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


• 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


• 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


• 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


PI: Leora Horn (Vanderbilt)

Advanced NSCLC


Resp to EGFR TKI>4 mo


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


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?


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



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


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


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


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


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

Acquired Resistance to Targeted Therapy in EGFR and ALK-Positive Lung Cancer: New Ideas, New Agents

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Transcript of Acquired Resistance to Targeted Therapy in EGFR and ALK-Positive Lung Cancer: New Ideas, New Agents