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Management Strategies for Lung Cancer Sensitive or Resistant to EGRF Inhibitors
Conor E. Steuer, MDAssistant ProfessorThe Winship Cancer Institute of Emory UniversityJuly 27, 2017
2Winship Cancer Institute | Emory University
Lung Cancer
• One of the most common cancers and leading cause of cancer deaths
• New cases, 2016 (estimated): US, 224,390
• Deaths, 2016 (estimated): US, 158,080
• 5-yr US survival rates• Overall: 18%• Metastatic: 4%
Siegel RL, et al. CA Cancer J Clin. 2016;66(1):7-30. National Cancer Institute. SEER www.cancer.gov.
3Winship Cancer Institute | Emory University
Advances in NSCLC Therapies
Targeted Therapy- FDA approved therapies for EGFR, ALK, ROS1, and possibly more coming
Chemotherapy-Histology Matters!(i.e. Alimta and Avastin for Adenocarcinomas)
Checkpoint Inhibitors-Nivolumab, Pembrolizumab, Atezolizumab
4Winship Cancer Institute | Emory University
Epidermal Growth Factor Receptor
EGFR is a glycoprotein that plays a complicated role in signal transduction and cellular processes and important in tumorigenesis
Significant research was performed examining the role of EGFR in NSCLC
Nyati MK, et al. Nat Rev Cancer. 2006;6(11):876-885. Shin DM, et al. Cancer Res. 1994;54(12):3153-3159. Brabender J, et al. Clin Cancer Res. 2001;7(7):1850-1855.
5Winship Cancer Institute | Emory University
The EGFR TKIs
• Erlotinib and gefitinib are EGFR tyrosine kinase inhibitors that reversibly bind to the ATP binding site, inhibiting downstream signaling
Moyer JD, et al. Cancer Res. 1997;57(21):4838-4848.
6Winship Cancer Institute | Emory University
BR.21- Erlotinib in NSCLC
• Randomized, phase 3 clinical trial for NSCLC patients who had progressed on at least 1 line of therapy
• Patients received either erlotinib 150mg daily or placebo
• 731 patients underwent randomization, UNSELECTED by EGFR status
• Median age was 61.4 years, 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy.
Shepherd FA, et al. N Engl J Med. 2005;353(2):123-132.
7Winship Cancer Institute | Emory University
BR.21 Results
• Overall survival: 6.7 months (erlotinib) vs. 4.7 months (placebo) (P<0.001)• FDA approval 2004
• Asian ethnicity, women, adenos, lifetime nonsmokers, and tumors that expressed EGFR in ≥ 10% of cells had improved response rates
Shepherd FA, et al. N Engl J Med. 2005;353(2):123-132. Pérez-Soler R, et al. J Clin Oncol. 2004;22(16):3238-3247.
8Winship Cancer Institute | Emory University
EGFR mutation predicts sensitivity to EGFR TKI
• A) L858R mutations in exon 21• B) G719S mutant in P-loop (exon
18)• C) Deletion mutants in EGFR
exon 19
Paez JG, et al. Science. 2004;304(5676):1497-1500.
9Winship Cancer Institute | Emory University
EGFR Mutations in NSCLC
• Found in 10% to 40% of NSCLC pts• More common in never-smokers, adenocarcinomas, females, Asians
• Predominantly located in EGFR exons 18-21• ~ 85% of EGFR mutations are either deletions in exon 19 or a single-point
mutation in exon 21 (L858R)
• Specific EGFR mutation identified is important• Some mutations (exon 20 insertions) are primarily resistant to EGFR inhibition
Pao W, et al. J Clin Oncol. 2005;23(11):256-2568. Wu YL, et al. J Thorac Oncol. 2007;2(5):430-439.
10Winship Cancer Institute | Emory University
EGFR Mutation Prevalence
Arcila ME, et al. Mol Cancer Ther. 2013;12(2):220-229.
11Winship Cancer Institute | Emory University
The IPASS study
• First large, randomized phase 3 trial of an EGFR TKI in a selected NSCLC population
• East Asian, never- or former light-smokers with metastatic lung adenocarcinoma
• No prior systemic treatment
• 1217 pts randomized to either gefitinib or platinum-doublet chemotherapy
Mok TS, et al. N Engl J Med. 2009;361(10):947-957.
12Winship Cancer Institute | Emory University
Progression Free Survival
Mok TS, et al. N Engl J Med. 2009;361(10):947-957.
13Winship Cancer Institute | Emory University
1st and 2nd generation EGFR TKI trialsRegimen ORR Median PFS Median OS
Study Year TKI (N) Chemo(N)
TKI (%)
Chemo (%)
TKI (months)
Chemo(months)
TKI(months)
Chemo(months
)Mok et al.18,
542009 Gefitinib
(132)Carbo-Taxol
(129)71.2 47.3 9.5 6.3 21.6 21.9
Mitsudomi et al.21, 55
2010 Gefitinib (86)
Cis-Taxotere
(86)
62.1 32.2 9.2 6.3 34.8 37.3
Maemondo et al.20
2010 Gefitinib (114)
Carbo-Taxol (114)
73.7 30.7 10.8 5.4 30.5 23.6
Zhou et al.56, 57
2011 Erlotinib (83)
Carbo-Gem (82)
83 36 13.1 4.6 22.7 28.9
Rosell et al.19
2012 Erlotinib (86)
Platinum Doublet (87)
64 18 9.7 5.2 19.3 19.5
Sequist et al.22, 58
2013 Afatanib (230)
Cis-Pem (115)
56 23 11.1 6.9 28.2 28.2
Wu et al.58,
592014 Afatanib
(242)Cis-Gem
(122)66.9 23 11 5.6 23.1 23.5
Steuer CE, et al. Mol Aspects Med. 2015;45:67-73.
14Winship Cancer Institute | Emory University
Improved QoL With First-line EGFR TKI vs. Chemotherapy• IPASS: Gefitinib vs platinum-based doublet chemotherapy showed
improvement with FACT-L• NEJ002: Gefitinib vs platinum-based doublet chemotherapy showed
improvement assessed with Care Notebook• First Signal: Gefitinib vs platinum-based doublet chemotherapy showed
improvement assessed with EORTC QoL C30 and Lung Cancer-13 questionnaires
• OPTIMAL: Erlotinib vs platinum-based doublet chemotherapy showed improvement in FACT-L and LCS scores
• Lux-Lung-3: Afatinib vs platinum-based doublet chemotherapy showed statistically significant delay in time to deterioration of cough, dyspnea; improvement in dyspnea scores, and cognitive, and physical role functions assessed by EORTC QoL C30 and Lung Cancer-13 questionnaires
Slide credit: clinicaloptions.comThongprasert S, et al. J Thorac Oncol. 2011;6(10):1663-1669. Oizumi S, et al. Oncologist. 2012;17(6):863-870. Han JY, et al. J Clin Oncol. 2012;31(10):1122-1128. Chen G, et al. Ann Oncol. 2013;24(6):1615-1622. Yang JC, et al. J Clin Oncol. 2013;31(127):3342-3350.
15Winship Cancer Institute | Emory University
Adverse Events
Landi L, et al. Transl Lung Cancer Res. 2013;2(!):40-49.
16Winship Cancer Institute | Emory University
Does the specific TKI matter?• LUX-Lung 7- afatinib vs. gefitinib first line in metastatic
EGFRm patients
Median PFS 11m (a) vs 10.9m (g)
• Grade ≥ 3 AE(afatinib vs gefitinib) – Diarrhea: 12.5% vs 1%– Rash/acne: 9% vs 3%– Fatigue: 6% vs 0– Increased ALT/AST: 0 vs 9%
• Dose reductions more common with afatinib (42% vs 2%)
• Drug discontinuation same (6%) in each arm
No sig. OS differencePark K, et al. Lancet Oncol. 2016;17(5):577-589.
17Winship Cancer Institute | Emory University
Dacomitinib
Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9007.
18Winship Cancer Institute | Emory University
Dacomitinib
Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9007.
19Winship Cancer Institute | Emory University
Dacomitinib
Dose Modification Dacomitinib 66% vs. Gefitinib 8% Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9007.
20Winship Cancer Institute | Emory University
Does the specific mutation matter?Exon 19 del Exon 21 L858R
Exon 21 insertions treated with EGFR TKI
Yang JC, et al. J Clin Oncol. 2013;31(127):3342-3350. Naidoo J, et al. Cancer. 2015;121(18):3212-3220.
21Winship Cancer Institute | Emory University
Adjuvant Erlotinib-RADIANT• Patients with completely
resected IB to IIIA NSCLC were treated with either placebo or erlotinib for 2 years.
• Primary endpoint- DFS
• EGFRm patients were a subgroup analysis
• NO difference in PFS or OS
Kelly K, et al. J Clin Oncol. 2015;33(34):4007-4014.
22Winship Cancer Institute | Emory University
ADJUVANT study design (NCT01405079)
Wu Y-L, et al. J Clin Oncol. 2017;35(suppl): Abstract 8500.
23Winship Cancer Institute | Emory University
Primary endpoint: DFS (ITT population)
•No PET required for n2 disease•About 20% of patients refused chemotherapy•No OS data
Wu Y-L, et al. J Clin Oncol. 2017;35(suppl): Abstract 8500.
24Winship Cancer Institute | Emory University
Progression on EGFR TKI?
• What to do if:• Slow, asymptomatic progression of disease?• Oligometastatic progression, esp. CNS?• REAL progression
25Winship Cancer Institute | Emory University
Slow/Oligo Progression• 10 patients who progressed on erlotinib or gefitinib, then had the TKI
discontinued, had scans 3 weeks later:• median 10% growth of tumor, 70% of patients had increased symptoms
• After restarting TKI, decrease in tumor size in 80% of pts
• Approximately 20% of patients undergoing wash-out of EGFR TKI experience a tumor flare
• In one study, 18 patients with oligometastatic progression who got local treatment had a median time to treatment change of 22 months
Riely GJ, et al. Clin Cancer Res. 2007;13(17):5150-5155. Chaft JE, et al. Clin Cancer Res. 2011;17(19):6298-6303. Yu HA, et al. J Throac Oncol. 2013;8(3):346-351.
26Winship Cancer Institute | Emory University
EGFR Tumor Flare
Riely GJ, et al. Clin Cancer Res. 2007;13(17):5150-5155.
27Winship Cancer Institute | Emory University
Cisplatin/Pemetrexed ± Gefitinib in EGFRmpts who progressed on TKI
Outcome Gefitinib (n = 133)
Placebo (n = 132) HR
Median PFS, mos 5.4 5.4 0.86 (P = .27)
Median OS, mos 14.8 17.2 1.62 (P = .03)
Soria JC, et al. Lancet Oncol. 2015;16(8):990-998.
28Winship Cancer Institute | Emory University
Resistance to EGFR-directed therapy
Camidge DR, et al. Nat Rev Clin Oncol. 2014;11(8):473-481.
29Winship Cancer Institute | Emory University
T790M
• Represents the resistance mechanism to EGFR TKI therapy for approximately 50-60% of patients
• Average time to 1st and 2nd gen EGFR TKI resistance is 9-13 months
• The substitution of threonine to a bulky methionine at amino acid position 790 (T790M) in exon 20 of the EGFR gene creates steric hinderance in the ATP binding domain of EGFR
Remon J, et al. Ann Oncol. 2017;28(4):784-790.
30Winship Cancer Institute | Emory University
What to do if tissue biopsy is not feasible?• Liquid Biopsy for ctDNA
• Retrospective study demonstrated similar t790m detection for liquid as tissue biopsies (50%)
• In patients with both liquid and tissue samples (n=25), 20% were only positive in blood testing
• In a prospective trial of osimertinib, T790M-positivity in plasma achieved an ORR of 62.5% and 6-months PFS 66.7% (similar to tissue)
Sandaresan TK, et al. Clin Cancer Res. 2016;22(5):1103-1110. Remon J, et al. Ann Oncol. 2017;28(4):784-790.
31Winship Cancer Institute | Emory University
Osimertinib• Only FDA approved 3rd generation EGFR TKI• Targets both the original EGFRm and T790M
EGFR
(L858R/T790M)
EGFR
(L858R)
EGFR
(L861Q)
EGFR
(wildtype)
Osimertinib 1 12 5 184
Afatinib 3 <1 <1 3
Gefitinib 155 <1 <1 3
Cross DA, et al. Cancer Discov. 2014;4(9):1046-1061.
32Winship Cancer Institute | Emory University
OsimertinibAURA ph I AURA
Extension(T790M+)
AURA2(T790M+)
AURA3(T790M+)Osimertinib vs. CT
N 253(T790M +: 138)
201 210 419
ORR 51% T790M+: 61%T790M-: 21%
62% 70% 71% vs. 31%, p<0.001
PFS 8.2 months (mo.)T790M+: 9.6 mo.T790M-: 2.8 mo.
12.3 mo 9.9 mo 10.1 vs. 4.4 mo.,HR 0.30; 95% CI, 0.23-
0.41, p<0.0001
Remon J, et al. Ann Oncol. 2017;28(4):784-790. Goss G, et al. Lancet Oncol. 2016;17(12):1643-1652.
33Winship Cancer Institute | Emory University
Osimertinib
Mok TS, et al. N Engl J Med. 2017;376(20):1993-1994.
34Winship Cancer Institute | Emory University
Resistance to Osimertinib
• Despite its efficacy, patients inevitably progress
• In a study of T790M EGFRm cell lines, the C797S mutation disrupted covalent bonding between osimertinib and the cysteine residue at the ATP-binding domain of EGFR
• Confirmed in patient samples.
• Other resistance mecanisms: • BRAF V600E, KRAS Q61K, FGFR3 fusion, transformations to small cell lung cancer
• Mechanism of resistance to Osimertinib in frontline EGFRm (T790M-) unclear at this time
Oxnard GR, et al. Presented at: American Association of Cancer Research Annual Meeting. April 4-5, 2017. Washington, DC. Abstract 4112.
35Winship Cancer Institute | Emory University
Resistance to Osimertinib
Piotrowska Z, et al. J Clin Oncol. 2017;35(suppl): Abstract 9020.
36Winship Cancer Institute | Emory University
FLAURA Study
Patients with EGFRm+ locally advanced or metastatic NSCLC who are treatment-naïve and eligible to receive first-line treatment with approved EGFR-TKI. EGFR-TKI orally once daily
(n=325)
AZD929180 mg orally once daily (n=325)
Progression
37Winship Cancer Institute | Emory University
Immunotherapy in EGFR
Gainor JF, et al. Clin Cancer Res. 2016;22(18):4585-4593. Lee CK, et al. J Thorac Oncol. 2017;12(2):403-407.
38Winship Cancer Institute | Emory University
Thank you!