acquired resistance patient forum

Acquired Resistance Patient Forum

September 6, 2014 | Boston

In ALK, ROS1 & EGFR Lung Cancers

Combinations for Treating EGFR Acquired Resistance

Melissa L. Johnson, MD

Dx: EGFR+ lung cancer

Acquired Resistance

Tarceva

Combination Treatments for EGFR Acquired Resistance

Tarceva+

NEW DRUGGilotrif

Gilotrif+

NEW DRUG

Can we make 1st Gen TKI Better?• We have tried!!• Selected approaches to enhancing EGFR TKI in order to overcome or prevent

resistanceErlotinib + ChloroquineErlotinib + SirolimusErlotinib + Onartuzumab (anti-Met)Erlotiinb + EntinostatErlotinib + R1507 (anti IGF-1)Erlotinib + Tivantinib Erlotinib + SorafanibErlotinib + DasatinibErlotinib + MK2206 (AKT)Erlotinib + MM-121 (anti-ErbB3)Erlotinib + XL184Erlotinib + Rilotumumab (anti-HGF)Erlotinib + Patritumumab (anti-ErbB3)Erlotinib + AUY-922 (HSP 90 inhibitor)

Slide adapted, courtesy of Thomas J. Lynch, Jr., MD


Dx: EGFR+ lung cancer

Acquired Resistance

Tarceva/Gilotrif(erlotinib/afatinib)


Tarceva/Gilotrif(erlotinib/afatinib)

+NEW DRUG

Flare associated with shorter TTP

Chaft, Clin Cancer Res 2011

• 14 of 61 patients (23%, 95% CI 14-35%) had a disease flare (hospitalization or death)• Median time from last TKI to flare was 8 days (range 3-21 days)• 3 patients went on to trial treatment


AUY922:An “Onco-Chaperone” Inhibitor

Neckers and Workman Clin Cancer Res 2012

AUY922 (in yellow) is a synthetic isoxazole resorcinol HSP90 inhibitor, shown here bound to the deep ATP pocket of HSP90

(in blue)

AUY922+ Erlotinib Melissa L. Johnson


Cohort Dose of AUY922 IV weekly

Dose of Erlotinib PO daily

# pts enrolled

1 25 mg/m2 75 mg 3

2 25 mg/m2 150 mg 3

3 37.5 mg/m2 150 mg 3

4 55 mg/m2 150 mg 3

5 70 mg/m2 150 mg 6

AUY922 + Erlotinib Phase I Dose-Escalation



Preliminary Activity

C1D1 C1D28

Patient 01-102AUY922 25 mg/m + Erlotinib 75 mgDuration of therapy: 6 months

HSP90 Inhibitors in Lung Adenocarcinoma


Stage IV Adenocarcinoma+EGFR mutationAcquired Resistance

Biopsy at resistance30 day erlotinib lead-in

Erlotinib 150mg PO qdayAUY922 70mg/m2

Key Inclusion Criteria•Advanced lung adenocarcinoma•EGFR mutation OR previous response to EGFR TKI•EGFR TKI for ≥6 months and 1 full month prior to study start•Biopsy at time of acquired resistance to EGFR TKI

Key Exclusion Criteria•Brain metastasis that are symptomatic and/or requiring escalating doses of steroids•Systemic treatment within 4 weeks, RT within 2 weeks

AUY922 + Erlotinib Phase II Study Design

Definition of Acquired Resistance19

• Previously treated with single-agent EGFR-TKI• Tumor harbors TKI-sensitive EGFR mutation (G719X, ex 19 del, L858R, L861Q)• EITHER RECIST-defined PR/CR OR ≥ 6 months clinical benefit (SD) with single-agent EGFR-TKI followed by systemic POD

Statistical Considerations:• stage I: 16 pts (if ≥2 responses, proceed to stage II)• stage II: 9 pts (if ≥ 5 responses overall, AUY922 and erlotinib are worthy of further study)• α=10%; β=10%; p0=10%; p1=30%

19 Jackman JCO 2009

Primary endpoint: Overall response rate ORR (CR + PR)Secondary endpoints: Progression-free survival, Overall survival, ORR in T790M+, Toxicity

Melissa L. Johnson

Molecular Characteristics

N=37

AUY922 25-55 mg/m2

N=12

AUY922 70 mg/m 2

N=25

Primary EGFR mutations

EGFR exon 19 deletion 25 10 15

EGFR exon 21 L858R 11 2 9

EGFR exon 21 L861Q: 1 0 1

EGFR mutation unknown

EGFR T790M found on repeat Tumor Biopsy, n (%) 16 (43%) 6 (50%) 10 (40%)

Median duration of EGFR-TKI therapy prior to developing acquired resistance, months (range)

12 (2-42) 13 (8-32) 11(2-42)


-60%

-40%

-20%

0%

20%

40%

60%

80%

100%

Best Response to AUY922 and Erlotinib

Partial Response (PR): 4/25 (16%)(95% CI 6-35%)Disease Control Rate (DCR): 14/25 (56%)(95% CI 37-73%)

Best

% c

hang

e in

targ

et le

sion

s

Progressive diseaseStable diseasePartial response

EGFR T790M


N=24

Pt ID EGFR 19/21 T790M

Best Response AUY922 + Erlotinib

Cycles Completed

Duration primary EGFR-TKI

(prior to AR)

96-501 21 T790M SD 2 7.43 DLT-prolonged QTc; junctional rhythm96-502 21 T790M* SD 1 11.00 Ophthalmologic tox ( gr 2 night blindness)96-503 19 T790M PR 2 11.57 Ophthalmologic tox (gr 2 night blindness/blurred)96-504 21 — POD 1 9.57 POD01-505 L861Q — POD 1 10.00 POD96-506 21 T790M POD 1 20.80 POD96-02 19 — POD 1 25.63 POD96-03 19 — POD 1 4.40 POD96-04 19 T790M POD 1 10.10 POD96-05 19 — SD 3 2.30 POD96-06 21 — SD 3 17.87 Patient withdrew consent96-07 21 — POD 1 11.93 POD96-08 21 T790M POD 1 12.80 POD96-09 19 Unk POD 1 8.83 Patient withdrew consent96-10 21 — POD 1 15.47 POD96-11 19 T790M PR 3 42.00 Patient withdrew consent96-12_ 21 — PR 13 19.80 96-13 19 T790M PR 3 25.00 Hepatic tox (gr 3 LFT elevation) 96-14 19 — SD 1 14.77 Opthalmologic tox (gr 2 night blindness) 96-15 19 — NEΩ 1 7.50 Hepatic tox (gr 3 LFT elevation) 96-16 19 — SD 2 6.60 Diarrhea (gr 3 colitis) 96-17 21 T790M SD 6 10.73 POD 96-18 19 — POD 1 3.03 POD 96-19 19 — NE∆ 1 16.63 POD 01-20_ 19 T790M NE∆ 2 6.00 POD

Individual Responses According to EGFR Mutations and Time on Primary EGFR-TKI

* Small cell transformation patient remains on study

Reason withdrawn from study


Afatinib + Cetuximab

Stop erlotinib/ gefitinib for ≥72 hours3

Disease progression2

Pathology confirmed NSCLC with

EGFR mutation1

OR

SD 6 monthson erlotinib/gefitinib

OR

Partial or complete response

to erlotinib/gefitinib MTD cohort expanded up to 80 EGFR mutation-positive patients4:

40 T790M+ and 40 T790M–

Dose escalation schema 3–6 patients per cohort

Afatinib p.o. daily + escalating doses of i.v. cetuximab q 2 weeks

Dose levels starting at:afatinib 40 mg +cetuximab 250 mg/m2

Predefined maximum dose:afatinib 40 mg +cetuximab 500 mg/m2

ECOG PS 0-2Age ≥ 18 years


Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor-Resistant EGFR Mutant Lung

Cancer with and without T790M

Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

Tumor Regression by T790M Mutation Statusat Recommended Dose

Horn at al. IASLC 2011


16Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

Cetux/Afatanib ToxicityN=126 All grades Gr 3-4

Rash 114 (90%) 25 (20%)

Diarrhea 89 (71%) 8 (6%)

Nail Effect 72 (57%) 0 (0%)

Stomatitis 71 (56%) 1 (1%)

Fatigue 59 (47%) 3 (2%)

Nausea 53 (42%) 3 (2%)

Xerosis 53 (42%) 3 (2%)


Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

Preliminary Efficacy ComparisonRR

T790M +RR

T790M - PFS

(months)

Tarceva/AUY922 30% 10% 1.7

Afatanib/Cetux 32% 28% 4.66

CO-1686 58% Inc.

AZD 9291 65% 22%

18


Toxicity Comparison

Any Grade Diarrhea Rash Unique Toxicities

Tarceva/AUY922 95% 81% Night blindness, elevated LFTs, prolongation of QTc

Afatanib/Cetux 71% 97% Nail effects, stomatitis

Tarceva/Bevacizumab 81% 99%

Hypertension, Proteinuria

19

T+A vs T (#8005)

• BeTa in second line setting• ATLAS as maintenance

– Both with compelling results in enriched populations of never smokers, East Asians

• Possible EGFR regulation of VEGF in EGFR mutant cell lines (Heymach)

Unselected Patient Population


JO25567 Study Design

• Primary endpoint: PFS (RECIST v1.1, independent review)

• Secondary endpoints: OS, tumor response, QoL, safety

• Exploratory endpoint: biomarker assessment

R

Chemotherapy-naïve

Stage IIIB/IV NSCLC or postoperative recurrence

Non-squamous

Activating EGFR mutations*

Exon 19 deletion

Exon 21 L858R

Age ≥20 years

PS 0–1

No brain metastasis

E monotherapyErlotinib 150mg qd

(n = 75)

EB combinationErlotinib 150mg qd +

bevacizumab 15mg/kg q3w(n = 75)

PD

PD

Stratification factors: sex, smoking status, clinical stage, EGFR mutation type

1:1

*T790M excluded

Abstract 8005: Presented by Terufumi Kato


Primary endpoint: PFS by independent review

75 72 69 64 60 53 49 38 30 20 13 8 4 4 077 66 57 44 39 29 24 21 18 12 10 5 2 1 0

00

1.0

EEBNumber at risk Time (months)

4 8 122 6 10 14 18 22 2616 20 24 28

0.2

0.4

0.6

0.8

PFS

prob

abili

ty

9.7 16.0

EBE

*log-rank test, two-sided


EB EMedian (months) 16.0 9.7

HR 0.54 (95% CI: 0.36–0.79)P value* 0.0015


PFS by EGFR Mutation TypeEB group E group

Median (months) 18.0 10.3HR 0.41

(95% CI: 0.24–0.72)

EB

E

E

EB

Number at risk

0

1.0

0

40

40 E

EB

Number at risk

EB

E

1.0

00

35

37

Time (months)

4 8 122 6 10 14 18 22 2616 20 24 28

38 33 2739 36 29 24 12 5 219 8 2 0

29 22 1235 26 16 9 5 1 09 3 0 0

Time (months)

4 8 122 6 10 14 18 22 2616 20 24 28

31 27 2233 28 24 14 8 3 211 5 2 0

28 17 1231 18 13 12 7 4 19 7 2 0

0.2

0.4

0.6

0.8

PF

S p

rob

ab

ility

PF

S p

rob

ab

ility

0.2

0.4

0.6

0.8

Exon 19 deletion Exon 21 L858REB group E group

Median (months) 13.9 7.1HR 0.67

(95% CI: 0.38–1.18)



Toxicity with Tarceva + Avastin JO25587

• No unforeseen toxicities or Rx-related deaths• Grade >3 toxicity 91% vs. 53% (esp. HTN, proteinuria)

• 41% discontinued bevacizumab for adverse effects– Primarily proteinuria (15%) or hemorrhagic (12%)– Bevacizumab discontinuation rate 10-15% in BeTa,

ATLAS trials


EGFR + NSCLC Trials-PFS (months)

1. Rosell et al. Lancet Oncol. 2012;13:239; 11. Zhou et al. Lancet Oncol. 2011;12:735; 3. Sequist et al. J Clin Oncol. 2013;31:3327; 4. Wu et al. Lancet Oncol. 2014;15:213; 5. Kato, Proc ASCO 2014, A#8005

EURTAC OPTIMAL Lux-LUNG-3 Lux-Lung-6 JO-25567-E JO-25567-E/B0

2

4

6

8

10

12

14

16

18

9.7

13.1 13.6

11.0

9.7

16

MedPFS (mo)

EURTAC1 OPTIMAL2 JO25587-Tarceva5

JO25587-T/A5

LUX-Lung-33

LUX-Lung-64


What’s next?Combination Treatments for EGFR Acquired Resistance

Akbay et al. Cancer Discovery 3:1355-1363, 2013

Summary

• TWICE the opportunity for success, but TWICE the side effects

• Upfront or after the development of Acquired Resistance?

• Future Directions: Tarceva + PDL-1 inhibitor?


acquired resistance patient forum

Documents

egfr tki

hsp90 inhibitor auy922

hsp90 inhibition

established client of

atp binding pocket of

deep atp pocket of hsp90

increased hsp90 expression

blue auy922 erlotinib