1
TPS (âĨ 50% vs 1% to 49%)
*In both the PD-L1 TPS
âĨ 1% and âĨ 50% populations.
Herbst RS, et al. Lancet. 2016;387:1540-1550.
69. KEYNOTE-010: OS
ī§ All pts experienced OS benefit from pembrolizumab
PD-L1 TPS âĨ 50%PD-L1 TPS âĨ 1%
100
80
60
40
20
0
50 10 15 20 25
OS(%)
Mos
100
80
60
40
20
0
50 10 15 20 25
OS(%)
Mos
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Docetaxel
Treatment Arm
Median OS,
Mos (95% CI) 1-Yr OS, %
HR vs Docetaxel
(95% CI); P Value
Pembro 2 mg/kg 10.4 (9.4-11.9) 43.2 0.71 (0.58-0.88); .0008
Pembro 10 mg/kg 12.7 (10.0-17.3) 52.3 0.61 (0.49-0.75); < .0001
Docetaxel 8.5 (7.5-9.8) 34.6 â
Treatment Arm
Median OS,
Mos (95% CI)
HR vs Docetaxel
(95% CI); P Value
Pembro 2 mg/kg 14.9 (10.4-NR) 0.54 (0.38-0.77); .0002
Pembro 10 mg/kg 17.3 (11.8-NR) 0.50 (0.36-0.70); < .0001
Docetaxel 8.2 (6.4-10.7) â
HR, 2 vs 10 mg/kg: 1.17
(95% CI: 0.94-1.45)
HR, 2 vs 10 mg/kg: 1.12
(95% CI: 0.77-1.62)
Herbst RS, et al. Lancet. 2016;387:1540-1550.
70. Atezolizumab vs Docetaxel in NSCLC
(POPLAR): All-Comer Phase II Study
Atezolizumab
1200 mg IV Q3W
until loss of clinical benefit
(n = 144)
Docetaxel
75 mg/m2 IV Q3W
until PD
(n = 143)
ī§ Primary objective
Ėļ Estimate OS by PD-L1
expression
ī§ Secondary objectives
Ėļ Estimate PFS, ORR,
DoR by PD-L1
expression
Ėļ Evaluate safety
Metastatic or locally
advanced NSCLC
(2nd/3rd line),
PD on prior
platinum-based tx
(N = 287)
Stratified by PD-L1 IHC expression
(0 vs 1 vs 2 vs 3), histology
(squamous vs nonsquamous),
prior chemotherapy regimens (1 vs 2)
Spira AI, et al. ASCO 2015. Abstract 8010.
71. POPLAR: Atezolizumab vs Docetaxel in
NSCLC Updated OS, Biomarker Analyses
Atezolizumab Docetaxel
HR
(95% CI)
P Valuen Median OS,
Mos
n Median OS,
Mos
ITT 144 12.6 143 9.7
0.69
(0.52-0.92)
.011
Smith DA, et al. ASCO 2016. Abstract 9028.
TC3 or IC3 24 Not reached 23 11.1
0.45
(0.22-0.95)
.033
TC2/3 or IC2/3 50 15.1 55 7.4
0.50
(0.31-0.80)
.003
TC1/2/3 or IC1/2/3 93 15.1 102 9.2
0.59
(0.41-0.83)
.003
TC0 and IC0 51 9.7 41 9.7
0.88
(0.55-1.42)
.601
Squamous 49 10.1 48 8.6
0.66
(0.41-1.05)
.075
Nonsquamous 95 14.8 95 10.9
0.69
(0.49-0.98)
.039
72. Pembrolizumab vs CT as First-line
Therapy for Adv NSCLC (KEYNOTE-024)
ī§ Primary endpoint: PFS
ī§ Secondary endpoints: ORR, OS, and safety
Pts with stage IV NSCLC
and ECOG PS 0/1, no
previous systemic
therapy, no actionable
EGFR/ALK mutations,
and PD-L1 TPS âĨ 50%*
(N = 305)
Pembrolizumab 200 mg IV Q3W
for up to 35 cycles
(n = 154)
Chemotherapy (histology
based) for up to 6 cycles
(n = 151)
Until PD or
unacceptable
toxicity
Stratified by ECOG PS (0 vs 1),
histology (squamous vs nonsquamous),
and enrollment region
Reck M, et al. N Engl J Med. 2016;[Epub ahead of print].
Until PD
(crossover to
pembrolizumab
allowed)
*âĨ 50% tumor cell staining using 22C3 companion diagnostic IHC assay.
73. KEYNOTE-024: Survival Outcomes
Reck M, et al. N Engl J Med. 2016;[Epub ahead of print].
PFS OS
Mos
PFS(%)
100
80
60
40
20
0
180 3 6 9 12 15
Pts at Risk, n
Pembrolizumab
Chemotherapy
154
151
104
99
89
70
44
18
22
9
3
1
1
0
HR for PFS: 0.50 (95% CI: 0.37-0.68;
P < .001)
Mos
OS(%)
100
80
60
40
20
0
210 3 6 9 12 15
154
151
136
123
121
106
82
64
39
34
11
7
2
1
Pembrolizumab
Chemotherapy
HR for OS: 0.60 (95% CI: 0.41-0.89;
P = .005)
0
0
18
6.0
10.3
74. Nivolumab vs CT as First-line Therapy for
Advanced NSCLC (CheckMate-026)
ī§ Primary endpoint: PFS (âĨ 5% PD-L1 positive)
ī§ Secondary endpoints: PFS (âĨ 1% PD-L1 positive),
ORR, OS
Pts with stage IV/recurrent
NSCLC, no previous systemic
therapy, no actionable
EGFR/ALK mutations, PD-L1
expression âĨ 1%
(N = 541)
Nivolumab 3 mg/kg IV Q2W
(n = 271)
Chemotherapy (histology
based) for up to 6 cycles
(n = 270)
Until PD or
unacceptable
toxicity
Stratified by PD-L1 expression (< 5%
vs âĨ 5%) and histology (squamous vs
nonsquamous)
Socinski M, et al. ESMO 2016. Abstract LBA7_PR.
Until PD (crossover
to nivolumab
allowed)
75. CheckMate-026: PFS by IRRC in Pts With âĨ
5% PD-L1 Expression
Socinski M, et al. ESMO 2016. Abstract LBA7_PR.
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27
Mos
PFS(%)
Nivolumab
Chemotherapy
Pts at Risk, n
Nivolumab
CT
211
212
104
144
71
74
49
47
35
28
24
21
6
8
3
1
1
0
0
0
Median PFS, mos
(95% CI)
1-yr PFS rate, %
Nivolumab
(n = 211)
CT
(n = 212)
4.2
(3.0-5.6)
23.6
5.9
(5.4-6.9)
23.2
77. Time to Onset of First Treatment-Related
Select AE With Nivolumab (Any Grade)
ī§ Majority of treatment-related AEs occurred within first
3 mos of treatment
Reckamp K, et al. WCLC 2015. ORAL02.01.
0
1
2
3
4
5
6
7
8
9
10
0-3 > 3-6 > 6-12 > 12-24
Mos
Skin
Gastrointestinal
Pulmonary
Endocrine
Renal
Hypersensitivity/infusion reaction
Hepatic
NumberofPtsWithFirstEvent
inCategory
Pts still on study, n
Pts still on treatment, n
Total pts with first event, n
131
131
24
112
73
6
85
51
2
52
25
1
78. Clinical Perspectives: First-line Immunotherapy for
NSCLC
ī§ Pembrolizumab is a recently approved standard of care for some pts
with newly diagnosed metastatic NSCLC
ī§ PD-L1 positive (âĨ 50% tumor cell staining) with FDA approved
assay using mAb 22C3
ī§ No EGFR, ALK, or ROS1 genetic aberrations
ī§ Combination first-line therapy with pembrolizumab + chemotherapy
appears promising
ī§ Multiple ongoing phase III trials are evaluating the combination
of checkpoint blockade + chemotherapy in the first-line setting
79. Thank You
Dr Alok Gupta MD, DM,
Consultant Medical Oncologist
Max Super Speciality Hospital, Saket
Phone No. 9167164364
Email: alokgupta16@yahoo.co.in