1. Combinations for Treating EGFR Acquired Resistance
Melissa L. Johnson, MD
Acquired Resistance Patient Forum
In ALK, ROS1 & EGFR Lung Cancers
September 6, 2014 | Boston

2. Combination Treatments for EGFR Acquired Resistance
Dx: EGFR+ lung cancer
Acquired Resistance
Tarceva
Tarceva +
NEW DRUG
Gilotrif
Key issue for combination therapies is: do you add the 2nd drug after patients begin to acquire resistance? Or do you start patients on 2 drugs from the beginning and hope the duration of therapy is longer than single agent alone?
Gilotrif +
NEW DRUG

3. Can we make 1st Gen TKI Better?
Combination Treatments for EGFR Acquired Resistance
Can we make 1st Gen TKI Better?
We have tried!!
Selected approaches to enhancing EGFR TKI in order to overcome or prevent resistance
Erlotinib + Chloroquine
Erlotinib + Sirolimus
Erlotinib + Onartuzumab (anti-Met)
Erlotiinb + Entinostat
Erlotinib + R1507 (anti IGF-1)
Erlotinib + Tivantinib
Erlotinib + Sorafanib
Erlotinib + Dasatinib
Erlotinib + MK2206 (AKT)
Erlotinib + MM-121 (anti-ErbB3)
Erlotinib + XL184
Erlotinib + Rilotumumab (anti-HGF)
Erlotinib + Patritumumab (anti-ErbB3)
Erlotinib + AUY-922 (HSP 90 inhibitor)
We have tried. Here’s just a representative list, including a trial I led that I’ll mention today. In each case, the drugs added to erlotinib were chosen because there was a rationale, at least in vitro, and usually preclinical data supporting the combinatino after the development of AR. Ill tell you about a couple of these trials—beccause they highlihgt some of the inherent problems of doing combination studies.
Slide adapted, courtesy of Thomas J. Lynch, Jr., MD

4. (erlotinib/afatinib) (erlotinib/afatinib)
Combination Treatments for EGFR Acquired Resistance
Dx: EGFR+ lung cancer
Acquired Resistance
Tarceva/Gilotrif
(erlotinib/afatinib) +
NEW DRUG
Tarceva/Gilotrif
(erlotinib/afatinib)
The second hypothesis is that you combine the two drugs from the beginning and hope the two prolong the existance of AR …we also saw an example of that at this year’s annual meeting…and we’ll talk about that as well.

5. Flare associated with shorter TTP
Combination Treatments for EGFR Acquired Resistance
Flare associated with shorter TTP
flare
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
Chaft, Clin Cancer Res 2011

6. An “Onco-Chaperone” Inhibitor
Combination Treatments for EGFR Acquired Resistance
AUY922:
An “Onco-Chaperone” Inhibitor
This was the strategy we employed for this trial combining erlotinib with HSP90 inhibitor AUY922
Here you see AUY922 in yellow binding deep within the ATP binding pocket of HSP90 shown in blue.
HSP90 is a chaperone protein responsible for late-stage maturation, activation and stability in a variety of client proteins. It is important for proper folding and function of both benign but especially malignant proteins. Increased HSP90 expression is associated with a worse prognosis for patients with non-small cell lung cancer (NSCLC)
Mutated EGFR is a well established client of HSP90 and there is a large body of pre-clinical data to suggest that HSP90 inhibition might therefore be a reasonable means of targeting AR .
AUY922 (in yellow) is a synthetic isoxazole resorcinol HSP90 inhibitor, shown here bound to the deep ATP pocket of HSP90 (in blue)
Neckers and Workman Clin Cancer Res 2012
AUY922+ Erlotinib Melissa L. Johnson

7. Dose of Erlotinib PO daily
Combination Treatments for EGFR Acquired Resistance
AUY922 + Erlotinib Phase I Dose-Escalation
Cohort
Dose of AUY922 IV weekly
Dose of Erlotinib PO daily
# pts enrolled 1
25 mg/m2
75 mg 3 2
150 mg
37.5 mg/m2 4
55 mg/m2 5
70 mg/m2 6
AUY922+ Erlotinib Melissa L. Johnson

8. HSP90 Inhibitors in Lung Adenocarcinoma
Preliminary Activity
Patient
AUY mg/m + Erlotinib 75 mg
Duration of therapy: 6 months
C1D1
C1D28
AUY922+ Erlotinib Melissa L. Johnson

9. AUY922 + Erlotinib Phase II Study Design
Stage IV Adenocarcinoma
+EGFR mutation
Acquired Resistance
Biopsy at resistance
30 day erlotinib lead-in
Erlotinib 150mg PO qday
AUY922 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
Primary endpoint: Overall response rate ORR (CR + PR)
Secondary endpoints: Progression-free survival, Overall survival, ORR in T790M+, Toxicity
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%
Melissa L. Johnson
19 Jackman JCO 2009

10. Molecular Characteristics
N=37
AUY mg/m2
N=12
AUY 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
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)
AUY922+ Erlotinib Melissa L. Johnson

11. Best Response to AUY922 and Erlotinib
Best % change in target lesions
Progressive disease
Stable disease
Partial response
EGFR T790M
Partial Response (PR): 4/25 (16%)(95% CI 6-35%)
Disease Control Rate (DCR): 14/25 (56%)(95% CI %)
AUY922+ Erlotinib Melissa L. Johnson

12. Individual Responses According to EGFR Mutations and Time on Primary EGFR-TKI
Pt ID
EGFR 19/21
T790M
Best Response AUY922 + Erlotinib
Cycles Completed
Duration primary EGFR-TKI (prior to AR)
96-501 21 SD 2
7.43
DLT-prolonged QTc; junctional rhythm
96-502
T790M* 1
11.00
Ophthalmologic tox ( gr 2 night blindness)
96-503 19 PR
11.57
Ophthalmologic tox (gr 2 night blindness/blurred)
96-504 —
POD
9.57
01-505
L861Q
10.00
96-506
20.80
96-02
25.63
96-03
4.40
96-04
10.10
96-05 3
2.30
96-06
17.87
Patient withdrew consent
96-07
11.93
96-08
12.80
96-09
Unk
8.83
96-10
15.47
96-11
42.00
96-12_ 13
19.80
96-13
25.00
Hepatic tox (gr 3 LFT elevation)
96-14
14.77
Opthalmologic tox (gr 2 night blindness)
96-15
NEΩ
7.50
96-16
6.60
Diarrhea (gr 3 colitis)
96-17 6
10.73
96-18
3.03
96-19
NE∆
16.63
01-20_
6.00
 POD
Reason withdrawn from study
Median number of cycles rec’d was 1. Even among pts who had a PR to therapy, med number of cycles was 3.
* Small cell transformation patient remains on study

13. Combination Treatments for EGFR Acquired Resistance
Afatinib + Cetuximab
Since its discovery, multiple clinical trials have studied therapies for acquired resistance to EGFR TKIs. Single agent second generation EGFR TKIs such as HKI 272 (inh EGFR and HER2), XL 647 (inh EGFR, HER2 and VEGF) an dBIBW an irreversible EGFR inhibitor which also inhibits EGFR, HER2 and HER4 also shown to have activity in transgenic mice with the T790M acquired resistance mutation. None of these agents, tested as single agents in patients with acquired resistance, demonstrating promising results. Targeted agents have also been tested in combination, shown here. Perhaps best shown on this schematic, Once again, every trial produced disappointing results

14. Combination Treatments for EGFR Acquired Resistance
Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor-Resistant EGFR Mutant Lung Cancer with and without T790M
Stop erlotinib/ gefitinib for ≥72 hours3
Disease progression2
Pathology confirmed
NSCLC with
EGFR mutation1 OR
SD 6 months
on erlotinib/gefitinib
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 0-2
Age ≥ 18 years
Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

15. Tumor Regression by T790M Mutation Status at Recommended Dose
Combination Treatments for EGFR Acquired Resistance
Tumor Regression by T790M Mutation Status at Recommended Dose
Horn at al. IASLC 2011

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

17. Cetux/Afatanib Toxicity
Combination Treatments for EGFR Acquired Resistance
Cetux/Afatanib Toxicity
N=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%)
Xerosis
Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

18. Preliminary Efficacy Comparison
Combination Treatments for EGFR Acquired Resistance
Preliminary Efficacy Comparison RR
T790M +
T790M -
PFS (months)
Tarceva/AUY922
30%
10%
1.7
Afatanib/Cetux
32%
28%
4.66
CO-1686
58%
Inc. 
AZD 9291
65%
22%

19. Toxicity Comparison Tarceva/AUY922
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
99%
Hypertension, Proteinuria

20. Combination Treatments for EGFR Acquired Resistance
T+A vs T (#8005)
Unselected Patient Population
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)
phase III Bevacizumab plus Tarceva (BeTa) trial of erlotinib with or without bevacizumab in the second-line treatment of NSCLC patients. The BeTa trial did not reach its primary endpoint of a longer OS time (9.3 months, versus 9.2 months for erlotinib plus placebo; HR, 0.97; 95% CI, 0.80–1.18; p = .75), although the combination resulted in a doubled PFS time (3.4 months, versus 1.7 months for erlotinib plus placebo; HR, 0.62; 95% CI, 0.52–0.75; p < .0001) and response rate (12.6%, versus 6.2% for erlotinib plus placebo; p = .006) with no evidence of greater toxicity beyond that expected with the individual agents alone (Table 2) [77]. The outcomes from the BeTa trial were disappointing because this initial test of the strategy of combining agents with maximal potency against each target turned out to be negative. Perhaps the heterogeneous nature of NSCLC [78] limits our ability to detect benefit from the inhibition of specific targeted pathways in an unselected patient sample. Molecular factors, such as somatic mutations to the EGFR and/or VEGFR signaling pathways may limit the benefits of targeted agents to subsets of patients that have yet to be properly identified [79]. In any case, several additional ongoing phase II and III trials are further exploring the combination of VEGFR and EGFR inhibition in NSCLC

21. Combination Treatments for EGFR Acquired Resistance
JO25567 Study Design
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
EB combination
Erlotinib 150mg qd +
bevacizumab 15mg/kg q3w
(n = 75) PD R
E monotherapy
Erlotinib 150mg qd
(n = 75)
1:1 PD
All were Asian, median age 67, pts more likely to be female and asian, ex 19 slightly more common than ex 21 mtns
Primary endpoint: PFS (RECIST v1.1, independent review)
Secondary endpoints: OS, tumor response, QoL, safety
Exploratory endpoint: biomarker assessment
Stratification factors: sex, smoking status, clinical stage, EGFR mutation type
*T790M excluded
Abstract 8005: Presented by Terufumi Kato

22. Primary endpoint: PFS by independent review
Combination Treatments for EGFR Acquired Resistance
Primary endpoint: PFS by independent review EB E
Median (months)
16.0
9.7 HR
0.54 (95% CI: 0.36–0.79)
P value*
0.0015
1.0
0.8
*log-rank test, two-sided
0.6 EB E
PFS probability
0.4
0.2
9.7
16.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time (months)
Number at risk EB 75 72 69 64 60 53 49 38 30 20 13 8 4 4 E 77 66 57 44 39 29 24 21 18 12 10 5 2 1
Abstract 8005: Presented by Terufumi Kato

23. PFS by EGFR Mutation Type
Combination Treatments for EGFR Acquired Resistance
PFS by EGFR Mutation Type
Exon 19 deletion
Exon 21 L858R
EB group
E group
Median (months)
18.0
10.3 HR
0.41 (95% CI: 0.24–0.72)
EB group
E group
Median (months)
13.9
7.1 HR
0.67 (95% CI: 0.38–1.18)
1.0
1.0
0.8
0.8
0.6
0.6
PFS probability
PFS probability
0.4
0.4 EB E EB E
0.2
0.2 2 4 6 8 10 12 14 16 18 20 22 24 26 28 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time (months)
Time (months)
Number at risk
Number at risk EB 40 39 38 36 33 29 27 24 19 12 8 5 2 2 EB 35 33 31 28 27 24 22 14 11 8 5 3 2 2 E 40 35 29 26 22 16 12 9 9 5 3 1 E 37 31 28 18 17 13 12 12 9 7 7 4 2 1
Abstract 8005: Presented by Terufumi Kato

24. Toxicity with Tarceva + Avastin JO25587
Combination Treatments for EGFR Acquired Resistance
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
More toxicity in Japanese patients, longer duration of treatment

25. EGFR + NSCLC Trials- PFS (months)
Combination Treatments for EGFR Acquired Resistance
EGFR + NSCLC Trials- PFS (months)
Med
PFS (mo)
LUX-
Lung-33
LUX-
Lung-64
JO25587-
Tarceva5
JO25587-
T/A5
EURTAC1
OPTIMAL2
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

26. Combination Treatments for EGFR Acquired Resistance
What’s next?
Akbay et al. Cancer Discovery 3: , 2013

27. Combination Treatments for EGFR Acquired Resistance
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?