This is a presentation I did for a meeting on new general management of acquired resistance in 2014, including the concept of local therapy for limited progression, and new treatment approaches and new agents for this setting. It features discussion of several of the most important trials.

1. 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

2. 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

3. 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

4. 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

5. 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.
B.
C.
D.
E.
F.
No change: continue erlotinib
Switch to chemotherapy-based treatment
Add chemo to ongoing erlotinib
Afatinib
Afatinib/cetuximab
Send for clinical trial with novel agent

6. 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.
B.
Yes
No

7. 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)

8. At Least 3 Clinical Subtypes of
Acquired Resistance to Targeted TKIs
PD-Subtype
CNS-PD
(Sanctuary)
Oligo-PD
Systemic-PD
Courtesy of D. Gandara

9. 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)

10. 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

11. 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

12. Local Therapy in Acquired Resistance:
Extracranial Oligoprogression
• 18/184 pts  local therapy for extracranial PD
(CNS PD excluded)
• Median time to new
systemic Rx: 22 months
Yu, J Thorac Oncol 2013

13. 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

14. 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 moddifferentiated 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

15. 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

16. 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

17. Does Detectable Progression Require a
Treatment Change?
Disease
burden
Time
NOT necessarily clinically significant progression

18. 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?)

19. Concurrent TKI and chemo-based Therapy
Treating distinct cancer cell populations
Risk of “flare response”/rebound progression
Disease
burden
D/C targeted Rx
continue targeted Rx
Time
TKI sensitive
TKI sensitive
TKI resistance
TKI sensitive
TKI resistance

20. Rapid Progression with Discontinuation of
EGFR TKI after Prolonged PFS
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)
Last day of TKI
Off EGFR TKI
Resumed TKI
Day 0
Day 21
Day 42
Also reported after discontinuation of crizotinib after acquired
resistance in ALK-positive NSCLC (Pop, J Thorac Oncol, 2012)

21. 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

22. Treatment Options after Acquired
Resistance to EGFR (or other) TKI
Oxnard, Clin Cancer Res, 2011

23. 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

24. 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

25. 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
Chemo alone
Chemo/erlotinib
Halmos, ASCO 2013, A#8114
Overall Survival
Chemo alone
Chemo/erlotinib

26. 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

27. Chemotherapy +/- Ongoing EGFR TKI for
Acquired Resistance
IMPRESS TRIAL
PI: Tony Mok & Jean-Charles Soria
Activating EGFR mutation
Progression on gefitinib
No prior chemotherapy
N = 250
R
A
N
D
Primary endpoint: progression-free survival
Cisplatin/Pemetrexed
Cisplatin/Pemetrexed
+ ongoing gefitinib

28. Chemotherapy +/- Ongoing EGFR TKI for
Acquired Resistance, with Retreatment
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
Cis or Carbo/Pemetrexed
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
Primary endpoint: progression-free survival
Erlotinib re-treatment

29. Chemo Without TKI Can Be
Followed by Re-treatment
Oxnard, Clin Cancer Res, 2011

30. 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?

31. 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

32. Re-challenge with EGFR TKI after
Acquired Resistance
• 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
Hata, ASCO 2012, A#7528

33. Mechanisms of Acquired Resistance in EGFR
Mutation-Positive Disease: Repeat Biopsies?
• SCLC in 3-15%
• Otherwise, rare to find
actionable result with current
approved agents
Paired biopsies (N=106)
• May provide some insight about
prognosis (+/- value of ongoing
TKI?)
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.

34. 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)

35. LUX Lung 1
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
Randomization
2:1
Oral BIBW 2992 50 mg once daily
plus best supportive care
Oral placebo once daily
plus best supportive care
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL, safety
Miller, Lancet Oncol 2012

36. LUX Lung 1: Efficacy
Progression-Free Survival
Miller, Lancet Oncol 2012
Overall Survival

37. Afatinib + Cetuximab in EGFR-mutated
NSCLC refractory to EGFR TKI
N = 60
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)

38. 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
Primary Endpoint: PFS
Rebiopsy at progression

39. MISSION Trial of Sorafenib vs. Placebo:
PFS based on EGFR mutation status
Patients with EGFR mut (in tumor or plasma)
Patients with EGFR wild type
• 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)
• 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)
Biomarker treatment interaction analysis: p-value=0.015
Mok, ESMO 2012

40. MISSION Trial of Sorafenib vs. Placebo:
OS based on EGFR mutation status
Patients with EGFR mut (in tumor or plasma)
Patients with EGFR wild type
• 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)
• 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

41. 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

42. 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

43. Series of Global Registration Trials
for CO-1686
TIGER: Third –gen Inhibitor of Mutant EGFR in Lung CancER
• 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

44. AZD9291: Preclinical data
•
AZD9291 is a potent oral, irreversible
inhibitor of EGFR that contains EGFRTKI-sensitizing (EGFRm+) and
resistance mutations (T790M)
•
AZD9291 achieved complete and
durable response in H1975 xenograft
Good potency and high selectivity
demonstrated in enzymatic and cellular
in vitro assays
Model
AZD9291
phosphoEGFR
IC50 μM
Wild-type
LoVo cells
EGFRm+
PC9 cells
EGFRm+/T
790M
H1975 cells
0.480
0.017
0.0115
AstraZeneca data on file
V, vehicle

45. AZD9291: Best % change from
baseline in target lesions
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
Ranson, WCLC 2013, Sydney

46. AZD9291: Clinical response
•
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
Preliminary data

47. AUY922: HSP90,
“Onco-Chaperone” Inhibitor
Johnson, Proc ASCO 2013

48. AUY922/Erlotinib in EGFR Mutation-Positive
with Acquired Resistance
Johnson, Proc ASCO 2013

49. 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

50. Chemotherapy +/- Ongoing Crizotinib for
Acquired Resistance in ALK-Positive NSCLC
SWOG 1300
PI: Ross Camidge, U Colorado
ALK rearrangement
Progression on crizotinib
After CR/PR or SD>3 mo
No prior pemetrexed
N = 108
R
A
N
D
Pemetrexed
+ ongoing crizotinib
Pemetrexed
Primary endpoint: progression-free survival
Crizotinib rechallenge

51. Second Generation ALK Inhibitors and
IC50s vs. Resistance Mutations
--- Approximate steady-state trough concentration at recommended phase 2 dose
10010000
0
N a tivN a tiv e
e
G A
G 1 2 6 91 2 6 9 A
IC 5 0 (n M )
IC 5 0 (n M )
1001000
0
L 1 1 5L 1 1 5 2 R
2R
L 1 1 9L 1 1 9 6 M
6M
100100
F 1 1 7F 1 1 7 4 L
4L
S Y
S 1 2 0 61 2 0 6 Y
C Y
C 1 1 5 61 1 5 6 Y
10
10
D N
D 1 2 0 31 2 0 3 N
T 1 1 5T 1 1 5s T in s
1 T in 1
GR
G 1 2 0 21 2 0 2 R
1
1
C in ib
A 113
C r iz ortiz o t in ib A P 2 6P 2 6 1 1 3
ARIAD Pharmaceuticals
LDK
C 24802
AS 26
L D K 3 7 83 7 8 C H 5 4H 5 4 2 4 8 0 2 A S P 3 0P 3 0 2 6

52. Activity of Ceritinib in CrizotinibResistant ALK Mutants
• Crizotinib resistance mechanisms
can be grouped into two broad
categories1–3
IC50 Values from Ba/F3 Cellular Assays1
IC50 (nM)
Mutation
Ceritinib
Crizotinib
– Alterations in or amplification of
the ALK gene
Ba/F3 EML4-ALK
20
120
L1152P
180
280
– Bypass mechanisms affecting non-ALK
signaling pathways (eg, EGFR, HER2)
C1156Y
130
350
I1171T
40
310
F1174C
340
440
L1196M
60
810
G1202R
490
1020
S1206A
150
250
G1269S
140
1600
• Ceritinib is active against many
known ALK crizotinib resistance
mutations1–3
• In EML4-ALK+ lung cancer
xenografts, ceritinib inhibited
growth of crizotinib-resistant
tumors4
1.
2.
3.
4.
Shaw AT et al. J Clin Oncol. 2013;31(suppl):Abstr 8010;
Doebele RC et al. Clin Cancer Res. 2012;18:1472-1482;
Takeda M et al. J Thoracic Oncol. 2013;8:654-657;
Li N et al. Presented at AACR-NCI-EORTC; November 12–16, 2011;
San Francisco, CA. Abstr B232.

53. Ceritinib: Activity in Patients with
Advanced ALK+ NSCLC

54. Ceritinib: Response in the CNS
T1- post
T1- post
Flair
Flair
Continued response in
CNS at 6 months
Baseline
After 6 weeks of ceritinib

55. Ceritinib: Ongoing Clinical Trials
Trial Description/Setting
ClinicalTrials.gov
Number
Phase
Status
Ceritinib in previously treated (criz
NCT01685060
+ chemo) ALK+ NSCLC
II
Ongoing,
not recruiting
Ceritinib in crizotinib-naïve ALK+
NCT01685138
II
Ongoing
Ceritinib vs. chemo in crizresistant ALK+ NSCLC
NCT01828112
III
Ongoing
Expanded access ceritinib in
ALK+ NSCLC
NCT01947608
NA
Ongoing

56. Alectinib (300 mg PO BID) in crizotinib-naïve
ALK+ Japanese NSCLC Pts
ORR 93.5%
(assessment by IRC)
Median duration of
treatment not yet reached
but >14 months
Nakagawa, ASCO 2013, A#8033

57. Alectinib in Crizotinib-Refractory ALK+
Non-Japanese Population (N = 47)
Gadgeel, WCLC Sydney, 2013, A# O16.06

58. AP26113: ALK+ NSCLC Anti-Tumor Activity
Target Lesions (N=34)
Best Change from Baseline in Target Lesion (%)
Best Overall Response:
58
•
40
20
b
Progressive Disease
Stable Disease
Partial Response
Complete Response
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)
0
-20
-40
a
c
b
-60
a
-80
-100
•
Response duration 8+ to 40+ weeks
• 14 confirmed, 4 awaiting confirmation
d
a
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
Data as of 6 Sept 2013

59. AP26113: ALK+ NSCLC Time on Treatment
Discontinued
Patients
(N=40)
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
0
10
20
30
40
50
60
70
80
Time on Treatment (Weeks)
First dose to last dose if discontinued, first dose to date of data cut if on study
Data as of 6 Sept 2013

60. 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. Gettinger
Data as of 6 Sept 2013

61. AP26113: Brain Metastases Activity
Baseline
After 8 wks of 180 mg AP26113
Patient 1
Both patients
have crizotinibresistant ALK+
NSCLC
Patient 2
Images courtesy
of
Dr. D.R. Camidge
Data as of 6 Sept 2013

62. AP26113: Brain Metastases Activity
Discontinued
Patients
On Study
0
10
20
30
40
50
60
Time on Treatment (Weeks)
• 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
Data as of 6 Sept 2013

63. HSP90 Chaperone Stabilizes Client Proteins:
Inhibitors leads to Client Protein Degradation
Proper folding
HSP90 binds to client protein
>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 inhibitor prevents HSP90
binding to client (competitively binds
the ATP pocket of hsp90)
Activated client; cell survival,
proliferation
Inactive client, degraded through
proteasome

64. IPI-504 (Retaspimycin): HSP90 Inhibitor Efficacy
by ALK FISH Status
Sequist, ASCO 2011

65. HSP90 Inhibitor Ganetespib Especially
Active in ALK-Positive Patients
Wong, ASCO 2011

66. Ganetespib activity in ALK+ NSCLC
24 year old male
Chemotherapy, progressed; crizotinib 1 year (PR), progressed
Baseline
After three weeks
(3 doses) ganetespib
66

67. 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

68. 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

69. 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