Life After Erlotinib: What Next?
Acquired Resistance Patient
Forum
In ALK, ROS1 & EGFR Lung Cancers
September 6, 2014 | Boston
Jared Weiss
Vice President, Cancergrace
Assistant Professor of Medicine, UNC
Lineberger Comprehensive Cancer Center
Yesterday’s victory is today’s challenge
EGFR mutation positive
Probability of progression-free survival
Gefitinib (n=132)
Carboplatin/paclitaxel (n=129)
1.0
0.8
2009 Perspective: 10
months PFS without
chemo!
0.6
2014 Perspective: Only
10 months? Now what?
0.4
0.2
0.0
0
Patients at risk :
Gefitinib 132
C/P
129
4
8
12
16
20
24
11
2
3
1
0
0
Months
108
103
71
37
31
7
Crizotinib for ALK: Like erlotinib for EGFR,
better than chemo, but again, now what
should be done?
Mok, ASCO 2014
Option 1: Learn from the politicians
Amount of Cancer
When this is a good idea
Time
West, ASCO 2013
Amount of Cancer
Now it’s time for a new idea
Time
West, ASCO 2013
Baseline: Start TKI
3m: Response
18m
45
24m
35m
14m: RECIST PD
30m
37m: Stop TKI
39m: First dyspnea
Oxnard, ASCO 2012 and Santa Monica Lung 2014
EGFR TKI beyond RECIST
• 42 pts with EGFR-mutant lung cancer
receiving 1st-line erlotinib on 3 clinical trials
• 45% of pts could delay change of therapy >3
months after RECIST progression
• 21% delayed treatment change >12 months
R
1st-line erlotinib
Post-progression erlotinib
Treatment break
S Surgery
R Radiation
R
SR
R
S
R
R
R
0
12
24
36
Oxnard et al, ASCO, 2012 and Santa Monica Lung 2014
48
60
S
72
84
Crizotinib past progression
Ou, Annals of Oncology 2014
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6, 2014 | Boston
9
Option 2: Weeding the garden
When weeding is a good idea
PD-Subtype
Systemic-PD
Oligo-PD
CNS-PD
(Sanctuary)
Slightly adapted from Gandara, CLC 2013
Why radiation can be a good way to weed
In vitro
1. Das, AACR 2006.
2. Das, AACR 2007.
In vivo
Mak, The Oncologist, 2011
It has been tried: MSKCC experience,
all EGFR (n=18)
Yu et al.
Yu, JTO 2013
Page 9
Figure 1.
U Colorado Experience: Mixed EGFR
(n=27) and ALK (n=38)
Figure 1.
Weickhardt, JTO 2012
PFS1 and PFS1+PFS2 survival curves of (A) All 25 patients treated with LAT; (B) 10
patients treated with LAT who first progressed only in the CNS; (C) 15 patients treated with
LAT who first progressed in extra-CNS (eCNS) locations, including 3 patients with
simultaneous CNS and eCNS progression.
Ongoing Trial: LCCC1123: Prospective Phase II
Inclusion:
*EGFR mutant
*Progression on
TKI
*PS 0-1
*No prior XRT to
sites of PD
*<5 sites of PD
*All sites of PD
amenable to SRS or
other local
treatment
SRS or Surgery
based on priority
system to defined
limit:
1) Sites of PD on
TKI
2) Areas of residual
FDG avidity on TKI
Site-specific rules
for local ablation
Re-initiation of
erlotinib until
progression
Collaborators:
• Cleveland Clinic
• UPMC
• U. Colorado
• UCSF
• Swedish
• FCCC
• Yale U.
• ECU
• UNC
Primary endpoint: PFS after SRS
Secondary endpoints: LCR of ablated lesions, mOS from initiation of SRS, QOL as measured
by FACT-L, attributable toxicity, serum-based biocorrelates (Veristrast)
PI: Jared Weiss
Flare Reaction: The Danger of Coming
off of EGFR TKI at progression
Last day of
TKI
Off EGFR TKI
Resumed TKI
Day 0
Day 21
Day 42
Chaft…Riely CCR 2011
Case studies describe the same
phenomenon with ALK
Disease well
controlled
Flare 15 days
After stopping
crizotinib
Pop JTO 2012
Third option: Keep the TKI going
with the new chemo
Chemo alone
Chemo + erlotinib
40
40
20
20
0
0
-20
-20
-40
-60
-80
18% RR
-40
-60
-80
Goldberg et al, Oncologist, 2013
41% RR
But, no advantage for PFS or OS
Platinum-based combination
chemotherapy
Goldberg, Oncologist 2013
Acquired Resistance Patient Forum | Sept.
6, 2014 | Boston
One drug
chemotherapy
19
And, there is a toxicity cost
Herbst, JCO 2005 (TRIBUTE data)
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6, 2014 | Boston
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Chemotherapy +/- Ongoing EGFR TKI for
Acquired Resistance: IMPRESS Trial
IMPRESS TRIAL
PI: Tony Mok & Jean-Charles Soria
Activating EGFR mutation
Progression on gefitinib
No prior chemotherapy
N = 250
R
A
N
D
Cisplatin/Pemetrexed
Cisplatin/Pemetrexed
+ ongoing gefitinib
Primary endpoint: progression-free survival
Chemotherapy +/- Ongoing EGFR TKI for
Acquired Resistance: Vanderbilt Trial
EGFR-mutant lung
cancer with acquired
resistance to erlotinib
Caboplatin / pemetrexed
with erlotinib
PD
Carboplatin / pemetrexed
PD
R
PI: Leora Horn, VICC
When chemo used, it’s worth coming
back to TKI later
Heon, ASCO 2012
Hata, ASCO 2012
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6, 2014 | Boston
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Systemic options other than chemo:
Combination trials and 3rd generation TKIs
• 3rd generation TKIs: CO1686, AZD9291,
HM61713, EGFR816, ASP8273: Look promising,
but most requires repeat biopsy (more on this in
next talk from Dr. Sequist). More on 3rd gen TKI
from Dr. Pasi Janne in afternoon breakout session
• Combination trials: Afatinib/cetuximab farthest
along; AUY922/erlotinib, MET inhibitor/EGFR TKI,
others. More on combo trials from Dr. Melissa
Johnson at afternoon breakout session)
• Other trials: Any active agent can be considered
including immunotherapy.
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Options, summarized
• Kick the can down the road
• Local ablation of spots that are growing then
restart TKI
• Chemo + TKI
• Chemo alone (but, must start quickly after
stopping TKI and reconsider TKI later)
• Combination Therapies
• 3rd Generation TKIs
• Other clinical trials