west egfr mutation acquired resistance
DESCRIPTION
Review by Dr. H. Jack West of current understanding of mechanisms behind and emerging treatment options for patients with advanced NSCLC with acquired resistance to EGFR tyrosine kinase inhibitors after a good initial response.TRANSCRIPT
How Do We Manage Acquired Resistance to EGFR TKI Therapy?
Howard (Jack) West, MD Swedish Cancer Institute
Seattle, WA
Challenging Cases in Breast & Lung Cancer
San Francisco, CA October 22, 2011
Why Do We See Acquired Resistance?
Overcoming T790M: Irreversible TKIs
T790M Mutation • Most common mechanism of resistance to EGFR TKIs
(50-68%) • May have a better prognosis than non-T790M
mechanisms: 19 vs. 12 mo post-progression, Oxnard, CCR 2010
N = 93
• T790M more likely to show progression in lungs/pleura
• Non-T790M more likely to progress distantly, & worse PS
Oxnard, Clin Cancer Res 2010
Rapid acceleration of disease progression resulting in hospitalization and/or death after discontinuation of gefitinib or erlotinib and before initiation of study drug (up to ~1/4 of pts in MSKCC series (Chaft, CCR, 2011) Last day of TKI Off EGFR TKI Resumed TKI
Day 0 Day 21 Day 42
From Riely, CCR 2007
Rapid Progression with Discontinuation of EGFR TKI after Prolonged PFS
Brakes may not be as good, but better than no brakes
Such Patients Often Show Slow, Modest Progression
Irreversible TKIs in Clinical Trials
• HKI-272 (EGFR + Her2) • RR 2% in TKI-resistant patients • Intriguing responses in G719X patients (Sequist, JCO 2010)
• XL-647 (EGFR, Her2, VEGF) • RR 2% in TKI-resistant patients (Pennell, Chicago Lung ’08)
• PF-299804 (EGFR + Her2) • RR 7% in TKI-resistant patients (Janne, ASCO ’09)
• BIBW-2992 (EGFR + Her2) • RR 7% in TKI-resistant pts, 2 mo PFS increase (Miller, ESMO’10) • Interesting ongoing study combining afatinib and cetuximab based on
a mouse model that was successfully treated w/ this combo
LUX-Lung 1: Trial design
Randomization 2:1 (Double Blind)
Oral afatinib (BIBW2992) 50 mg once daily plus BSC
Oral placebo once daily plus BSC
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL (LC13 & C30), safety • Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter • Exploratory biomarkers:
Archival tissue testing for EGFR mutations (optional; central lab) Serum EGFR mutational analysis (all patients)
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
Miller, ESMO 2010
Maximum decrease in tumor size from baseline (independent review)
Miller, ESMO 2010
Afatinib vs. Placebo: Disease control rate and objective responses
Independent Review
Afatinib (%) Placebo (%)
PR, (regardless of confirmation)
PR, (confirmed)
13*
7*
0.5
0.5
SD ≥ 8 wks 51 18
DCR (PR+SD) ≥ 8 wks 58** 19
Median duration of confirmed response: 24 weeks
* P < 0.01 compared to placebo ** P < 0.0001 compard to placebo
Miller, ESMO 2010
Afatinib vs. Placebo: PFS by independent review
Miller, ESMO 2010
Afatinib vs. Placebo: Patient Reported Outcomes
*All scores were estimated from the EORTC QLQ-LC13 except for “Short of Breath” and “Pain” which used EORTC QLQ-C30; improved means that EORTC symptom scores were ≥10 points lower than baseline at any time during the study
**EORTC cough, dyspnea and pain endpoints as pre-specified in the trial protocol Miller, ESMO 2010
Afatinib vs. Placebo: Primary analysis of Overall Survival
Miller, ESMO 2010
Expansion cohort part4 MTD cohort expanded up to 80 EGFR mutation-positive patients: 40 T790M-positive and 40 T790M-negative
1 EGFR G719X, exon 19 deletion, L858R, L861Q 2Progression of disease (RECIST v1.1) on continuous
treatment with erlotinib or gefitinib within the last 30 days.
3Amended from original 14 days interval 4Acquisition of tumor tissue after the emergence of
acquired resistance was mandated
Dose escalation schema 3-6 patients per cohort
afatinib p.o. daily + escalating doses of cetuximab IV q 2 weeks
Dose levels starting at: afatinib 40 mg + cetuximab 250 mg/m2
Predefined maximum dose: afatinib 40mg + cetuximab 500 mg/m2
NSCLC w/ EGFR mut’n1
and SD ≥ 6 mo on erlotinib/gefitinib
or CR or PR to erlotinib/gefitinib
Jangigian & Pao, ASCO 2011, #7525
Afatinib/Cetuximab in EGFR TKI-Resistant NSCLC
PD2
Stop EGFR TKI For ≥ 72 hours3
Afatinib + Cetuximab at MTD: Responses by EGFR Mutation
40% confirmed response rate and a clinical benefit rate of 90% Jangigian & Pao, ASCO 2011, #7525
Afatinib + Cetuximab: Insights & Future Directions
• Remarkable efficacy seen in EGFR TKI-resistant tumors – Requires further validation
• Activity not specific to common T790M mutant
• Need to further define biology and refine patient population for phase III trial
MET Overexpression
Met Inhibitors in Clinical Trials
• ARQ-197, specific MET inhibitor – Randomized phase II of erlotinib +/- ARQ-197 in TKI-naïve patients
showed some benefit of combo but wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Schiller, ASCO 2010)
• Met-Mab – Randomized phase II of erlotinib +/- MET-Mab in TKI-naïve pts
showed benefit of combo, but again wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Spigel , ASCO 2011
• XL-184, MET + RET + VEGF – Randomized phase II of erlotinib +/- XL-184 in TKI-resistant patients,
completed but not reported yet
• PF-02341066: – Still in early phase studies
MetMAb is an anti-Met Monovalent Antibody that Inhibits HGF-MediatedActivation
Rationale for targeting Met: • Met is amplified, mutated,
overexpressed or uniquely activated in many tumors
• Met expression is associated with worse prognosis in many cancers including NSCLC
• Met activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations
MetMAb: • One-armed format designed to
prevent HGF-mediated stimulation of pathway
• Preclinical activity across multiple tumor models
MetMAb
Met
HGF HGF
Met
Growth Migration Survival
No activity
HGF: Hepatocyte growth factor Spigel, ASCO 2011, #75051
Randomized Phase II: Erlotinib + MetMAb or Placebo in 2nd/3rd line NSCLC
Stage IIIB/IV NSCLC 2nd/3rd line Tissue required PS 0–2 Stratification factors: • Tobacco history • Performance status • Histology
N = 137
N = 69
Co-primary objectives: • PFS in ‘Met Diagnostic
positive’ patients (est. 50%) • PFS in overall ITT population
Other key objectives: • OS in ‘Met Diagnostic positive’
patients • OS in overall ITT patients • Overall response rate • Safety/tolerability
PD
add MetMAb Must be eligible to be treated with MetMAb
Spigel, ASCO 2011, #7505
Erlotinib 150 mg PO daily MetMAb 150 mg/kg IV Q3wk R
A N D Erlotinib 150 mg PO daily
Placebo IV Q3wk N = 68
N = 27
Met Dx Negative
Development of Met IHC for Use as a Companion Diagnostic
• Technical metrics – Tissue was obtained from 100% of patients. – 93% of patients had adequate tissue for evaluation of Met by IHC
• Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories
• Met diagnostic status was assessed after randomization and prior to unblinding – ‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining intensity
Negative (0) Weak (1+)
Moderate (2+) Strong (3+)
Met Dx Negative
Met Dx Positive
MET IHC score 1 2 3
0
1
10
100
1000
0
Met Dx Positive
MET
mR
NA
(2-Δ
ct)
52% patients enrolled were ‘Met Diagnostic Positive’
Spigel, ASCO 2011, #7505
Note: + = censored value.
Erlotinib + MetMAb or Placebo: Efficacy in ITT Population
Time to progression (months) 0 3 6 9 12 15 18
Prob
abili
ty o
f pro
gres
sion
free
0.0
0.2
0.4
0.6
0.8
1.0
Placebo + erlotinib
7.4
41
MetMAb + erlotinib
8.9 0.80
(0.50–1.3) 0.34 34
Median (mo) HR (95% CI) Log-rank p-value No. of events
Overall survival (months) 0 3 6 9 12 15 18 21
Prob
abili
ty o
f sur
viva
l 0.0
0.2
0.4
0.6
0.8
1.0
Placebo + erlotinib
2.6
56
MetMAb + erlotinib
2.2 1.09
(0.73–1.62) 0.69 48
Median (mo) HR (95% CI) Log-rank p-value No. of events
Note: + = censored value.
PFS: HR=1.09 OS: HR=0.8
Control arm was consistent with previous studies in a similar population (Br21 PFS 2.2 mo, OS 6.7 mo, ORR 8.9%)
Spigel, ASCO 2011, #75051
Erlotinib + MetMAb or Placebo: Efficacy in Met Diagnostic Positive NSCLC Patients
Time to progression (months) 0 3 6 9 12 15 18
Prob
abili
ty o
f pro
gres
sion
free
0.0
0.2
0.4
0.6
0.8
1.0
Placebo + erlotinib
3.8
26
MetMAb + erlotinib
12.6 0.37
(0.19–0.72) 0.002
16
Median (mo) HR (95% CI) Log-rank p-value No. of events
Overall survival (months) 0 3 6 9 12 15 18 21
Prob
abili
ty o
f sur
viva
l 0.0
0.2
0.4
0.6
0.8
1.0
Placebo + erlotinib
1.5
27
MetMAb + erlotinib
2.9 0.53
(0.28–0.99) 0.042
20
Median (mo) HR (95% CI) Log-rank p-value No. of events
The addition of MetMAb to erlotinib doubled the progression free survival and nearly tripled the overall survival in this population
PFS: HR=0.53 OS: HR=0.37
Spigel, ASCO 2011, #75051
ARQ-197: c-MET Receptor Tyrosine Kinase
• Implicated in tumor cell migration, invasion, proliferation, and angio- genesis1
• Only known high-affinity receptor for hepatocyte growth factor (HGF)1
1. Birchmeier C and Gherardi E. Trends Cell Biol 1998;8:404–10 2. Cappuzzo F et al. JCO 2009;27:1667–74 3. Engelman JA et al. Science 2007;316:1039–43 4. Bean J et al. PNAS 2007;104:20932–7
• c-MET amplification associated with: • Poor prognosis in NSCLC2
• Resistance to EGFR TKIs3,4
Rand Phase II: Erlotinib + Tivantinib (ARQ-197) or Placebo in Prev Treated Adv NSCLC
Inop Loc Adv/Met NSCLC >1 prior line of Rx No prior EGFR TKI PS 0–2 Stratification factors: sex, age, ECOG PS, smoking status, histology, prior Rx, best response, & geography (U.S. vs. ex-U.S.)
N = 167
N = 84
Endpoints • 1° PFS • 2° ORR, OS • Subset analyses • Crossover: ORR
PD
add ARQ-197
Sequist, JCO 2011
Erlotinib 150 mg PO daily ARQ-197 360 mg PO BID R
A N D Erlotinib 150 mg PO daily
Placebo PO BID N = 83
N = 21
Erlotinib + Tivantinib or Placebo: Efficacy (ITT Population)
Sequist, J Clin Oncol 2011
Erlotinib + Tivantinib or Placebo: PFS & OS in Non-Squamous NSCLC Patients
Sequist, J Clin Oncol 2011
Erlotinib + Tivantinib or Placebo: Time to New Metastatic Lesions (ITT & Non-Squamous)
Sequist, J Clin Oncol 2011
5.0 2.0
Erlotinib + Tivantinib or Placebo: PFS in Histologic and Molecular Subgroups
ARQ197/erlotinib
Placebo/ erlotinib
Unadjusted HR (95% CI) N Median PFS (95% CI, weeks)
Squamous Cell 26 / 24 13.7 (8.0‒18.1) 8.4 (7.9‒21.0)
Non-Squamous Cell 58 / 59 18.9 (15.0‒31.1) 9.7 (8.0‒16.0)
c-MET FISH >4 19 / 18 15.4 (8.1‒24.4) 15.3 (7.1‒16.3)
c-MET FISH >5 8 / 11 24.1 (16.3‒NE) 15.6 (7.9‒31.4)
EGFR mutant 6 / 11 24.1 (8.0‒32.1) 21.0 (8.1‒36.0)
EGFR wt 51 / 48 13.7 (8.1‒18.1) 8.1 (7.9‒9.9)
KRAS mutant 10 / 5 9.7 (7.9‒NE) 4.3 (1.1‒8.0)
KRAS wt 49 / 45 15.4 (8.1‒18.1) 9.9 (8.0‒16.0)
1.0 0 Favors
ARQ 197/Erlotinib Favors
Erlotinib/placebo
HR=0.70
HR=0.18
0.5 1.5
HR=1.01
HR=1.23
HR=0.45
HR=0.71
HR=1.05
HR=0.71
Schiller, ASCO 2010
2 PR2
34 Crossover Patients
23 Evaluable for Response1
1 Baseline + ≥1 post-baseline scan. Reasons for non-evaluable incl: - Clinical progression (n=4) - Active but haven’t received 1st post-progression scan (n=2)
- Death (n=1) - Dosing delay (n=1) - Withdrew consent (n=1) - Investigator decision (n=1)
9 SD3
12 PD
2 Pt # 24: EGFR IND KRAS WT
c-MET > 4
Pt # 58: EGFR MUT KRAS WT c-MET > 5
3 3‒18+ weeks
Erlotinib + Tivantinib or Placebo: Crossover Patients
Schiller, ASCO 2010
Research Efforts for Acquired Resistance to EGFR TKIs
• Afatinib/cetuximab promising • Unexpectedly, not correlated with T790M • Phase III trial in development
• MetMAb phase II trial encouraging in subset • Benefit appears limited to high Met expression (detrimental in low Met expression) • Phase III trial in development
• Tivantinib phase II trial favorable, esp in non-squamous • Phase III trial now ongoing • Possibly particularly helpful for KRAS mut’n positive
• Increasing interest in post-PD biopsies
Acquired Resistance to EGFR TKIs: Practical Principles for the Clinic
• Patients can respond to EGFR TKI with rechallenge, especially after long interval off of EGFR TKI (breaks onc rule of “you can never go back”
• Some patients will have a rebound rapid progression after being taken off of an EGFR TKI • Heterogeneous populations of cancer cells • Is it better to continue the EGFR TKI and add an agent/
regimen, or to stop it and potentially restart it later?? • I favor continuing EGFR TKI when PD < PR, but not
when PD is very clear • No comparison and no good data to address this