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.
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West egfr mutation acquired resistance
1. 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
4. T790M Mutation
â˘âŻ Most common mechanism of resistance to EGFR TKIs
(50-68%)
â˘âŻ May have a better prognosis than non-T790M
mechanisms: 19 vs. 12 mo post-progression, Oxnard, CCR 2010
N = 93
â˘âŻ T790M more likely to show
progression in lungs/pleura
â˘âŻ Non-T790M more likely to
progress distantly, & worse PS
Oxnard, Clin Cancer Res 2010
5. Rapid Progression with Discontinuation of
EGFR TKI after Prolonged PFS
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
6. Such Patients Often Show
Slow, Modest Progression
Brakes may not be as good, but better than no brakes
7. Irreversible TKIs in Clinical Trials
â˘âŻ HKI-272 (EGFR + Her2)
â˘âŻ RR 2% in TKI-resistant patients
â˘âŻ Intriguing responses in G719X patients (Sequist, JCO 2010)
â˘âŻ XL-647 (EGFR, Her2, VEGF)
â˘âŻ RR 2% in TKI-resistant patients (Pennell, Chicago Lung â08)
â˘âŻ PF-299804 (EGFR + Her2)
â˘âŻ RR 7% in TKI-resistant patients (Janne, ASCO â09)
â˘âŻ BIBW-2992 (EGFR + Her2)
â˘âŻ RR 7% in TKI-resistant pts, 2 mo PFS increase (Miller, ESMOâ10)
â˘âŻ Interesting ongoing study combining afatinib and cetuximab based on
a mouse model that was successfully treated w/ this combo
8. LUX-Lung 1: Trial design
Patients with:
â˘âŻ Adenocarcinoma of the lung
â˘âŻ Stage IIIB/IV
â˘âŻ Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen) and
âĽ12 weeks of treatment with erlotinib or gefitinib
â˘âŻ ECOG 0â2
N=585
Randomization 2:1
(Double Blind)
Oral afatinib (BIBW2992) 50 mg once daily Oral placebo once daily
plus BSC plus BSC
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL (LC13 & C30), safety
â˘âŻ Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter
â˘âŻ Exploratory biomarkers:
Archival tissue testing for EGFR mutations (optional; central lab)
Serum EGFR mutational analysis (all patients)
Miller, ESMO 2010
9. Maximum decrease in tumor size from
baseline (independent review)
Miller, ESMO 2010
10. Afatinib vs. Placebo:
Disease control rate and objective responses
Independent Review
Afatinib (%) Placebo (%)
PR, (regardless of confirmation) 13* 0.5
PR, (confirmed) 7* 0.5
SD ⼠8 wks 51 18
DCR (PR+SD) ⼠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
12. Afatinib vs. Placebo:
Patient Reported Outcomes
*All scores were estimated from the EORTC QLQ-LC13 except for âShort of Breathâ and âPainâ which used EORTC QLQ-C30; improved
means that EORTC symptom scores were âĽ10 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
14. Afatinib/Cetuximab in
EGFR TKI-Resistant NSCLC
Dose escalation schema
NSCLC w/ 3-6 patients per cohort
EGFR mutân1
and PD2
afatinib p.o. daily + escalating doses of
SD ⼠6 mo on Stop EGFR TKI cetuximab IV q 2 weeks
erlotinib/gefitinib For ⼠72 hours3
or Dose levels starting at:
CR or PR afatinib 40 mg +
to erlotinib/gefitinib cetuximab 250 mg/m2
Predefined maximum dose:
afatinib 40mg +
cetuximab 500 mg/m2
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 Expansion cohort part4
days. MTD cohort expanded
3Amended from original 14 days interval
up to 80 EGFR mutation-positive patients:
4Acquisition of tumor tissue after the emergence of
40 T790M-positive and 40 T790M-negative
acquired resistance was mandated
Jangigian & Pao, ASCO 2011, #7525
15. Afatinib + Cetuximab at MTD:
Responses by EGFR Mutation
40% confirmed response rate and a clinical benefit rate of 90%
Jangigian & Pao, ASCO 2011, #7525
16. Afatinib + Cetuximab:
Insights & Future Directions
â˘âŻ Remarkable efficacy seen in EGFR TKI-
resistant tumors
â⯠Requires further validation
â˘âŻ Activity not specific to common T790M mutant
â˘âŻ Need to further define biology and refine patient
population for phase III trial
18. Met Inhibitors in Clinical Trials
â˘âŻ ARQ-197, specific MET inhibitor
â⯠Randomized phase II of erlotinib +/- ARQ-197 in TKI-naĂŻve patients
showed some benefit of combo but wasnât designed to look at EGFR
mutants or acquired resistance to EGFR TKIs (Schiller, ASCO 2010)
â˘âŻ Met-Mab
â⯠Randomized phase II of erlotinib +/- MET-Mab in TKI-naĂŻve pts
showed benefit of combo, but again wasnât designed to look at EGFR
mutants or acquired resistance to EGFR TKIs (Spigel , ASCO 2011
â˘âŻ XL-184, MET + RET + VEGF
â⯠Randomized phase II of erlotinib +/- XL-184 in TKI-resistant patients,
completed but not reported yet
â˘âŻ PF-02341066:
â⯠Still in early phase studies
19. MetMAb is an anti-Met Monovalent
Antibody that Inhibits HGF-MediatedActivation
Rationale for targeting Met:
HGF HGF â˘âŻ Met is amplified, mutated,
overexpressed or uniquely activated
in many tumors
MetMAb â˘âŻ Met expression is associated with
worse prognosis in many cancers
including NSCLC
Met Met
â˘âŻ Met activation is implicated in
resistance to erlotinib/gefitinib in pts
with activating EGFR mutations
MetMAb:
Growth No
Migration activity â˘âŻ One-armed format designed to
Survival prevent HGF-mediated stimulation of
pathway
HGF: Hepatocyte growth factor â˘âŻ Preclinical activity across multiple
Spigel, ASCO 2011, #75051 tumor models
20. Randomized Phase II: Erlotinib + MetMAb
or Placebo in 2nd/3rd line NSCLC
Stage IIIB/IV NSCLC N = 69
2nd/3rd line Erlotinib 150 mg PO daily
Tissue required R MetMAb 150 mg/kg IV Q3wk
PS 0â2 A
Stratification factors: N
â˘âŻTobacco history
â˘âŻPerformance status
D Erlotinib 150 mg PO daily
â˘âŻHistology Placebo IV Q3wk
N = 68
N = 137
PD
N = 27
Co-primary objectives: Other key objectives:
â˘âŻ PFS in âMet Diagnostic â˘âŻ OS in âMet Diagnostic positiveâ add MetMAb
positiveâ patients (est. 50%) patients Must be eligible to be
â˘âŻ PFS in overall ITT population â˘âŻ OS in overall ITT patients treated with MetMAb
â˘âŻ Overall response rate
â˘âŻ Safety/tolerability
Spigel, ASCO 2011, #7505
21. Development of Met IHC for
Use as a Companion Diagnostic
â˘âŻ Technical metrics
â⯠Tissue was obtained from 100% of patients.
â⯠93% of patients had adequate tissue for evaluation of Met by IHC
â˘âŻ Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories
Met Dx Met Dx
1000 Negative Positive
MET mRNA (2-Îct)
Negative (0) Weak (1+)
100
Met Dx
Negative 10
1
Moderate (2+) Strong (3+)
Met Dx 0
Positive 0 1 2 3
MET IHC score
â˘âŻ Met diagnostic status was assessed after randomization and prior to unblinding
â⯠âMet Diagnostic Positiveâ was defined as majority (âĽ50%) of tumor cells with moderate or strong staining intensity
52% patients enrolled were âMet Diagnostic Positiveâ
Spigel, ASCO 2011, #7505
22. Erlotinib + MetMAb or Placebo:
Efficacy in ITT Population
PFS: HR=1.09 OS: HR=0.8
Placebo + MetMAb + Placebo + MetMAb +
erlotinib erlotinib erlotinib erlotinib
Median (mo) 2.6 2.2 Median (mo) 7.4 8.9
1.0 HR 1.09 1.0 HR 0.80
Probability of progression free
(95% CI) (0.73â1.62) (95% CI) (0.50â1.3)
Probability of survival
Log-rank p-value 0.69 Log-rank p-value 0.34
0.8 No. of events 56 48 0.8 No. of events 41 34
0.6 0.6
0.4 0.4
0.2 0.2
Note: + = censored value. Note: + = censored value.
0.0 0.0
0 3 6 9 12 15 18 0 3 6 9 12 15 18 21
Time to progression (months) Overall survival (months)
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
23. Erlotinib + MetMAb or Placebo: Efficacy
in Met Diagnostic Positive NSCLC Patients
PFS: HR=0.53 OS: HR=0.37
Placebo + MetMAb + Placebo + MetMAb +
erlotinib erlotinib erlotinib erlotinib
Median (mo) 1.5 2.9 Median (mo) 3.8 12.6
1.0 HR 0.53 1.0 HR 0.37
Probability of progression free
(95% CI) (0.28â0.99) (95% CI) (0.19â0.72)
Log-rank p-value 0.042 Log-rank p-value 0.002
0.8 No. of events 27 20 0.8 No. of events 26 16
Probability of survival
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
0 3 6 9 12 15 18 0 3 6 9 12 15 18 21
Time to progression (months) Overall survival (months)
The addition of MetMAb to erlotinib doubled the progression free survival
and nearly tripled the overall survival in this population
Spigel, ASCO 2011, #75051
24. ARQ-197: c-MET Receptor Tyrosine Kinase
â˘âŻ Implicated in tumor cell migration,
invasion, proliferation, and angio-
genesis1
â˘âŻ Only known high-affinity receptor for
hepatocyte growth factor (HGF)1
â˘âŻ c-MET amplification associated with:
â˘âŻ Poor prognosis in NSCLC2
â˘âŻ Resistance to EGFR TKIs3,4
1.âŻBirchmeier C and Gherardi E. Trends Cell Biol 1998;8:404â10
2.âŻCappuzzo F et al. JCO 2009;27:1667â74
3.âŻEngelman JA et al. Science 2007;316:1039â43
4.âŻBean J et al. PNAS 2007;104:20932â7
25. Rand Phase II: Erlotinib + Tivantinib (ARQ-197)
or Placebo in Prev Treated Adv NSCLC
Inop Loc Adv/Met NSCLC
>1 prior line of Rx N = 84 Erlotinib 150 mg PO daily
No prior EGFR TKI R ARQ-197 360 mg PO BID
PS 0â2 A
Stratification factors:
sex, age, ECOG PS, N
smoking status, histology, D Erlotinib 150 mg PO daily
prior Rx, best response, & Placebo PO BID
geography (U.S. vs. ex- N = 83
U.S.) PD
N = 167 N = 21
Endpoints
add ARQ-197
â˘âŻ 1° PFS
â˘âŻ 2° ORR, OS
â˘âŻ Subset analyses
Sequist, JCO 2011 â˘âŻ Crossover: ORR
31. Research Efforts for
Acquired Resistance to EGFR TKIs
â˘âŻ Afatinib/cetuximab promising
â˘âŻ Unexpectedly, not correlated with T790M
â˘âŻ Phase III trial in development
â˘âŻ MetMAb phase II trial encouraging in subset
â˘âŻ Benefit appears limited to high Met expression
(detrimental in low Met expression)
â˘âŻ Phase III trial in development
â˘âŻ Tivantinib phase II trial favorable, esp in non-squamous
â˘âŻ Phase III trial now ongoing
â˘âŻ Possibly particularly helpful for KRAS mutân positive
â˘âŻ Increasing interest in post-PD biopsies
32. Acquired Resistance to EGFR TKIs:
Practical Principles for the Clinic
â˘âŻ Patients can respond to EGFR TKI with rechallenge,
especially after long interval off of EGFR TKI (breaks
onc rule of âyou can never go backâ
â˘âŻ Some patients will have a rebound rapid progression
after being taken off of an EGFR TKI
â˘âŻ Heterogeneous populations of cancer cells
â˘âŻ Is it better to continue the EGFR TKI and add an agent/
regimen, or to stop it and potentially restart it later??
â˘âŻ I favor continuing EGFR TKI when PD < PR, but not
when PD is very clear
â˘âŻ No comparison and no good data to address this