ALK e meccanismi di resistenza

Lucio CrinòS.C. di Oncologia Medica

Azienda Ospedaliera di Perugia

Outline

• Current evidence with ALK-TKIs in naïve patients

• ALK-TKIs in crizotinib-refractory disease

• Challenging brain mets in ALK+ disease

• Resistance to crizotinib: focus on ‘unknown’ mechanisms

Outline

• Current evidence with ALK-TKIs in naïve patients

• ALK-TKIs in crizotinib-refractory disease

• Challenging brain mets in ALK+ disease

• Resistance to crizotinib: focus on ‘unknown’ mechanisms

Crizotinib for ALK+ advanced NSCLC: RR appr. 60%, PFS 7.7-9.7 mos

Crizotinib for ALK+ advanced NSCLC: RR appr. 60%, PFS 7.7-9.7 mos

Study No. of patients RR (%) PFS (mos.)

A8081001 143 60.8 9.7

A8081005 261 59.8∞ 8.1

A8081007 173 65* 7.7

French Temporary Authorization for use of Crizotinib

230 56.5 Not reported

∞259 pts evaluable for response*Independent radiologic review

Camidge, et al. Lancet Oncol 2012Kim, et al. ASCO 2012

Shaw, et al. NEJM 2013Perol, et al. ECCO 2013

[TITLE]

Presented By Fabrice Barlesi, MD, PhD at 2013 ASCO Annual Meeting

Drug Inhibition of secondary L1196M ‘gatekeeper’

mutation

Company Clinical stage

AP-26113 Yes Ariad Pharmaceuticals

Phase I/II

LDK378 Yes Novartis Phase II/III

Alectinib Yes Chugai Pharmaceuticals

Phase I/II

TSR-011 Yes Tesaro Phase I

NMS-E628 Yes Nerviano Medical Phase I

ASP-3026 Yes Astellas Phase I

X-376 and -396 Yes Xcovery Phase I

CEP-28122 Yes Cephalon Preclinical

2nd generation ALK-inhibitors in clinical development

2nd generation ALK-inhibitors in clinical development

RR with 2nd generation ALK-inhibitors in Crizotinib-naïve patients

RR with 2nd generation ALK-inhibitors in Crizotinib-naïve patients

Author Drug No. of pts RR (%)

Camidge (ECCO 2013)

AP26113* 3 100

Shaw (ASCO 2013)

LDK378** 35 60

Seto (Lancet Oncol 2013)

Alectinib*** 46 93.5

*60-300 mg/d**400-750 mg/d***300 mg x 2/d; Asiatic (Japanese) patients

Outline

• Current evidence with ALK-TKIs in naïve patients

• ALK-TKIs in crizotinib-refractory disease

• Challenging brain mets in ALK+ disease

• Resistance to crizotinib: focus on ‘unknown’ mechanisms

CHEMOTHERAPY

TKI beyond PD or 2nd generation TKI ± local therapy

TKI beyond PD + brain RT

ALK rearrangementProgression on

Crizotinib after response or SD > 3 mo

No prior pemetrexedN=114

Pemetrexed alone

Pemetrexed +ongoing Crizotinib

RANDOMIZE

Co-primary endpoint: progression-free survivalRespnse rate, pemetrexed alone

Chemotherapy +/- ongoing crizotinib for acquired resistance in ALK-positive NSCLC

Chemotherapy +/- ongoing crizotinib for acquired resistance in ALK-positive NSCLC

SWOG 1300 (in development)SWOG 1300 (in development)

PI: Ross CamidgePI: Ross Camidge

Crizotinib beyond progressionCrizotinib beyond progression

Ou, et al. IASLC 2013

AP26113 in ALK+ NSCLCs (N=34)

13All 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, 4 not confirmed

Data as of 6 Sept 2013

Be

st

Ch

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ge

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m B

as

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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)

Camidge, et al. IASLC 2013

Alectinib in crizotinib-refractory patients Overall RR 54.5% across all cohorts for all patients

Waterfall plot% tumor shrinkage

Days on

study

Duration on study(*: off study, data cut-off Sept. 12, 2013)

* ** *

*

**

**

*

**

**

Overall RR 59.5% for cohorts of 460 mg dose or higher

24 of the 47 patients received the drug for 120 days or longer

Gadgeel, et al. IASLC 2013

Outline

• Current evidence with ALK-TKIs in naïve patients

• ALK-TKIs in crizotinib-refractory disease

• Challenging brain mets in ALK+ disease

• Resistance to crizotinib: focus on ‘unknown’ mechanisms

• 13/28 (46%) patients at U. of Colorado with first progression in CNS

- 2/13 had synchronous systemic progression

Weickardt et al. JTO 2013

• Decreased CSF:plasma (0.0026) ratio suggestive of pharmacological failure of Crizotinib

Costa et al. JCO 2011

The problem of CNS progression to Crizotinib in ALK+ patients

The problem of CNS progression to Crizotinib in ALK+ patients

Crizotinib antitumour activity in patients with or without brain metastasis (BM) at baseline

  Previously untreatedfor BM (n=109)

  Previously treated for BM (n=166)

  No BM detected(n=613)

  n Outcome   n Outcome   n Outcome

DCR at 12 weeks, % (95%CI)                

IC 109 56 (46−66)   166 62 (54−70)     NA

Systemic 109 63 (54−72)   166 65 (57−72)   613 71 (68−75)

ORR, % (95% CI)                

IC 109 7 (3−14)   166 7 (4−12)     NA

Target-lesion BM 22 18 (5−40)   18 33 (13−59)     NA

Systemic 109 53 (43−63)   166 46 (39−54)   613 55 (51−59)

Median time to tumor response (range),a weeks

IC 8 6.0 (4.9−12.4)   12 6.4 (5.9−17.7)     NA

Systemic 58 6.1 (2.0−31.4)   77 6.1 (3.1−35.3)   336 6.1 (3.0−49.1)

Median duration of responseb (range),a weeks

IC 8 26.4 (6.1−59.3)  12 NR (6.0−59.9)     NA

Systemic 58 47.9 (5.3−55.0)  77 55.6 (4.4−95.3)   336 49.0 (4.1−96.1)

Median systemic PFS,b (95% CI),c mo 109 8.3 (6.7−14.0)  166 13.5 (6.2−16.5)   613 9.9 (8.8−12.2)

NR, not reachedaIn patients with confirmed objective response; bKaplan−Meier method; cBrookmeyer−Crowley method Costa, et al. IASLC 2013

Example of a complete response of a brain lesion in response to crizotinib treatment

Before initiation of crizotinib 6 weeks after crizotinib 250 mg BID

This patient presented with a brain lesion previously treated with chemotherapy and palliative IC radiation, which was classified as a target lesion. A CR in this lesion was observed after 6 weeks of treatment and had persisted for 54 weeks by data cutoff (courtesy of J-Y Han, National Cancer Center, Goyang, South Korea)

Systemic progression-free survival (PFS) by presence or absence of brain metastases (BM) at baseline (BL)

The presence of BM at BL does not significantly affect systemic PFS to crizotinib

Costa, et al. IASLC 2013

CNS activity of alectinib• ORR of the 21 patients as determined by central image review

• 9/21 patients with baseline CNS metastasis had measurable CNS lesions and received no prior radiation within 4 weeks from first dose of alectinib

– No CR. 5/9 achieved CNS PR (≥ 30% reduction in sum of largest dimension). 2/9 had CNS stable disease and 2/9 had CNS progression.

Brain RT > 4 wks

No brain RT91+ 203+ 42

224+

224+287+98+ 196+

294+

Days on study

CR PR SD PD

Total N=21 6 5 8 2

% 29% 24% 38% 10%

PR

Progressing CNS mets Ou, et al. IASLC 2013

Outline

• Current evidence with ALK-TKIs in naïve patients

• ALK-TKIs in crizotinib-refractory disease

• Challenging brain mets in ALK+ disease

• Resistance to crizotinib: focus on ‘unknown’ mechanisms

Unraveling the mechanisms of resistance to EGFR-TKIs and Crizotinib

Unraveling the mechanisms of resistance to EGFR-TKIs and Crizotinib

Katayama, et al. Sci Trans Med. 2012Doebele, et al. Clin Cancer Res. 2012

Unknown

Bypass tracksEGFR MTKRAS MT

Am

plifi

ed

L1196M

G1269A

S1206YG1202R1151TinsL1152RC1156Y

No ALKamp or mut

ALKamp

ALKmutALK+

IGF-1R and IRS-1 are up-regulated in ALK TKI resistant cells

pIGF-1R Y1131

IRS-1 pY941

AKT

pAKT S473

S6

pERK

ERK

IRS-1

IGF-1R

pS6

DMSO

500

5000ALK TKI [nM]

TKI sensitive

DMSO

500

5000

TKI resistant

pALK Y1604

ALK

References: Lovly, C et al 2011 Cancer Research and Lovly, C et al submitted

Generation of isogenic pairs of ALK TKI sensitive and ALK TKI resistant cells

pIGF-1R and IRS-1 are up-regulated in patient biopsy samples at the time of acquired

resistance to crizotinib

Reference: Lovly, C et al submitted

pIGF-1R and IRS-1 are up-regulated in patient biopsy samples at the time of acquired

resistance to crizotinib

Key:- X-376: ALK TKI- MAb391: IGF-1R MAb

IGF-1R inhibitors sensitize H3122 ALK TKI resistant cells

to the anti-proliferative effects of ALK inhibitors

- Soft agar assay in H3122 X-376 resistant cells- Similar results seen in H3122 crizotinib resistant cells- Analogous results seen with IGF-1R TKIs in addition to IGF-1R MAbs

Reference: Lovly, C et al submitted

Rationale for double ALK/HSP90 inhibition in ALK+ advanced NSCLC

Rationale for double ALK/HSP90 inhibition in ALK+ advanced NSCLC

From Crystal and Shaw, Clin Cancer Res 2012

Hsp90 inhibitor AUY922: activity in ALK+ patients (n=19/22)

Hsp90 inhibitor AUY922: activity in ALK+ patients (n=19/22)

Felip, et al. ESMO 2012

Tumor #6transplanted

H2228R tumor xenografts treated with AT13387

• AT13387 treatment inhibits the growth of an ALK-dependent tumor xenograft with acquired resistance to crizotinib

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1 8 15 22 29

Tum

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Day

Crizotinib 50 mg/kg po qd + cyclodextrin ip 1qw

Crizotinib 50 mg/kg po qd + AT13387 55 mg/kg ip 1qw

Wallis, IASLC 2013

The Hsp90i AT13387 overcomes acquired resistance to crizotinib

The Hsp90i AT13387 overcomes acquired resistance to crizotinib

ALK: (e.g. ALK-TKI + Hsp90 inhibitor; ALK-TKI + IGFR-1R inhibitors )

Therapy Therapy Therapy Resistance

Selection for genetic instabilitySelection for genetic instability

Selection for resistance

Rationale for the upfront use of combination regimens

Rationale for the upfront use of combination regimens

Sang et al. Cancer Discov 2013

Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition: ALK-TKI + Ganetespib

Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition: ALK-TKI + Ganetespib

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1 8 15 22 29 36

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Vehicle (cyclodextrin) ip 1qw

AT13387 55 mg/kg ip 1qw

Crizotinib 50 mg/kg po qd

Crizotinib 50 mg/kg po qd + AT13387 55 mg/kg ip 1qw

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1 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127

Rel

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Crizotinib

Crizotinib+AT13387

Continuous treatment

Final tumor weight (Day 126)

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125450500

Crizotinib Crizotinib+ AT13387

• Combination of AT13387 and crizotinib shows improved inhibition of tumor growth over monotherapies

• Combining crizotinib upfront with AT13387 delays the emergence of resistance in vivo

Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition: ALK-TKI + AT13387

Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition: ALK-TKI + AT13387

Wallis, IASLC 2013

Regimen Phase ClinicalTrials.gov Identifier

Crizotinib + AT13387 I/II NCT01712217

Crizotinib + Ganetespib I/II NCT01579994

LDK378 + AUY922 Ib NCT01772797

Clinical attempt to better Crizotinib: trials of ALK/HSP90 inhibition

Clinical attempt to better Crizotinib: trials of ALK/HSP90 inhibition

ALK-inhibition in ALK+ NSCLC• Platform networks required tools for optimization of NSCLC treatment

• 2nd generation ALK-TKIs may break the boundary of 60% response rate observed with Crizotinib

• Appr. 60% of RR with 2nd generation ALK-TKIs in Crizotinib-refractory patients

• 2nd generation ALK-TKIs may prevent CNS pharmacological failure

• Hsp90 activity and IGF-1R upregulation may be partly responsible for the non-ALK dominant mechanisms of resistance to crizotinib

• Robust preclinical evidence of anticancer efficacy with ALK-TKIs + HSP90 or IGF-1R inhibitors in ALK+ advanced NSCLC

lucio.crino@ospedale.perugia.itlucio.crino@ospedale.perugia.it

Thanks for your attention