Transcript PowerPoint - Q-CROC
Clinical data on EGFR-TKIs and Overcoming Resistance in Metastatic NSCLC
2
nd
Quebec Conference on Therapeutic Resistance in Cancer
Vera Hirsh, MD, FRCPC McGill University Health Centre Montreal, QC, CANADA
EGFR expression in human tumours
Tumours showing high EGFR expression
NSCLC Prostate Gastric Head and neck Breast Colorectal Pancreatic Ovarian 40-80% 40-80% 33-74% 90-100% 14-91% 25-77% 30-50% 35-70%
High expression generally associated with
Invasion Metastasis Late-stage disease Poor outcome
EGFR mutation causes conformational change and increased activation
Wild Type EGFR Mutant EGFR Ligand Extracellular domain Trans-membrane domain Tyrosine kinase domain Tyrosine phosphorylation ATP Ras-Raf-MAPK Proliferation Pi3K-AKT Survival EGFR internalisation Degradation/recycling EGFR signals for longer at the cell membrane
Arteaga 2006, Gadzar et al 2004, Hendricks et al 2006, Sordella et al 2004
The distribution of activating mutations among EGFR mutation positive patients is similar in Asian and non-Asian studies
Regulatory domain ATP binding cleft C-lobe N-lobe Transmembrane region Extracellular domain TK domain A-loop
Chelix P-loop 21 20 19 18 Literature review Most prevalent mutation types Exon 19 deletion Exon 21 point mutation L858R Exon 20 Exon 18 G719A/C Exon 21 L861Q Distribution of mutation types (% of mutations) Asian studies Literature (n=1523) 51% 42% 2% 3% 1% Non-Asian studies Literature (n=583) 58% 32% 6% 2% 1% Some patients had more than one mutation type
BR.21 Study Design
Stratified by: Centre PS, 0/1 vs 2/3 Response to prior Rx (CR/PR:SD:PD) Prior regimens, (1 vs 2) Prior platinum, (Yes vs no) R A N D O M I Z E
Erlotinib* 150 mg daily
Placebo “150 mg” daily
*2:1 Randomization
BR.21: Overall Survival
1.00
0.75
Erlotinib (n=488) Placebo (n=243) Median survival (months) 6.7 4.7 1-year survival (%) 31 21 HR=0.70 (95% CI, 0.58-0.85); P < 0.001* 0.50
31% 42.5% improvement in median survival 0.25
Erlotinib 21% Placebo 0 0 5 10 15 20 25 30 Survival time (months) *HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.
Shepherd et al.
N Engl J Med
. 2005;353:123-132.
IPASS: first-line study design
•
Patients Chemo naïve
•
Age ≥18 years
•
Adenocarcinoma histology
•
Never or light ex smokers*
•
Life expectancy ≥12 weeks
•
PS 0-2
•
Measurable stage IIIB/ IV disease Gefitinib (250 mg/day) 1:1 randomisation Carboplatin (AUC 5 or 6)/ paclitaxel (200 mg/m 2 ) 3 weekly † Endpoints
•
Primary PFS (non-inferiority)
• • • • •
Secondary ORR OS QoL Disease-related symptoms Safety and tolerability
•
Exploratory Biomarkers
•
EGFR mutation
• •
EGFR-gene-copy number EGFR protein expression *Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped
15 years ago and smoked
10 pack years † Maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression; AUC, area under curve Mok et al 2009
Patients (%)
IPASS: ORR
Odds ratio (95% CI) = 1.59 (1.25, 2.01) p=0.0001
(n=609) Odds ratio >1 implies a greater chance of response on gefitinib Odds ratio and p-value from logistic regression with covariates (n=608) Mok et al 2009
IPASS: pre-planned analysis of ORR by EGFR mutation status
Gefitinib Carboplatin / paclitaxel ORR (%) 71.2
47.3
EGFR M+ OR (95% CI) 2.75 (1.65, 4.60), p=0.0001 EGFR M OR (95% CI ) 0.04 (0.01, 0.27), p=0.0013 23.5
1.1
(n=91) (n=85) (n=132) (n=129) ITT population OR>1 implies greater chance of response on gefitinib OR and p-value from logistic regression with covariate Mok et al 2009
IPASS: PFS
Probability of PFS 1.0
0.8
0.6
N Events Gefitinib Carboplatin / paclitaxel 609 608 453 (74.4%) 497 (81.7%) HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001
Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free 5.7
61% 48% 25% 5.8
74% 48% 7% 0.4
0.2
0.0
0 4 8 Primary Cox analysis with covariates; ITT population HR <1 implies a lower risk of progression on gefitinib ITT, intent-to-treat 12 16 20 24 Months Mok et al 2009
1.0
0.8
0.6
IPASS: pre-planned analysis of PFS by EGFR mutation status
EGFR M+ EGFR M 1.0
N Gefitinib 132 Carboplatin / paclitaxel 129 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001
Median (m) 9.5
6.3
0.8
N Gefitinib 91 Carboplatin / paclitaxel 85 HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001
Median (m) 1.5
5.5
0.6
0.4
0.4
0.2
0.0
0 4 8 12 16 20 Time from randomisation (months) 24 0.2
0.0
0 4 8 12 16 20 Time from randomisation (months) 24 Primary Cox analysis with covariates; intent-to-treat (ITT) population Hazard ratio (HR) <1 implies a lower risk of progression on gefitinib Mok et al 2009
IPASS: EGFR mutation is a strong predictor for differential PFS benefit between gefitinib and doublet chemotherapy
Probability of PFS 1.0
0.8
Treatment by subgroup interaction test, p<0.0001
0.6
0.4
0.2
Gefitinib EGFR M+ (n=132) Gefitinib EGFR M- (n=91) Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) EGFR M+ HR=0.48, 95% CI 0.36, 0.64
p<0.0001
EGFR M HR=2.85, 95% CI 2.05, 3.98
p<0.0001
0.0
0 4 8 12 16 Time from randomisation (months) M+, mutation positive; M-, mutation negative 20 24
PFS by EGFR mutation type: IPASS
1.0
0.8
0.6
0.4
Exon 19 deletion N Gefitinib 66 Carboplatin / paclitaxel 74 HR (95% CI) = 0.337 (0.255, 0.560) p<0.0001
0.2
0.0
0 4 8 12 16 20 Time from randomisation (months) 24 1.0
0.8
0.6
0.4
N L858R Gefitinib 64 Carboplatin / paclitaxel 47 HR (95% CI) = 0.553 (0.352, 0.868) p=0.0101
0.2
0.0
0 4 8 12 16 20 Time from randomisation (months) 24 Mok et al 2009 Post hoc Cox analysis with covariates; ITT population
IPASS: QoL and symptom improvement rates for overall population
Gefitinib (n=590) Carboplatin/paclitaxel (n=561) p=0.0148
p=0.3037
% patients with sustained clinically relevant improvement a p<0.0001
Evaluable for QoL population ; logistic regression model with covariates a ≥6-point improvement (FACT-L and TOI); ≥2-point improvement (LCS), maintained ≥21 days
Mok et al 2009
IPASS: post hoc QoL and symptom improvement rates for EGFR M+ patients
Gefitinib (n=131) Carboplatin / paclitaxel (n=128) p<0.0001
p<0.0001
p=0.0003
% patients with sustained clinically relevant improvement a 80 70 60 50 40 30 20 10 0 70.2
44.5
70.2
38.3
75.6
53.9
Total FACT-L TOI LCS Evaluable for QoL population; logistic regression model with covariates a 6-point improvement (FACT-L and TOI); 2-point improvement (LCS), maintained ≥21 days Mok et al N Engl J Med 2009
IPASS:
2010
updated OS analysis (ITT)
Probability of survival 1.0
0.8
0.6
Gefitinib (n=609) Carboplatin / paclitaxel (n=608) HR (95% CI) 0.90 (0.79, 1.02); p=0.109
No. events G 484 (80%) C / P 470 (77%) Median OS G 18.8 months C / P 17.4 months 0.4
0.2
0.0
0 4 8 12 16 Patients at risk : Gefitinib C / P 609 608 514 525 468 443 400 364 331 301 20 24 28 32 270 232 227 183 192 151 148 119 36 97 65 40 44 28 44 48 13 9 3 1 52 0 0
Primary Cox analysis with covariates A hazard ratio <1 implies a lower risk of death on gefitinib No formal adjustment made for multiple testing
Yang CH et al. ESMO 2010
IPASS:
2010
summary of subsequent systemic therapy (ITT)
No further systemic treatment Chemotherapy Platinum based** C / P** EGFR TKI** Gefitinib # Erlotinib # Other #
Gefitinib (n=609)*
31% 65% 60% 49% 20% 5% 12% 5% C / P (n=608) 38% 41% 9% 1% 52% 41% 14% 6% *% exclude 20 patients in the gefitinib arm with ongoing randomised treatment **Patients may have also received other chemotherapy and / or EGFR TKI during the study. Excludes single platinum based chemotherapy #Categories are not mutually exclusive Radiotherapy, surgery, medical procedures and other treatments excluded
Yang CH et al. ESMO 2010
IPASS:
2010
OS by
EGFR
mutation status (ITT)
EGFR
mutation +
Gefitinib (n=132) Carboplatin / paclitaxel (n=129) EGFR mutation Gefitinib (n=91) Carboplatin / paclitaxel (n=85) 1.0
0.8
0.6
HR (95% CI) 1.00 (0.76, 1.33); p=0.990
No. events G 104 (79%) C / P 95 (74%) Median OS G 21.6 months C / P 21.9 months 1.0
0.8
0.6
HR (95% CI) 1.18 (0.86, 1.63); p=0.309
No. events G 82 (90%) C / P 74 (87%) Median OS G 11.2 months C / P 12.7 months 0.4
0.4
0.2
0.2
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time from randomisation (months) Patients at risk : Gefitinib 132 C / P 129 126 123 121 112 103 95 88 80 70 68 58 55 46 48 38 40 24 26 11 15 6 7 3 0 0 0 0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 Time from randomisation (months) 91 85 69 76 52 57 40 44 29 33 26 25 19 19 16 16 11 11 8 3 5 1 1 1 0 1 52 0 0
Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib No formal adjustment for multiple testing was made, therefore statistical significance at the traditional 5% level cannot be claimed
Yang CH et al. ESMO 2010
IPASS:
2010
overall survival:
EGFR
mutation non-evaluable (ITT)
Probability of survival 1.0
0.8
0.6
0.4
Gefitinib (n=386) Carboplatin / paclitaxel (n=394) HR (95% CI) 0.82 (0.70, 0.96); p=0.015
* No. events G 298 (77%) C / P 301 (76%) Median OS G 18.9 months C / P 17.2 months 0.2
0.0
0 4 Patients at risk: Gefitinib C / P 386 394 319 326 8 295 274 12 16 20 24 28 32 36 Time from randomisation (months) 40 257 225 214 188 174 139 150 109 130 87 99 68 65 36 28 12 44 6 1 48 0 0 52 0 0
Primary Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib * No formal adjustment for multiple testing was made, therefore statistical significance at the traditional 5% level cannot be claimed
Yang CH et al. ESMO 2010
IPASS: PFS and OS by known
EGFR
mutation status
OS (2010) 1.0
0.8
PFS (2008) Gefitinib EGFR M+ Gefitinib EGFR M C / P EGFR M+ C / P EGFR M 1.0
0.8
Mutation + 0.6
0.6
0.4
0.4
0.2
0.0
0 4 8 12 16 20 24 Time from randomisation (months) Patients at risk: Gefitinib M+ 132 Gefitinib M 91 C / P M+ 129 C / P M 85 108 21 103 58 71 4 37 14 31 2 7 1 11 1 2 0 3 0 1 0 0 0 0 0 0.2
Mutation 0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time from randomisation (months) 132 91 129 85 126 69 123 76 121 52 112 57 103 40 95 44 88 29 80 33 70 26 68 25 58 19 55 19 46 16 48 16 38 11 40 11 24 8 26 3 11 5 15 1 6 1 7 1 3 0 0 1 0 0 0 0
Patients at risk excludes censored patients and those who have experienced an event
Yang CH et al. ESMO 2010
IPASS conclusions: updated survival analysis
• • • • Mature OS (secondary endpoint) was similar for gefitinib and carboplatin / paclitaxel with no statistically significant difference between treatments in the overall population A consistent OS outcome was observed across clinical subgroups with no significant difference in OS There was no significant difference in OS across the
EGFR
biomarker subgroups The true effect of the initial randomised treatment on OS is likely to have been confounded by the subsequent therapy , in particular the switching of patients to the alternative study therapy
Yang CH et al. ESMO 2010
• • • •
IPASS conclusions: overall summary
IPASS has demonstrated that positive
EGFR
mutation status is predictive of benefit from treatment with gefitinib over chemotherapy in terms of PFS, ORR and HRQoL PFS is an endpoint unlikely to be confounded by subsequent treatments, therefore is a more appropriate endpoint for evaluation of treatment effect in first-line treatment of NSCLC than OS IPASS has demonstrated the importance of biomarker testing in NSCLC, making a significant step towards personalised medicine IPASS has changed clinical practice and treatment guidelines for patients with advanced NSCLC who harbour an
EGFR
mutation HRQoL, health-related quality of life; NSCLC, non-small-cell lung cancer; ORR, objective response rate
Yang CH et al. ESMO 2010
Recently reported Phase III studies of gefitinib as first-line treatment for NSCLC in selected populations
NEJ002 (Japan)
• • •
Patients Chemo naïve EGFR mutation positive PS 0 –1 Gefitinib 250 mg/day Carboplatin AUC 6 & paclitaxel 200 mg/m 2 3-weekly Endpoints
•
Primary PFS (superiority)
•
Secondary OS, ORR, QoL, disease-related symptoms safety and tolerability First-SIGNAL (Korea)
• • • •
Patients Chemo naïve Adenocarcinoma Never smokers ECOG † PS 0 –2 Gefitinib 250 mg/day Gemcitabine (1250 mg/m 2 ) & cisplatin (80 mg/m 2 ) 3-weekly* Endpoints
•
Primary OS
•
Secondary PFS, ORR, QoL, disease-related symptoms safety and tolerability † Eastern Cooperative Oncology Group * Maximum 9 cycles Kobayashi et al 2009; Lee et al 2009
PFS and ORR with first-line gefitinib versus doublet chemotherapy in EGFR mutation-positive Asian patients across three Phase III studies
1.0
HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001
1.0
0.8
0.8
0.6
0.4
0.6
0.4
0.2
0.0
0 4 8 12 months 16 IPASS p<0.0001
20 24 0.2
0.0
0 HR (95% CI) = 0.613 (0.308, 1.221) p=0.084 1.0
HR (95% CI) = 0.36 (0.25, 0.51) p<0.001
0.8
0.6
0.4
5 0.2
25 30 0.0
0 500 10 15 months 20 First-SIGNAL p=0.002
100 200 300 days NEJ002 p<0.001
400 100 80 60 40 20 0 71.2
47.3
Gefitinib (n=132) C / P (n=129) 100 80 60 40 20 0 84.6
37.5
Gefitinib (n=26) G / C (n=16) 100 80 60 40 20 0 74.5
29.0
Gefitinib (n=98) C / P (n=100) Mok et al 2009; Lee et al 2009; Kobayashi et al 2009
1st-line treatment for mutation positive patients with NSCLC
EURTAC – Spanish Lung Cancer Group Phase III 1 : Erlotinib IIIB/IV NSCLC chemotherapy naïve EGFR mutation Platinum + taxane or gemcitabine
New-generation erbB inhibitors
Reversible
Gefitinib Erlotinib
Lapatinib Irreversible BIBW 2992 Neratinib (HKI-272) AV-412 XL647 PF-00299804 BIBW 2992 – potency and selectivity (IC 50 ): EGFR HER2 c-Met VEGFR [nM] [nM] [nM] [nM] 0.5
14 >10000 >10000 Solca F et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118:A242 Solca F et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118:A244
Resistance mutations
Mutations known to cause resistance to 1st-generation EGFRi include: •Exon 20 in frame insertions •Exon 20 point mutations (e.g. T790M) Sharma et al.
Nat Rev Cancer
. 2007;7:169 –181
BIBW 2992 – active against resistance mutation
NCI-H1975 cells express L858R/T790M double-mutant EGFR Li et al.
Oncogene
. 2008;27:4702 –4711
LUX-Lung 1: Trial design
• • • • 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
Randomization 2:1 (Double
Blind
) Oral afatinib 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)
Median age, (range)
Demographics/prior treatment
Afatinib (n=390)
58 (30 –85) yrs
Placebo (n=195)
59 (32 –82) yrs Female (%) ECOG PS 0/1/2 (%) 59 24/69/8 60 27/65/8 Caucasian/East Asian/other (%) 31/ 58 /11 37/56/7 Never smoker/Light ex-smoker/Other (%) Stage IIIB/IV (%) 63/7/30 4/96 Prior chemo: 1 line/> 1 line (%) 59/41 Prior EGFR TKI: E/G/E+G (%) 55/39/6 Median duration of prior E/G ≥ 48 wks duration on prior E/G (%) < 8 wks between prior E/G and randomization (%) CR/PR on prior E/G (%) 10.2 mos 45 57 46 62/7/31 3/97 61/39 55/41/4 9.7 mos 47 63 44 31
Disease control rate and objective responses
PR, (regardless of confirmation) PR, (confirmed) SD ≥ 8 wks
Independent Review Afatinib (%)
13* 7*
Placebo (%)
0.5
0.5
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
PFS by independent review
Primary analysis: Overall survival
Summary of anticancer therapy after treatment discontinuation
Anticancer therapy
Any Chemotherapy Pemetrexed Docetaxel Vinorelbine Other EGFR TKI Anti-angiogenesis Radiotherapy
Afatinib (%)
68 61 36 21 15 26 12 4 9
Placebo (%)
79 70 47 26 19 26 24 6 14
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
LUX-Lung 2: Study design
Patients with: Adenocarcinoma of the lung Stage IIIB/IV EGFR mutation Chemo naïve or progressive disease following first-line chemotherapy ECOG 0 –2 N=120 Oral BIBW 2992 once-daily until disease progression or undue toxicity Response assessment at 4, 8, 12 weeks; every 8 weeks thereafter Primary endpoint: objective response rate Secondary endpoints: PFS, clinical benefit; time to OR; duration of OR; OS; safety
Results
High degree of efficiency observed: - For all patients: Confirmed ORR: 60% DCR: 86% Median PFS: 14 months Median OS: 24 months
-
For patients with del19/L858R Confirmed ORR: 64% DCR: 88% Median PFS: 15 months
-Similar efficacy results in the first and second-line settings and across all subgroups -Similar magnitude of efficacy in patients with L858R as with del19 mutations
LUX-Lung 3: Phase III first-line trial in lung cancer patients with EGFR mutations
Patients (n=330) with: Stage IIIB/IV adenocarcinoma of the lung Presence of EGFR mutation in the tumour tissue Chemonaive ECOG 0 or 1 Randomization 2:1 Oral BIBW 2992 40 mg once-daily Cisplatin/pemetrexed Primary endpoint: PFS
Conclusion
• EGFR-TKIs for EGFR-mutated tumours are becoming standard Rx in first-line metastatic NSCLC • BIBW 2992 activity in NSCLC, especially in EGFR-mutated tumours - Active against receptors that are resistant to first generation inhibitors (e.g.EGFRL858R/T790M)