Management Strategies for Lung Cancer Sensitive or ... · Management Strategies for Lung Cancer...

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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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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EGFR Mutation Prevalence

Arcila ME, et al. Mol Cancer Ther. 2013;12(2):220-229.

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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.

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Progression Free Survival

Mok TS, et al. N Engl J Med. 2009;361(10):947-957.

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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.

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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.

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Adverse Events

Landi L, et al. Transl Lung Cancer Res. 2013;2(!):40-49.

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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.

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Dacomitinib

Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9007.

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Dacomitinib

Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9007.

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Dacomitinib

Dose Modification Dacomitinib 66% vs. Gefitinib 8% Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9007.

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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.

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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.

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ADJUVANT study design (NCT01405079)

Wu Y-L, et al. J Clin Oncol. 2017;35(suppl): Abstract 8500.

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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.

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Progression on EGFR TKI?

• What to do if:• Slow, asymptomatic progression of disease?• Oligometastatic progression, esp. CNS?• REAL progression

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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.

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EGFR Tumor Flare

Riely GJ, et al. Clin Cancer Res. 2007;13(17):5150-5155.

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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.

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Resistance to EGFR-directed therapy

Camidge DR, et al. Nat Rev Clin Oncol. 2014;11(8):473-481.

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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.

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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.

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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.

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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.

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Osimertinib

Mok TS, et al. N Engl J Med. 2017;376(20):1993-1994.

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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.

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Resistance to Osimertinib

Piotrowska Z, et al. J Clin Oncol. 2017;35(suppl): Abstract 9020.

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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

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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.

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Thank you!