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Transcript of EGFR-Mutated Advanced NSCLC The Coming Paradigm Shift Faculty Suresh S. Ramalingam, MD Professor of...
EGFR-Mutated Advanced NSCLCEGFR-Mutated Advanced NSCLCThe Coming Paradigm Shift
FacultySuresh S. Ramalingam, MDProfessor of Hematology/Oncology Director, Lung Cancer Program Winship Cancer InstituteEmory UniversityAtlanta, Georgia
Program GoalsProgram Goals
• Outline the challenges with resistance to first-generation EGFR TKIs in patients with EGFR-mutated advanced NSCLC
• Identify the rationale for rebiopsy in patients with known EFGR-mutated advanced NSCLC
• Evaluate the clinical efficacy and safety of investigational third-generation EGFR TKIs
Program OutlineProgram Outline
• EGFR inhibition in advanced NSCLC
• Resistance mediated by the EGFR T790M mutation
• Promising therapeutic agents to treat EGFR-mutated NSCLC with acquired resistance to first-line EGFR TKIs
• Update on ongoing clinical trials relevant to the setting of acquired resistance to first-line EGFR TKIs
3
Incidence of Driver Mutations in Advanced NSCLCLung Cancer Mutation Consortium
Incidence of Driver Mutations in Advanced NSCLCLung Cancer Mutation Consortium
Driver Mutation Incidence
KRAS 25%
EGFR (sensitizing) 17%
ALK 8%
EGFR (other) 4%
Mutation in > 1 gene 3%
HER2 3%
BRAF 2%
PI3KCA 1%
MET 1%
NRAS 1%
MEK1 <1%
No oncogenic driver detected 36%
Kris MG, et al. JAMA. 2014;311:1998-2006.[1]
Molecularly Targeted TKI Therapy in Advanced NSCLCMolecularly Targeted TKI Therapy in Advanced NSCLC
• > 10 years since the presence of EGFR mutations in advanced NSCLC shown to correlate with clinical response to EGFR TKI therapy− Lynch TJ, et al. Activating mutations in the epidermal
growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med. 2004a
− Paez JG, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004b
a. Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139[3]; Paez JG, et al. Science. 2004;304:1497-1500.[2]
EGFR Mutations and EGFR TKI Therapy in Advanced NSCLCEGFR Mutations and EGFR TKI Therapy in Advanced NSCLC
• Approximate distribution and frequency of EGFR mutations in advanced NSCLCa
• In the first-line setting, erlotinib (first-generation EGFR TKI) and afatinib (second-generation EGFR TKI) are FDA approved for use in patients with advanced NSCLC with tumors characterized by EGFR-sensitizing mutationsb,c
− EGFR exon 19 deletion− EGFR exon 21 (L858R) substitution mutations
a. Mitsudomi T, et al. Cancer Sci. 2007;98:1817-1824[11]; b. Tarceva® PI 2012[15]; c. Gilotrif® PI 2014.[16]
Study (EGFR TKI)
N (EGFR- mutation-positive)
ORR (EGFR
TKI)
Median PFS(EGFR TKI vs chemotherapy)
Median OS(EGFR TKI vs chemotherapy)
IPASSa
(gefitinib*) 261 71.7% 9.5 vs 6.3 mo; HR = 0.48 (0.36-0.64); P <.001
WJTOG 3405b (gefitinib)
177 73.7% 9.2 vs 6.3 mo; HR = 0.489 (0.336-0.710); P <.0001
NEJ002c
(gefitinib) 230 62% 10.8 vs 5.4 mo; HR = 0.30 (0.22-0.41); P <.001
30.5 vs 23.6 mo; P =NS
OPTIMALd
(erlotinib) 165 73.7% 13.1 vs 4.6 mo; HR = 0.16 (0.10-0.26); P <.0001
19.3 v 19.5; P = .87
EURTACe
(erlotinib) 153 58% 9.7 vs 5.2 mo; HR = 0.37 (0.25-0.54); P <.0001
22.9 vs 18.8 mo; P =.42
a. Mok TS, et al. N Engl J Med. 2009;361:947-957[4]; b. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128[6]; c. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388[5]; d. Zhou C, et al. Lancet Oncol. 2011;12:735-742[7]; e. Rosell R, et al. Lancet Oncol. 2012;13:239-246.[8]
*First-line EGFR therapy licensed for use in some countries outside the United States.
First-Line EGFR TKI Therapy vs Platinum-Doublet Chemotherapy in EGFR-Mutated Advanced NSCLC: PFS
First-Line EGFR TKI Therapy vs Platinum-Doublet Chemotherapy in EGFR-Mutated Advanced NSCLC: PFS
First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLCStudy Design
First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLCStudy Design
• Afatinib (oral) 40 mg/d• n = 230
• Patients with treatment-naïve, stage IIIB/IV lung adenocarcinoma
• EGFR-activating mutation
• ECOG PS = 0,1
RANDOMIZE
• Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d, up to 6 cycles
• n = 115
Treatment until disease
progression
2:1• Primary end point
� PFS• Secondary end points include
� ORR; DCR; DoR; OS; PROs; safety; PK
• Stratification factors include
� EGFR mutation (exon 19 del, L858R, other)
� Race (Asian, non-Asian)
Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.[10]
Afatinib Cis/Pem
PFS event, n (%)for overall population; n = 230 [afatinib]; n = 115 [chemo]
152 (66) 69 (60)
Median PFS, mo for overall population 11.1 6.9
HR (95% CI) for overall population 0.58 (0.43-0.78)P = .0004
PFS event, n (%)for patients with EGFR exon 19 del or L858R mutation only; n = 204 [afatinib]; n = 104 [chemo]
130 (64) 61 (59)
Median PFS, mo for patients with EGFR exon 19 del or L858R mutation only 13.6 6.9
HR (95% CI) for patients with EGFR exon 19 del or L858R mutation only
0.47 (0.34-0.65)P = .001
First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLCPFS
First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLCPFS
Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.[10]
First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC Safety
First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC Safety
Selected Treatment-Related AEs (%)
Afatinib (n = 229)
Cis/Pem (n = 111)
All Grades
≥Grade 3
All Grades
≥Grade 3
Diarrhea 95.2% 14.4% 15.3% 0%
Rash/acne 89.1% 16.2% 6.3% 0%
Stomatitis/mucositis 72.1% 8.7% 15.3% 0.9%
Nausea 17.9% 0.9% 65.8% 3.6%
Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.[10]
First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLCStudy Design
First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLCStudy Design
• Patients with chemotherapy-naïve stage III/IV or postoperative recurrent NSCLC
• Activating mutations (exon del 19, L858R)
• ECOG PS = 0,1• No brain
metastases
• Erlotinib (oral) 150 mg/d once daily
• Bevacizumab 15 mg/kg IV every 3 wk
• n = 77
RANDOMIZE
Treatment until disease
progression
1:1 • Primary end point� PFS
• Secondary end points include:• OS, tumor response, QoL, safety
• Stratification factors include� EGFR mutation type
• Erlotinib (oral) 150 mg/d once daily
• n = 77
Seto T, et al. Lancet Oncol. 2014;15:1236-1244.[23]
Erlotinib + Bev (n = 77) Erlotinib (n = 75)
Median PFS, mo 16.0 9.7
HR (95% CI) 0.54 (95% CI, 0.36-0.79)
P value* .0015
*Log-rank test, 2-sided.
Most Common Grade 3 AEs Erlotinib + Bev (n = 77) Erlotinib (n = 75)
Rash 25% 19%
Hypertension 60% 10%
Proteinuria 8% 0%
Serious AEs
Occurred with the same frequency (~25%) in both arms.
Seto T, et al. Lancet Oncol. 2014;15:1236-1244.[23]
First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLCPFS and Safety
First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLCPFS and Safety
Some Characteristics of EGFR-Mutated Advanced NSCLC With Acquired Resistance to First-Line EGFR TKI
Some Characteristics of EGFR-Mutated Advanced NSCLC With Acquired Resistance to First-Line EGFR TKI
Molecular Alteration Approximate Frequency, %
EGFR Target Alteration (~60%)
• T790M alone ~40 - 55
• T790M with EGFR amplification ~10
• Other EGFR point mutations 1 - 2
Bypass Tracts (~20%)
• HER2 amplification ~8 - 13
• SCLC alone ~6
• SCLC with PI3K ~4
• MET amplification ~5
• PI3KCA ~1 - 2
• BRAF ~1
No Acquired Resistance Mechanism Identified (~15% to 20%)Camidge DR, et al. Nat Rev Clin Oncol. 2014;11:473-481.[26]
EGFR T790M Mutation-Positive Advanced NSCLC in Acquired Resistance
EGFR T790M Mutation-Positive Advanced NSCLC in Acquired Resistance
• EGFR T790M-mutated advanced NSCLC− Occurs on exon 20 and is found in > 50% of patients with
acquired resistance to an EGFR TKI
− Increases relative affinity of mutated EGFR for ATP, and may also sterically hinder binding of erlotinib
− More likely to show progression in lungs/pleura
− Less commonly detected in CNS
• Patients with disease characterized by the EGFR T790M mutation may have a better prognosis than patients with EGFR T790M mutation-negative disease
Oxnard GR, et al. Clin Cancer Res. 2011;17:1616-1622.[27]
Rationale for Rebiopsy Following Disease Progression on First-Line EGFR TKI
Rationale for Rebiopsy Following Disease Progression on First-Line EGFR TKI
• To determine whether transformation to SCLC has occurred
• To evaluate for the presence of the EGFR T790M mutation and identify appropriate clinical trials when available
• To evaluate for the presence of other actionable mutations for which a clinical trial may be available
A rebiopsy is critically important for optimal assessment and treatment selection of patients with disease
progression on first-line EGFR TKI therapy
IMPRESSStudy DesignIMPRESSStudy Design
• Primary end point� PFS
• Secondary end points include� ORR; OS; DCR; safety; health-related QoL
*Tumor assessments performed ≤ 4 weeks before the start of treatment (baseline), and every 6 weeks (±7 days) after randomization until progressive disease.
Treatment until disease progression*
RANDOMIZE
• Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d (up to 6 cycles) +
• Gefitinib (oral) 250 mg/d• n = 133
• Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d up to 6 cycles +
• Placebo (oral) 250 mg• n = 132
• Patients with chemotherapy-naïve advanced NSCLC
• EGFR-activating mutation
• Achieved CR/PR ≥ 4 mo or SD > 6 mo with first-line gefitinib
• Disease progression ≤ 4 weeks prior to study randomization
1:1
Mok TSK, et al. ESMO 2014. Abstract LBA2_PR.[31]
Gefitinib Placebo0
10
20
30
40
50
60
70
80
90
100
31.6 34.1
Gefitinib Placebo0
10
20
30
40
50
60
70
80
90
100
84.278.8
IMPRESSORR and DCRIMPRESSORR and DCR
Odds ratio >1 favours gefitinib Odds ratio and p-value from logistic regression with covariatesCI, confidence interval
OR (95% CI) = 0.92 (0.55-1.55);P = .760
OR (95% CI) = 1.39 (0.74, 2.62); P = .308
OR
R,
%
DC
R,
%
n = 133 n = 132
Mok TSK, et al. ESMO 2014. Abstract LBA2_PR.[31]
n = 133 n = 132
IMPRESSPFSIMPRESSPFS
Gefitinib (n = 133)
Placebo (n = 132)
PFS event, n (%) 98 (73.7) 107 (81.1)
Median PFS, mo 5.4 5.4
HR (95% CI) 0.86 (0.65-1.13)
P value .273
Mok TSK, et al. ESMO 2014. Abstract LBA2_PR.[31]
OS: 14.8 vs 17.2 mo, in favor of chemotherapy arm (P = .029, although OS data are not yet mature)
Third-Generation EGFR TKIsThird-Generation EGFR TKIs
• Orally administered agents that block T790M-mutated EGFR and EGFR characterized by the original sensitizing mutation (eg, exon 19 deletion; L858R)*
− AZD9291
− CO-1686 (rociletinib)
*HM61713 is another third-generation EGFR TKI in early-phase development.[44]
AURAStudy DesignAURAStudy Design
• Phase 1, open-label, multicenter study of AZD9291 in patients with advanced NSCLC and progression on prior therapy with an EGFR TKIa,b
• Rolling 6 study design allowing for enrollment of 2 to 6 patients concurrently on to a dose levelc − 5 doses evaluated: 20 mg; 40 mg; 80 mg; 160 mg; 240 mg− Dose administered once daily− Dose escalation not preselected by EGFR T790M mutation status
• Expansion study includes only patients with EGFR T790M mutation-positive disease according to central laboratory testing
*cobas® EGFR Mutation Test (Roche Molecular Systems)ESMO 2014; Poster Discussion, Developmental
therapeutics; Sunday, September 28, 2014a. Yang J C-H, et al. J Clin Oncol. 2014;32. Abstract 8004[22]; b. Yang JC, et al. ESMO 2014. Abstract 449PD[36]; c. Skolnik JM, et al. Clin Oncol. 2008;26:190-195.[45]
AURA SafetyAURA Safety
Patients With an AE, %20 mg N = 21
40 mgN = 58
80 mgN = 90
160 mgN = 63
240 mg N = 21
TotalN = 253
Any AE, drug-related 67% 66% 79% 94% 100% 80%
Any AE Grade ≥ 3, drug-related
10% 3% 11% 25% 14% 13%
Serious AE, drug-related 14% 2% 4% 10% 5% 6%
Selected AEs
• Diarrhea 24% 41% 33% 68% 76% 47%
• Rash 4% 22% 32% 63% 71% 40%
• Nausea 14% 17% 18% 30% 33% 22%
• Hyperglycemia 0% 2% 3% 3% 0% 2%
• QT prolongation 0% 3% 4% 6% 5% 4%
• Pneumonitis-like event 0% 0% 2% 6% 0% 2%
Yang JC, et al. ESMO 2014. Abstract 449PD.[36]
AURA: Preliminary Outcomes in Patients With Centrally Tested EGFR T790M-Positive Disease
AURA: Preliminary Outcomes in Patients With Centrally Tested EGFR T790M-Positive Disease
• ORR− 61%− ORR by dose
− Disease control rate (CR+PR+SD): 95%
• Duration of confirmed response− Preliminary median duration of response at 80 mg: 8.2 mo (N=138)− The longest duration of response to date is ongoing at > 11 mo
• Median PFS− Preliminary median PFS: 9.6 mo (30% maturity; N=138)
AZD9291 Dose 20 mg 40 mg 80 mg 160 mg 240 mgN (Total = 127) 10 32 43 28 14
ORR 50% 59% 70% 61% 50%
Yang JC, et al. ESMO 2014. Abstract 449PD.[36]
Ongoing Studies of AZD9291Ongoing Studies of AZD9291
• AURA3
− Phase 3 randomized trial
− AZD9291 vs platinum-doublet chemotherapy as second-line therapy in chemotherapy-naïve patients with advanced NSCLC characterized by an EGFR T790M mutation and progression on a first-line EGFR TKI
• FLAURA
− Phase 3 randomized trial
− AZD9291 vs erlotinib or gefitinib as first-line therapy in treatment-naïve patients with disease characterized by an EGFR-sensitizing mutation (includes patients with or without disease characterized by an EGFR T790M mutation)
a. ClinicalTrials.gov. NCT02151981[37]; b. ClinicalTrials.gov. NCT02296125.[38]
CO-1686 (Rociletinib)Pre-Clinical StudiesCO-1686 (Rociletinib)Pre-Clinical Studies
• Transgenic murine model with tumor characterized by EGFR L858R/T790M
− Dramatic tumor regression with CO-1686 in contrast to tumor progression observed with afatinib
• Cellular viability assay using A431 model, which is characterized by high levels of EGFR wild type
− Less cell inhibition observed with increasing doses of CO-1686 compared with other EGFR TKIs
− Suggests that CO-1686 may be associated with an increased likelihood of EGFR wild-type sparing
. Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010[39]; Walter AO, et al. Cancer Discov. 2013;3:1404-1415.[40]
Phase 1 and Extended Phase 2 Expansion Studies of CO-1686Phase 1 and Extended Phase 2 Expansion Studies of CO-1686
• Formulation and dosing− Initially evaluated as a free base
− Hydrobromide (HBr) salt formulation subsequently shown to be more efficacious
• Twice-daily doses of 500 mg, 625 mg, 750 mg, 1000 mg have been evaluated
• Study designs− Phase 1: Patients with advanced or recurrent NSCLC characterized by an
activating EGFR mutation and prior EGFR-directed therapy
• CO-1686 dose escalation to MTD
• Primary end points: Safety, PK
− Phase 2: Patients with EGFR T790M mutation-positive disease that has progressed on prior EGFR-directed therapy
• 3 doses (500 mg, 625 mg, 750 mg twice daily) being evaluated as second- or higher-line therapy in 2 patient populations characterized by prior treatment
• Primary end points: ORR, DoR
Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.[39]
• Evaluated in 40 patients with EGFR T790M mutation-positive disease treated with therapeutic doses of CO-1686
• ORR − 58%
• PFS− Median not yet reached (estimated > 12 mo)*
CO-1686Preliminary OutcomesCO-1686Preliminary Outcomes
Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.[39]
*Reported in June 2014.
CO-1686SafetyCO-1686Safety
Selected AEs (%)(N = 72*) Grade 1 Grade 2 Grade 3 Grade 4
Diarrhea 19% 4% 0% 0%
Rash 4% 0% 0% 0%
Nausea 19% 14% 1% 0%
Hyperglycemia and IGT 19% 11% 22% 0%
QT prolongation 4% 4% 7% 0%
*Includes patients treated at efficacious doses.
Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.[39]
TIGER TrialsTIGER Trials
TIGER 1a
• Phase 2 randomized trial• CO-1686 vs erlotinib as first-line therapy in treatment-naïve patients
with disease characterized by an EGFR-sensitizing mutation
TIGER 2b
• Phase 2 single arm trial• CO-1686 as second-line therapy in patients with advanced NSCLC
characterized by an EGFR T790M mutation and progression on a first-line EGFR TKI
TIGER 3c
• Phase 3 randomized trial• CO-1686 vs single-agent chemotherapy in patients with advanced
NSCLC characterized by an EGFR-sensitizing mutation and progression on ≥ 1 prior EGFR TKI and platinum-doublet chemotherapy
a. ClinicalTrials.gov. NCT02186301[41]; b. ClinicalTrials.gov. NCT02147990[42]; c. ClinicalTrials.gov. NCT02322281.[43]
SummarySummary
• Resistance to first-line EGFR TKI therapy is a challenging clinical problem
• The acquired resistance mutation, EGFR T790M, accounts for resistance to prior EGFR TKI therapy in nearly 60% of patients
• Third-generation TKIs have demonstrated robust activity in patients with acquired resistance to a first-line EGFR TKI
• Tumor biopsy after disease progression on a first-line EGFR TKI is necessary to determine the mechanism(s) of acquired resistance
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