current standards and practice changing studies in ... · ramalingam, esmo 2018. impower 150: oas...
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:
Current standards and practice changing studies
in metastatic NSCLC with actionable mutations
Rolf Stahel
Comprehensive Cancer Center Zürich
1 |
Kazan, June 11, 2019
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Disclosures
Consultant or Advisory Role in the last two years
I have received honoraria as a consultant at advisory boards from Abbvie,
AstraZeneca, Boehringer Ingelheim, MSD, Pfizer, Roche and Takeda.
Speaker Honoraria in the last two years
I have received honoraria as a speaker from Astra Zeneca, Boehringer
Ingelheim, Lilly, MSD and Roche.
DMC in the last two years
Roche and Takeda
Financial Support of ETOP trials (president and scientific chair)
AstraZeneca, BMS, Boehringer Ingelheim, Genentech, MSD, Roche, and
Pfizer.
2 |
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CapmatinibTepotiib
NSCLC with oncogenic driver mutations: current status3 |
Activating
mutations
Amplifications
and/or
mutations
Entectinib
Loxo-292BLUE-667
Larotrectinib
Gene
translocatons
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4 |
Planchard, updated ESMO guidelines 2019
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A phase II study of pembrolizumab in EGFR-mutant, PD-L1+,
Ttyrosine kinase inhibitor naïve patients with advanced NSCLC
5 |
Lisberg, JTO 2018
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6 |
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EGFR mutations
8/9
0/7
Gefitinib responders
Non-respondersLynch, NEJM 2004
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T790M mediates gefitinib resistance8 |
Point mutation leading to threonine-to-methionine amino acid change at position
790 of EGFR
Kobayashi, NEJM 2005
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IPASS study on first line EGFR TKI vesus chemotherapy9 |
0
10
20
30
40
50
60
70
80
Mutation positive patients Mutation negative patients
Gefitinib
Carboplatin / paclitaxel
EGFR M+ odds ratio (95% CI) = 2.75
(1.65, 4.60), p=0.0001
EGFR M- odds ratio (95% CI) = 0.04
(0.01, 0.27), p=0.0013
Overall
response
rate (%)
(n=132) (n=129) (n=91) (n=85)
71.2%
47.3%
1.1%
23.5%
Mok, ESMO 2008
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Mode of Actions of EGFR TKIs10 |
Liao, Curr Opin Oncol 2015
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11 |
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LUX-Lung 7: Comparison of afatinib versus gefitinib in first line
treatment of EGFR-mutated NSCLC
12 |
Estim
ate
d P
FS
pro
ba
bili
ty
PFS
Pas-Ares, ESMO 2016; Ann Oncol 2017
Controlled ZNS metastases included
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Dacomitinib versus gefitinib as first-line treatment for patients with
EGFR-mutation-positive non-small-cell lung cancer (ARCHER
1050): a randomised, open-label, phase 3 trial*
13 |
Wu, Lancet Oncol 2017
*CNS metastases excluded,
Asian patients on,y
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EGFR-mutated NSCLC: Erlotinib with bevacizumab in first-line14 |
• JO25567: Ph2, randomized, Japanese
multicenter, open-label[a]
Seto, Lancet Oncol 2014; Rosell, Lancet Respir Med. 2017
PFS
BELIEF: Ph2, multicenter, single-arm study, stratified by pretreatment T790M status[b]
PFS
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RELAY: A multinational, double-blind, randomized phase 3 study of
erlotinib in combination with ramucirumab or placebo in previously
untreated patients with EGFRm metastatic NSCLC
15 |
Nakagawa, ASCO 2019
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NEJ009: Study Design and Endpoints16 |
Nakamural, ASCO 2018
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Phase III randomized trial comparing gefitinib to gefitinib with
pemetrexed-carboplatin chemotherapy in patients with advanced
untreated EGFR mutant NSCLC
17 |
Noronha, ASCO 2019
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Phase III randomized trial comparing gefitinib to gefitinib with
pemetrexed-carboplatin chemotherapy in patients with advanced
untreated EGFR mutant NSCLC
18 |
Median PFS
• 16 months
• 8 months
Median OS
• NR
• 21 months
Noronha, ASCO 2019
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FLAURA: First or third generation TKI inhibitors as first line therapy for
patients with EGFR mutated NSCLC
19 |
Ramalingam, ESMO 2017
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FLAURA: Adverse events20 |
Soria NEJM 2018
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CNS response to osimertinib versus standard EGFR tyrosine Kinase
inhibitors in patients with untreated EGFR-mutated advanced NSCLC
21 |
CNS progression-free survival Cumulative incidence of CNS progression
Reungwetawattana, JCO 2018
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Mechanisms of acquired resistance to first-line osimertinib:
Preliminary data from the phase III FLAURA study: Control group
22 |
Ramalingam, ESMO 2018
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Mechanisms of acquired resistance to first-line osimertinib:
Preliminary data from the phase III FLAURA study: Osimertinib group
23 |
Ramalingam, ESMO 2018
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Impower 150: OAS analyses of a randomized phase III study of carboplatin
and paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-
squamous metastatic NSCLC: Patients with EGFR-mutated tumors*
24 |
Reck, ELCC 2019 and Lancet Oncol 2019
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Severe immune related adverse events are common with
sequential PD-(L)1 blockade and osimertinib
25 |
Frequency of severe immune related adverse events by EGFR-TKIs since
last dose of PD-(L)1 inhibitor
Schoenfeld, Ann Oncol 2019
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26 |
TATTON Phase Ib: osimertinib + savolitinib arm in patients who
recieved prior treatment with 3rd generation EGFR TKIs
Safety and preliminary antitumor activity of U3-1402: A HER3-targeted
antibody drug conjugate in EGFR TKI-resistant, EGFRm NSCLC
JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in
EGFR-driven advanced NSCLC
Haura, ASCO 2019
Jänne, ASCO 2019
Sequist, AACR 2019
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Systemic therapy for patients with NSCLC with activating EGFR
mutations
• There is no clear preference between first and second generation EGFR
TKIs. Second generation EGFR TKIs provide a superior PFS, but are
associated with higher toxicity.
• Combinations of first generation EGFR TKIs with anti-angiogenic agents
provide a longer PFS, combinations with caboplatin-based chemotherapy
might also provide a longer OS.
• Osimertinib provides a superior PFS and is associated less side effects and
better CNS efficacy as compared to first generation EGFR TKIs. It is
approved either as first line treatment or in second line for patients with
acquired resistance based on the T790M mutation
• Currently available data doe not yet allow a final judgment on the optimal
sequencing of therapies
27 |
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28 |
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Crizotinib versus platin-based chemotherapy in fist line treatment of
advanced ALK-positive NSCLC: PRORILFE 1014
29 |
Salomon, NEJM 2014
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Final overall survival analysis from a study comparing first-line
crizotinib versus chemotherapy in ALK-mutation-positive NSCLC
30 |
Solomon, JCO 2018
Overall survival OS adjusted for cross-over
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Case 1: 62-y/o man
• July 2012: Adenocarcinoma of the lung, stage IIIB with bilateral mediastinal
and supraclavicular nodal metastases, EGFR WT
• July – September 2012: Treatment with 3 cycles of carboplatin and
pemetrexed: Stable disease
• September 2012: Start of Crizotinb
31 |
July 2012 September 2012
FISH in initial biopsy:
ALK gene
rearrangement
present
November 2012 March 2017
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Case 1: 62-y/o man
Continuing crizotinib
• March 2017: Stereotactic radiotherapy of the 4 cerebellar lesions
• November 2018: Stereotactic radiotherapy of lesion at nucleus olivaris
32 |
March 2017 October 2018 February 2019
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Alectinib, brigatinib, or ceritinib after crizotinib failure in ALK+ NSCLC patients
33 |
Alectinib Brigatinib Ceritinib
CharacteristicNP287611,a
n = 87
NP286732,3
,a
n = 138
Phase 1/24,5,b,c
n = 25ALTA5,6,a,c
n = 110
ASCEND-17,8,b
n = 163
ASCEND-29,a
n = 140
Median follow-up, mo 9.9 21 28.3d 8.3 11.1e 11.3
ORR, n/N (%) [95% CI]
35/67(52)
[40–65]
62/122(51)
[42–60]
19/25(76)
[55–91]
58/110(53)
[43–62]
92/163(56)
[49–64]
50/140(36)
[28–44]
DCR, n/N (%) [95% CI]
55/69(80)[Not
reported]f
96/122(79)
[70–86]
22/25(88)
[69–98]
92/110(84)
[75–90]
121/163(74)[Not
reported]
88/140(63)
[54–71]
Median DOR, mo[95% CI]
13.5[6.7–NE]
15.2[11.2–24.9]
14.8[7.9–NE]
13.8[9.3–NE]
8.3[6.8–9.7]
9.7[5.6–12.9]
Median PFS, mo [95% CI]
8.1[6.2–12.6]
8.9[5.6–12.8]b
16.3[9.2–NE]
16.7[11.0–NE]
6.9[5.6–8.7]
7.2[5.4–9.0]
Dose reduction due to AEs, n/N (%)
Pooled safety population57/253 (23)3,g
6/32(19)h
22/110(20)
152/246(62)e
64/140(46)
Discontinuation due to AEs, n/N (%)
2/87(2)
12/138(9)
4/32(13)h
9/110(8)
26/246(11)e
11/140(8)
NE = not estimable
1. Shaw Lancet Oncol. 2016; 2. Barlesi 41st Annual Congress, ESMO. Oct 2016, Denmark; 3. Ou S-H J Clin Oncol. 2016; 4. Gettinger Lancet Oncol. 2016; 5. ARIAD data on file; 6. Camidge J Thorac Oncol. 2016; 7. Kim D-W Lancet Oncol. 2016; 8. Kim ASCO 2014. 9. Crinò J Clin Oncol 2016
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First line alectinib versus crizotinib in advanced ALK-positive
NSCLC: Progression-free survival
34 |
Camidge, ASCO 2018
ICB
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Brigatinib vs crizotinib in patients with ALK inhibitor–naïve
advanced ALK+ NSCLC: First Report of a Phase 3 Trial (ALTA-1L)
35 |
Camidge, WCLC 2018
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Targeting ALK: Precision medicine takes on drug resistance36 |
Lin, Cancer Discovery 2017
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Lorlatinib in patients with ALK-positive NSCLC: Results from a
global phase 2 study
37 |
Solomon, Lancet Oncol 2018
Treatment naive Treatment post crizotinib
Treatment post non-crizo ALK TKI Treatment post 2 ore more ALK
TKI
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Systemic therapy for patients with NSCLC with ALK gene
rearrangements and other oncogenic driver mutations
• Crizotinib, certitinib and alectinib are approved by EMA for the first line
treatment of patients with ALK translocated translocated NSCLC.
• Ceritinib, alectinib and brigatinib are approved for patients progressing under
crizotinib.
• Lorlatinib will likely be approved for third line therapy.
• Currently, based on its activity and approval, alectinib is the preferred agent in
first line.
• Crizotinib is approved for ROS1 translocated tumors, other active agents include
ceritinib, lorlatininb and entractinib.
38 |
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ROS1 rearrangement in NSCLC: Activity of crizotinib
• ROS1 fusion with the transmembrane solute carrier protein SLC34A2
resulting in a constitutive kinase activity in a NSCLC cell lineRikova, Cell 2007
39 |
Shaw, NEJM 2014
Response rate 72% Median PFS 19.2 months
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Systemic therapy for patients with NSCLC with ALK gene
rearrangements and other oncogenic driver mutations
• Dabrafenib and trametinib combination is approved for NSCLC with V600E
BRAF mutation.
• Encouraging developments are seen for NSCLC with MET exon 14 mutations
(tepotinib, capmatinib), RET (LOXO-292, BLU-667) and NTRK (larotrectinib,
entrectinib) fusions.
40 |
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Dabrafenib plus trametinib in patients with previously untreated
BRAFV600E-mutant metastatic NSCLC: an open-label, phase 2 trial
41 |
Planchard, Lancet Oncol 2017
Response rate 64% Medien PFS 10.4 months Median OS 24.6 months
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Capmatinib (INC280) in METΔex14-mutated advanced NSCLC:
Efficacy data from the phase II GEOMETRY mono-1 study
42 |
RR 40%
RR 61%
Wolf, ASCO 2019
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Newer agents targeting RET fusions43 |
Drilon, ASCO 2018
Paradigms for uncommon mutations in NSCLC
Biomarker-selected studies in RET fusions
*Response evaluable population1. Gainor and Shaw. Oncologist 2013; 2. Zhao, et al. Lung Cancer 2016
3. Gautschi, et al. J Clin Oncol 2017; 4. Drilon, et al. ASCO 2018 (Abst 102)
RET rearrangements1–2% of NSCLC1
Predominently
adenocarcinoma2
RET fusions:
eight different genes1
Cabozantinib
Vandetinib
Sunitinib
Targeted options for RET
rearrangments3,4
Loxo-292
ORR: 77%
40
-100
0
-20
-60
-80
20
-40
Ma
xim
um
ch
an
ge
in
tu
mo
r siz
e (
%)
*
NSCLC
Thyroid
Pancreatic
Tumour type
Tumour responses to LOXO-292 in RET
fusion-positive NSCLC (n=39)4
A phase 1 study of LOXO-292, a potent
and highly selective RET inhibitor, in
patients with RET-altered cancers
Gainor, ASCO 2019
Clinical activity and tolerability of BLU-
667, a highly potent and selective RET
inhibitor, in patients (pts) with advanced
RET-fusion+ NSCLC
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New agents for NTRK fusions44 |
Efficacy and safety of entrectinib in patients with
NTRK fusion-positive tumours: pooled analysis of
STARTRK-2, STARTRK-1 and ALKA-372-001
Efficacy of larotrectinib in TRK fusion–positive
cancers in adults and children
0
-30
-50
-90
Bes
t %
ch
ang
e fr
om
bas
elin
e
15
-80
-70
-60
-40
-20
-10
20
30
40
-100
50
CRCNSCLCSarcoma
Neuroendocrine tumours
PancreaticThyroidMASC Breast
CholangiocarcinomaGynaecological
NTRK+ patients (n=54)
ORR (95% CI) 57.4% (43.2–70.8)
SD 9 (16.7)
PD 4 (7.4)
Non-CR/PD, missing or unevaluable 10 (18.5)
Results per Blinded Independent Central Review (BICR)
Demetri, ESMO 2018 Drilon, NEJM 2018
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Novel NSCLC agents targeting exon 20 insertions in the EGFR and
HER2 genes (standard TKIs are ineffective)
45 |
Antitumor activity of TAK-788 in NSCLC with
EGFR exon 20 insertions
• Response 43%
• PFS 7.3 months
• Grade 3 toxicities 40%
Jänni, ASCO 2019
Tumour responses to poziotinib in HER2 exon 20 mutations2
Best response HER2 (evaluable patients n=12)
Progressive Disease
Stable DiseasePartial Response
Response not confirmed/Follow-up pending
Ma
xim
um
resp
onse
from
baselin
e
ORR: 50%
* **
*
*
30
-60
-15
-45
15
0
-30
Heymach, WCLC 2018
Antitumor activity of paziotinib in HER2
exon 20 insertions
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Trastuzumab emtansine (T-DM1) in patients with previously treated
HER2-overexpressing metastatic NSCLC: Efficacy, safety, and
biomarkers
46 |
Peters, CCR 2018
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Thomas Hart Benton
America Today
Thomas Hart Benton:
“America Today”