Acquired Resistance to Targeted Therapy in EGFR and ALK-Positive Lung Cancer: New Ideas, New Agents
-
Upload
h-jack-west -
Category
Health & Medicine
-
view
4.684 -
download
1
description
Transcript of Acquired Resistance to Targeted Therapy in EGFR and ALK-Positive Lung Cancer: New Ideas, New Agents
Acquired Resistance to Targeted Therapies in Advanced Non-Small Cell Lung Cancer:
New Strategies and New Agents
H. Jack West, MD
Medical Director, Thoracic Oncology Program
Swedish Cancer Institute
Seattle, WA
February , 2014
Is Acquired Resistance a New Problem?
“We’ve always seen acquired resistance before targeted therapies
– this isn’t any different from chemo”
But…
This is a prospectively defined population
Response rate 60-75%, often profound
Median duration of response 9-13 months
This is a distinct clinical entity with its own natural history,
reflective of a new era of molecular oncology
Case: EGFR Mutation, Isolated Progression
• 43 year old never-smoking Caucasian woman with no
PMH noted R chest/shoulder pain, also heartburn
symptoms that worsened over several weeks.
• RUQ U/S shows no abd pathology but R pleural
effusion noted
• CXR shows effusion and pleural nodules
• CT chest – mod to large pleural effusion compressing
R middle and lower lobes, 2.5 x 0.7 cm nodule along
pleural surface in R midlung, smaller pleural-based
nodules elsewhere
Case: EGFR Mutation, Isolated Progression
• Thoracentesis yields 1700 cc serosang fluid, cytology
shows TTF-1 positive adenocarcinoma effusion noted
• Cell block: pos for exon 19 mutation in EGFR gene,
negative for ALK rearrangement
• No other areas of disease noted on PET/CT, brain MRI
• She starts erlotinib marked clinical and radiographic
response
Case: EGFR Mutation, Isolated Progression
• 7 months later, she develops headache and vision
changes: head MRI shows 2 cm L occipital lesion &
no other lesions
• She undergoes gamma knife radiosurgery.
What do you recommend for her systemic therapy?
A. No change: continue erlotinib
B. Switch to chemotherapy-based treatment
C. Add chemo to ongoing erlotinib
D. Afatinib
E. Afatinib/cetuximab
F. Send for clinical trial with novel agent
Case: EGFR Mutation, Isolated Progression
• Would your answer be the same if she had a solitary
new lung lesion instead of a solitary brain lesion?
A. Yes
B. No
Acquired Resistance to Targeted Therapy:
Heterogeneous Patterns
Diverse molecular mechanisms of resistance
diverse clinical patterns of progression
• Single focus of progression
(still decreased tumor burden vs. pre-targeted therapy)
• Slow, minimal multifocal progression
(still decreased tumor burden vs. pre-targeted therapy)
• Rapid, more diffuse progression
(exceeding tumor burden pre-targeted therapy)
At Least 3 Clinical Subtypes of
Acquired Resistance to Targeted TKIs
Oligo-PD
PD-Subtype
CNS-PD
(Sanctuary)
Courtesy of D. Gandara
Systemic-PD
If significant progression, is it isolated
or more diffuse?
Is “oligoprogression” analogous to
oligometastatic/precocious metastatic disease?
Perhaps especially for CNS disease – why?
• Poor CNS penetration of both EGFR TKIs and crizotinib,
so brain mets may not represent resistance to drug
(Bronischer CCR, 2007; Costa JCO 2011)
• T790M seen in 60% of progressing lesions in acquired
resistance, but only 10% of lesions from CNS progression
(Hata, ASCO 2012, A#7528)
Prolonged Benefit from Rx to Intracranial
Mets with Ongoing Targeted Therapy
• Growing number of patients who have been continued on
EGFR TKI or crizotinib after radiation to brain metastases in
absence of extracranial progression
- median duration of ongoing response is months
- some patients continue to do well without change in
systemic therapy for years
Local Therapy in Acquired Resistance: University of Colorado Experience
• 65 pts (38 ALK+, 27 EGFR mut’n+) of whom 51 (28 ALK, 23 EGFR)
progressed
• 25 (49%) with CNS (no LMC) or <4 extracranial sites of progression
Weickhardt, J Thorac Oncol 2013
Local Therapy in Acquired Resistance:
Extracranial Oligoprogression
• 18/184 pts local therapy for extracranial PD
(CNS PD excluded)
Yu, J Thorac Oncol 2013
• Median time to new
systemic Rx: 22 months
Local Therapy for Acquired Resistance
• As a proof of principle, a subset of pts can have
prolonged non-progression and excellent survival after
local therapy
• There may still be value in ongoing targeted therapy
• Could pts have potentially done just as well by not doing
imaging or ignoring the lesion? Is this just favorable
natural history?
• Only 4 mo median PFS in U. CO experience – perhaps
multifocal PD is too liberal
• MGH applied this approach to only 10% of AR pts
• Criteria need to be defined before broad adoption
Case: EGFR Mutation, Multifocal Progression
• 70 year old Indian maintenance man with remote prior
smoking history (8 pack-years, quit 45 years ago)
• Presented with cervical LAN that ultimately proved to
be benign, but he’s found to have 2.5 cm RUL mod-
differentiated adenocarcinoma resected
• 8 months after surgery, he’s found to have multifocal
recurrence in lungs bilaterally
• Biopsy confirms lung adenocarcinoma, EGFR
activating mutation in exon 19
• Starts erlotinib and responds with good PR
Case: EGFR Mutation, Mild progression
• 11 months later, several of the lung lesions appear to
have grown by about 1-2 mm, though still smaller than
pre-treatment baseline. He feels well.
• What do you recommend for his systemic therapy?
A. No change: continue erlotinib
B. Switch to chemotherapy-based treatment
C. Add chemo to ongoing erlotinib
D. Afatinib
E. Afatinib/cetuximab
F. Send for clinical trial
Case: EGFR Mutation, Subsequent Course &
Faster Progression• He continues on erlotinib, and follow up scan 2
months later demonstrates minimal progression. He
remains asymptomatic.
• Unfortunately, after another 2 month interval, his scan
shows that he has multiple new lung lesions and most
existing ones have grown significantly.
• What do you recommend for his systemic therapy?
A. Switch to chemotherapy-based treatment
B. Add chemo to ongoing erlotinib
C. Afatinib
D. Afatinib/cetuximab
Does Detectable Progression Require a
Treatment Change?
NOT necessarily clinically significant progression
Disease burden
Time
What DOESN’T Constitute
Clinically Significant Progression?
Mild increase in metabolic activity on PET
Rising serum tumor marker
Slow, slight increase in tumor size
(1-2 small new nodules against background of
excellent disease control?)
Concurrent TKI and chemo-based Therapy
Treating distinct cancer cell populations
TKI sensitive TKI sensitiveTKI resistance
TKI sensitiveTKI resistance
Disease burden
Time
D/C targeted Rx
continue targeted Rx
Risk of “flare response”/rebound progression
Rapid acceleration of PD hospitalization and/or death after
discontinuation of EGFR seen in up to ~1/4 of pts in MSKCC series
(Chaft, Clin Cancer Res, 2011)
Also reported after discontinuation of crizotinib after acquired
resistance in ALK-positive NSCLC (Pop, J Thorac Oncol, 2012)
Last day of TKI Off EGFR TKI Resumed TKI
Day 0 Day 21 Day 42
Rapid Progression with Discontinuation of EGFR TKI after Prolonged PFS
For Cancers with a Known Driver Mutation, Continuing
Inhibition of that Target is Beneficial after Progression
• Progression of CML on imatinib increase dose, or dasatinib, or
nilotinib lead to consistent response
• Solid tumor example: HER2+ breast cancer
Von Minckwitz, JCO 2009
Treatment Options after Acquired Resistance to EGFR (or other) TKI
Oxnard, Clin Cancer Res, 2011
Continued treatment beyond progression, Dana Farber Experience
• 42 EGFR mutn-pos pts s/p 1st line erlotinib on one of 3
clinical trials
• 45% continued without significant progression > 3 months
• 21% required no further treatment change for > 12 months
Oxnard, ASCO 2012, A#7524
Chemo/Erlotinib vs. Chemo Alone at Progression after Acquired Resistance
• N = 78 retrospective review of
outcomes
– chemo alone (N = 44) or
– chemo/erlotinib (N = 34)
• RR 18% (chemo) vs. 41% with
chemo/erlotinib)
• No differences in PFS or OS between
these two strategies
Goldberg, ASCO 2012, A#7524
Prospective Rand Ph 2 Rand Trial Suggests No
Benefit to Treatment Beyond Progression• N = 39 pts w/clin benefit after >12 weeks erlotinib, then PD
• EGFR mutation not required; CR/PR not required
• Randomized to chemo (pem or docetaxel) +/- erlotinib
• Closed due to slow accrual
Progression-Free Survival Overall Survival
Chemo alone
Chemo/erlotinib
Chemo alone
Chemo/erlotinib
Halmos, ASCO 2013, A#8114
Chemo with Concurrent EGFR TKI
• Studies in unselected or clinically selected populations show no
benefit but no signal of increased harm
• Combinations of chemo and TKIs are certainly feasible
• Little prospective study in setting of acquired resistance yet
• ph II trial of pem/EGFR TKI as 3rd line (Yoshimura, JTO 2013)
• N = 27; RR 26%, DCR 78%, med PFS 7.0 mo, med OS 11.4 mo
• Unclear if they are significantly more favorable than
chemo alone in acquired resistance
Chemotherapy +/- Ongoing EGFR TKI for
Acquired Resistance
Primary endpoint: progression-free survival
Activating EGFR mutation
Progression on gefitinib
No prior chemotherapy
N = 250
R
A
N
D
Cisplatin/Pemetrexed
IMPRESS TRIAL
PI: Tony Mok & Jean-Charles Soria
Cisplatin/Pemetrexed+ ongoing gefitinib
Chemotherapy +/- Ongoing EGFR TKI for
Acquired Resistance, with Retreatment
Primary endpoint: progression-free survival
PI: Leora Horn (Vanderbilt)
Advanced NSCLC
Activating EGFR mutation
Resp to EGFR TKI>4 mo
No prior chemotherapy
PS 0/1
N = 120
R
A
N
D
Cis or Carbo/Pemetrexed+ ongoing erlotinib
Stratification by:
EGFR mut’n exon 19 vs. exon 21
Time to progression on EGFR TKI <1 yr vs. >1 yr
PS 0 vs. 1
Cis or Carbo/Pemetrexed
Erlotinib re-treatment
Chemo Without TKI Can Be Followed by Re-treatment
Oxnard, Clin Cancer Res, 2011
Activity of EGFR TKIs on Re-Challenge
• Many small series published: RR<10%, PFS <4 months
• Minority of patients can demonstrate significant tumor shrinkage
• Larger subset will have stability again for many months
• Reacquisition of TKI sensitivity, loss of T790M, etc., most
notably in patients off targeted therapy for 6-12 months or longer
• Seen after crizotinib re-challenge as well (Browning, JTO 2013)
• Is this meaningfully beneficial? If so, is this as good as, better
than, or worse than ongoing treatment beyond progression?
EGFR TKI Re-treatment after Acquired Resistance: DFCI/MGH Experience
• Retrospective, 24 pts (over 9.5 yrs)
with activating EGFR mutation after AR
to gefitinib (30%) or erlotinib (70%)
• RR 4%, SD 63%
• Median interval off EGFR TKI 5 mo
(range 2-46 mo)
• Greater benefit w/longer interval of
EGFR TKI (PFS 4.4 vs. 1.9 mo for 6
mo interval off EGFR TKI)
Heon, ASCO 2012, A#7525
Re-challenge with EGFR TKI after
Acquired Resistance
Hata, ASCO 2012, A#7528
• N = 73 pts with acquired resistance
• OS post-PD better for 56 who had
EGFR TKI re-administered vs. 17
who did not
• No correlation of benefit w/interval off EGFR TKI seen
Paired biopsies (N=106)
Mechanisms of Acquired Resistance in EGFR
Mutation-Positive Disease: Repeat Biopsies?
Oxnard, Clin Cancer Res, 2011
Repeat biopsies are not standard of care and have a relatively
low probability of being immediately actionable, but they are likely
to drive our understanding and future treatments in this setting.
• SCLC in 3-15%
• Otherwise, rare to find
actionable result with current
approved agents
• May provide some insight about
prognosis (+/- value of ongoing
TKI?)
Novel Agents:
Irreversible TKIs in Clinical Trials
• HKI-272 (EGFR + Her2)
• RR 2% in TKI-resistant patients
• Intriguing responses in G719X patients (Sequist, JCO 2010)
• Cabozantinib (EGFR, Her2, VEGF)
• RR 2% in TKI-resistant patients (Pennell, Chicago Lung ’08)
• Dacomitinib (EGFR + Her2)
• RR 7% in TKI-resistant patients (Janne, ASCO ’09)
• Afatinib (EGFR + Her2)
• RR 7% in TKI-resistant pts, 2 mo PFS improvement
(Miller, Lancet Oncol 2012)
LUX Lung 1
Randomization
2 : 1
Oral BIBW 2992 50 mg once daily
plus best supportive care
Oral placebo once daily
plus best supportive care
Patients with:
• Adenocarcinoma of the lung
• Stage IIIB/IV
• Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen) and ≥12 weeks of
treatment with erlotinib or gefitinib
• ECOG 0–2
N=585
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL, safety
Miller, Lancet Oncol 2012
LUX Lung 1: Efficacy
Miller, Lancet Oncol 2012
Progression-Free Survival Overall Survival
Afatinib + Cetuximab in EGFR-mutated
NSCLC refractory to EGFR TKI
Response rate: 30%
Clinical benefit (DCR): 75%
Janjigian, et al. ESMO 2012
• This is specific for afatinib combination:
Erlotinib/cetuximab had RR 0/13 (Janjigian, CCR 2011)
N = 60
Trial Concepts: Afatinib + Cetuximab
Advanced NSCLC
Activating EGFR mutation
No prior chemotherapy
PS 0-2
SWOG: EGFR TKI-naïve
ECOG: Acquired Resistance
R
A
N
D
Afatinib 40 mg PO daily
Afatinib 40 mg PO daily+ Cetuximab IV weekly
Rebiopsy at progressionPrimary Endpoint: PFS
MISSION Trial of Sorafenib vs. Placebo:
PFS based on EGFR mutation status
Biomarker treatment interaction analysis: p-value=0.015
Patients with EGFR mut (in tumor or plasma)• Sorafenib N=44; Placebo N=45
• HR=0.27 (95% CI 0.16,0.46)
• P-value<0.001
• Sorafenib median PFS= 2.7 mo (83d)
• Placebo median PFS= 1.4 mo (42d)
Patients with EGFR wild type• Sorafenib N=122; Placebo N=136
• HR=0.62 (95% CI 0.48,0.82)
• P-value<0.001
• Sorafenib median PFS= 2.7 mo (82d)
• Placebo median PFS= 1.5 mo (46d)
Mok, ESMO 2012
MISSION Trial of Sorafenib vs. Placebo:
OS based on EGFR mutation statusPatients with EGFR mut (in tumor or plasma)• Sorafenib N=44; Placebo N=45
• HR=0.48 (95% CI 0.3,0.76)
• P-value=0.002
• Sorafenib median OS= 13.9 mo (423d)
• Placebo median OS= 6.5 mo (197d)
Patients with EGFR wild type• Sorafenib N=122; Placebo N=136
• HR=0.92 (95% CI 0.7,1.21)
• P-value=0.559
• Sorafenib median OS= 8.3 mo (253d)
• Placebo median OS= 8.4 mo (256d)
Biomarker*treatment interaction analysis: p-value=0.023
Mok, ESMO 2012
T790M Mutation
• May have a better Px than non-T790M mechanisms:
19 vs. 12 mo post-progression
N = 93
• T790M more likely to
show progression in
lungs/pleura
• Non-T790M more likely
to progress distantly, &
with worse PS
Oxnard, Clin Cancer Res 2010
CO-1686: Oral Inhibitor of EGFR Mutations & T790M Mutations (not EGFR wild type)
• 67% response rate in T790M+ patients (WCLC, 2013)
– Dosing 900 mg PO BID
• No rash (c/w absence of systemic wt EGFR inhibition)
Soria, WCLC 2013, Sydney
Series of Global Registration Trials for CO-1686
• TIGER1: Ph 2/3 rand trial vs. erlotinib in newly Dx’d pts
• TIGER2: Ph 2 in 2nd line T790M+ pts w/PD after 1 EGFR TKI
• TIGER3: Ph 2 of later T790M+ pts after >1 EGFR TKI or chemo
post-progression
• TIGER4: Ph 2 in 2nd line or later for T790M+ detected by
blood/plasma assay
• TIGER5: Ph 3 rand trial vs. chemo in 2nd line or later
TIGER: Third –gen Inhibitor of Mutant EGFR in Lung CancER
AZD9291: Preclinical data
• AZD9291 is a potent oral, irreversible
inhibitor of EGFR that contains EGFR-
TKI-sensitizing (EGFRm+) and
resistance mutations (T790M)
• Good potency and high selectivity
demonstrated in enzymatic and cellular
in vitro assays
AstraZeneca data on file
Model Wild-type
LoVo cells
EGFRm+
PC9 cells
EGFRm+/T
790M
H1975 cells
AZD9291
phospho-
EGFR
IC50 μM
0.480 0.017 0.0115
AZD9291 achieved complete and
durable response in H1975 xenograft
V, vehicle
AZD9291: Best % change from
baseline in target lesions
Ranson, WCLC 2013, Sydney
89 patients with documented radiological PD
while on EGFR-TKI
No DLTs at 20-160 mg/d (dosing to 240 mg/d)
No dose reductions
AZD9291: Clinical response
Preliminary data
• Patient with Ex19Del & T790M+ pre-gefitinib; PD on gefitinib immediately before AZD9291
• Dose escalation Cohort 1 (20 mg/day)
• 24 weeks exposure
• No AEs greater than Grade 1
• Ongoing confirmed partial response
AUY922: HSP90,
“Onco-Chaperone” Inhibitor
Johnson, Proc ASCO 2013
AUY922/Erlotinib in EGFR Mutation-Positive
with Acquired Resistance
Johnson, Proc ASCO 2013
Acquired Resistance in ALK+ NSCLC:
Mechanisms are Diverse
ALK resistance mutations
ALK amplification
Alternative signaling pathways
ALK+
• At this time, there is no established role for rebiopsy, but potential to
identify bypass tracks
Chemotherapy +/- Ongoing Crizotinib for
Acquired Resistance in ALK-Positive NSCLC
Primary endpoint: progression-free survival
ALK rearrangement
Progression on crizotinib
After CR/PR or SD>3 mo
No prior pemetrexed
N = 108
R
A
N
DPemetrexed
SWOG 1300
PI: Ross Camidge, U Colorado
Pemetrexed+ ongoing crizotinib
Crizotinib rechallenge
IC5
0 (
nM
)
C r iz o tin ib A P 2 6 1 1 3 L D K 3 7 8 C H 5 4 2 4 8 0 2 A S P 3 0 2 6
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
N ative
G 1 2 6 9 A
L 1 1 5 2R
L 1 1 9 6 M
F 1 1 7 4 L
S 1 2 0 6 Y
C 1 1 5 6 Y
D 1 2 0 3 N
T 1 15 1T ins
G 1202R
Second Generation ALK Inhibitors and
IC50s vs. Resistance Mutations
--- Approximate steady-state trough concentration at recommended phase 2 dose
IC5
0 (
nM
)
C r iz o tin ib A P 2 6 1 1 3 L D K 3 7 8 C H 5 4 2 4 8 0 2 A S P 3 0 2 6
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
N ative
G 1 2 6 9 A
L 1 1 5 2R
L 1 1 9 6 M
F 1 1 7 4 L
S 1 2 0 6 Y
C 1 1 5 6 Y
D 1 2 0 3 N
T 1 15 1T ins
G 1202R
ARIAD Pharmaceuticals
Activity of Ceritinib in Crizotinib-
Resistant ALK Mutants
• Crizotinib resistance mechanisms
can be grouped into two broad
categories1–3
– Alterations in or amplification of
the ALK gene
– Bypass mechanisms affecting non-ALK
signaling pathways (eg, EGFR, HER2)
• Ceritinib is active against many
known ALK crizotinib resistance
mutations1–3
• In EML4-ALK+ lung cancer
xenografts, ceritinib inhibited
growth of crizotinib-resistant
tumors4
Mutation
IC50 (nM)
Ceritinib Crizotinib
Ba/F3 EML4-ALK 20 120
L1152P 180 280
C1156Y 130 350
I1171T 40 310
F1174C 340 440
L1196M 60 810
G1202R 490 1020
S1206A 150 250
G1269S 140 1600
1. Shaw AT et al. J Clin Oncol. 2013;31(suppl):Abstr 8010;
2. Doebele RC et al. Clin Cancer Res. 2012;18:1472-1482;
3. Takeda M et al. J Thoracic Oncol. 2013;8:654-657;
4. Li N et al. Presented at AACR-NCI-EORTC; November 12–16, 2011;
San Francisco, CA. Abstr B232.
IC50 Values from Ba/F3 Cellular Assays1
Ceritinib: Activity in Patients with
Advanced ALK+ NSCLC
Ceritinib: Response in the CNS
T1- post
Flair
T1- post
Flair
Baseline After 6 weeks of ceritinib
Continued response in
CNS at 6 months
Ceritinib: Ongoing Clinical Trials
Trial Description/SettingClinicalTrials.gov
NumberPhase Status
Ceritinib in previously treated (criz
+ chemo) ALK+ NSCLCNCT01685060 II
Ongoing,
not recruiting
Ceritinib in crizotinib-naïve ALK+ NCT01685138 II Ongoing
Ceritinib vs. chemo in criz-
resistant ALK+ NSCLCNCT01828112 III Ongoing
Expanded access ceritinib in
ALK+ NSCLCNCT01947608 NA Ongoing
Alectinib (300 mg PO BID) in crizotinib-naïve
ALK+ Japanese NSCLC Pts
Nakagawa, ASCO 2013, A#8033
ORR 93.5%
(assessment by IRC)
Median duration of
treatment not yet reached
but >14 months
Alectinib in Crizotinib-Refractory ALK+
Non-Japanese Population (N = 47)
Gadgeel, WCLC Sydney, 2013, A# O16.06
AP26113: ALK+ NSCLC Anti-Tumor Activity
Target Lesions (N=34)
58
All patients received prior crizotinib unless otherwise indicated; Doses ranged from 60-240 mg/d (23 pts ≥180mg/d); aTKI-naïve; bReceived prior
crizotinib and LDK378; cPD by RECIST 1.1 due to 2nd primary tumor of melanoma; dCrizotinib-intolerant
• Response duration 8+ to 40+ weeks
• 14 confirmed, 4 awaiting confirmation
Data as of 6 Sept 2013
Be
st
Ch
an
ge
fro
m B
as
elin
e in
Ta
rge
t L
es
ion
(%
)
-100
-80
-60
-40
-20
0
20
40
Progressive Disease Stable Disease Partial Response Complete ResponseBest Overall Response:
c
b
b
a
a
a
d
• 65% (22/34) objective response rate (95% CI: 47-80%)
• 61% (19/31) post-crizotinib (incl. 1 criz intolerant)
• 100% (3/3) in TKI-naïve (incl. 1 CR)
AP26113: ALK+ NSCLC Time on Treatment
Data as of 6 Sept 2013
Time on Treatment (Weeks)
Patien
ts
0 10 20 30 40 50 60 70 80
DiscontinuedOn Study
First dose to last dose if discontinued, first dose to date of data cut if on study
• 30/40 (75%) patients still on therapy
• 15 ALK+ NSCLC patients have received
treatment for at least 6 months, 12 (80%)
continue on study
(N=
40
)
AP26113: Response at 60 mg BID in
Crizotinib-resistant ALK+ NSCLC
Baseline After 12 Weeks of AP26113
PR is ongoing, 16+ weeks; Images courtesy of Dr. S. GettingerData as of 6 Sept 2013
AP26113: Brain Metastases Activity
Baseline After 8 wks of 180 mg AP26113
Both patients
have crizotinib-
resistant ALK+
NSCLC
Images courtesy
of
Dr. D.R. Camidge
Data as of 6 Sept 2013
Patient 1
Patient 2
• 8 of 10 ALK+ NSCLC patients with active brain lesions at baseline
had evidence of radiographic improvement in brain
• Duration of CNS benefita ranging from 8+ to 40+ weeks
AP26113: Brain Metastases Activity
Data as of 6 Sept 2013
Time on Treatment (Weeks)
Pati
en
ts
0 10 20 30 40 50 60
DiscontinuedOn Study
Activated client; cell survival,
proliferationHSP90 binds to client protein
HSP90 inhibitor prevents HSP90
binding to client (competitively binds
the ATP pocket of hsp90)
Inactive client, degraded through
proteasome
>200 client proteins
identified. Examples:
ALK, AKT, BCR-ABL,
BRAF, CDK4, CHK1,
EGFR, FLT3, HER2,
HIF1α, KIT, MET,
PDGFRα, CRAF, SRC,
VEGFR, AR, ER …
HSP90 Chaperone Stabilizes Client Proteins:
Inhibitors leads to Client Protein Degradation
Proper folding
IPI-504 (Retaspimycin): HSP90 Inhibitor Efficacy
by ALK FISH Status
Sequist, ASCO 2011
HSP90 Inhibitor Ganetespib Especially
Active in ALK-Positive Patients
Wong, ASCO 2011
Ganetespib activity in ALK+ NSCLC
24 year old male
Chemotherapy, progressed; crizotinib 1 year (PR), progressed
66
Baseline
After three weeks
(3 doses) ganetespib
Acquired Resistance:
General Principles
• No clear evidence-based approaches yet
• Conclusions/dogma derived from decades of experience
with chemo don’t necessarily apply
• Consider local therapy to limited area(s) of PD, especially
within the CNS, which may be an issue of drug exposure,
not true resistance
• Slow progression may not necessitate any change in
systemic therapy
• Consider rebiopsy: tissue findings have small chance of
revealing actionable off-protocol results, are integral for
trials in this setting, & will increase our understanding
Multiple Options for Acquired Resistance in
EGFR Mutation-Positive Advanced NSCLC
• Commercially available options– Switch to standard chemotherapy +/- bevacizumab
– Add chemo to ongoing EGFR TKI
– Afatinib +/- cetuximab (financial toxicity)
• Clinical trial options– Large trials of chemo +/- EGFR TKI beyond progression
– Afatinib/cetuximab
– AZ9291
– CO1686
– AUY922
Multiple Options for Acquired Resistance in
ALK Rearrangement-Positive Advanced NSCLC
• Commercially available options– Switch to std chemo (esp pemetrexed?) +/- bevacizumab
– Add chemo to ongoing crizotinib
• Clinical trial options
– SWOG trial of pemetrexed +/- ongoing crizotinib
– Ceritinib (LDK378)
– Alectinib (CH5424802)
– AP26113
– HSP90 inhibitors