Presentation on theme: "EGFR-Mutated Advanced NSCLC"— Presentation transcript:
1EGFR-Mutated Advanced NSCLC The Coming Paradigm ShiftTitle Slide LayoutFacultySuresh S. Ramalingam, MDProfessor of Hematology/OncologyDirector, Lung Cancer ProgramWinship Cancer InstituteEmory UniversityAtlanta, Georgia
2Program GoalsOutline the challenges with resistance to first- generation EGFR TKIs in patients with EGFR-mutated advanced NSCLCIdentify the rationale for rebiopsy in patients with known EFGR-mutated advanced NSCLCEvaluate the clinical efficacy and safety of investigational third-generation EGFR TKIs
3Program Outline EGFR inhibition in advanced NSCLC Resistance mediated by the EGFR T790M mutationPromising therapeutic agents to treat EGFR- mutated NSCLC with acquired resistance to first-line EGFR TKIsUpdate on ongoing clinical trials relevant to the setting of acquired resistance to first-line EGFR TKIs
4Incidence of Driver Mutations in Advanced NSCLC Lung Cancer Mutation Consortium KRAS25%EGFR (sensitizing)17%ALK8%EGFR (other)4%Mutation in > 1 gene3%HER2BRAF2%PI3KCA1%METNRASMEK1<1%No oncogenic driver detected36%Kris MG, et al. JAMA. 2014;311: 
5Molecularly 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 therapyLynch 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 aPaez JG, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004ba. Lynch TJ, et al. N Engl J Med. 2004;350: ; Paez JG, et al. Science. 2004;304: 
6EGFR Mutations and EGFR TKI Therapy in Advanced NSCLC Approximate distribution and frequency of EGFR mutations in advanced NSCLCaIn 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,cEGFR exon 19 deletionEGFR exon 21 (L858R) substitution mutationsa. Mitsudomi T, et al. Cancer Sci. 2007;98: ; b. Tarceva® PI 2012; c. Gilotrif® PI 2014.
7N (EGFR- mutation-positive) First-Line EGFR TKI Therapy vs Platinum-Doublet Chemotherapy in EGFR-Mutated Advanced NSCLC: PFSStudy(EGFR TKI)N (EGFR- mutation-positive)ORR (EGFR TKI)Median PFS(EGFR TKI vs chemotherapy)Median OSIPASSa (gefitinib*)26171.7%9.5 vs 6.3 mo; HR = 0.48 ( ); P <.001WJTOG 3405b (gefitinib)17773.7%9.2 vs 6.3 mo; HR = ( ); P <.0001NEJ002c(gefitinib)23062%10.8 vs 5.4 mo; HR = 0.30 ( ); P <.00130.5 vs 23.6 mo; P =NSOPTIMALd(erlotinib)16513.1 vs 4.6 mo; HR = 0.16 ( ); P <.000119.3 v 19.5; P = .87EURTACe15358%9.7 vs 5.2 mo; HR = 0.37 ( ); P <.000122.9 vs 18.8 mo; P =.42*First-line EGFR therapy licensed for use in some countries outside the United States.a. Mok TS, et al. N Engl J Med. 2009;361: ; b. Mitsudomi T, et al. Lancet Oncol. 2010;11: ; c. Maemondo M, et al. N Engl J Med. 2010;362: ; d. Zhou C, et al. Lancet Oncol. 2011;12: ; e. Rosell R, et al. Lancet Oncol. 2012;13: 
8Treatment until disease progression First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC Study DesignAfatinib (oral) 40 mg/dn = 230Patients with treatment-naïve, stage IIIB/IV lung adenocarcinomaEGFR-activating mutationECOG PS = 0,1RANDOMIZECisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d, up to 6 cyclesn = 115Treatment until disease progression2:1Stratification factors includeEGFR mutation (exon 19 del, L858R, other)Race (Asian, non-Asian)Primary end pointPFSSecondary end points includeORR; DCR; DoR; OS; PROs; safety; PKSequist LV, et al. J Clin Oncol. 2013;31: 
9First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC PFS Cis/PemPFS event, n (%)for overall population; n = 230 [afatinib]; n = 115 [chemo]152 (66)69 (60)Median PFS, mo for overall population11.16.9HR (95% CI) for overall population0.58 ( ) P = .0004for 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 only13.6HR (95% CI) for patients with EGFR exon 19 del or L858R mutation only0.47 ( )P = .001Sequist LV, et al. J Clin Oncol. 2013;31: 
10First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC Safety Selected Treatment-Related AEs (%)Afatinib(n = 229)Cis/Pem(n = 111)All Grades≥Grade 3Diarrhea95.2%14.4%15.3%0%Rash/acne89.1%16.2%6.3%Stomatitis/mucositis72.1%8.7%0.9%Nausea17.9%65.8%3.6%Sequist LV, et al. J Clin Oncol. 2013;31: 
11Treatment until disease progression First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLC Study DesignPatients with chemotherapy-naïve stage III/IV or postoperative recurrent NSCLCActivating mutations (exon del 19, L858R)ECOG PS = 0,1No brain metastasesErlotinib (oral) 150 mg/d once dailyBevacizumab 15 mg/kg IV every 3 wkn = 77RANDOMIZETreatment until disease progression1:1Erlotinib (oral) 150 mg/d once dailyn = 77Primary end pointPFSSecondary end points include:OS, tumor response, QoL, safetyStratification factors includeEGFR mutation typeSeto T, et al. Lancet Oncol. 2014;15: 
12First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLC PFS and Safety Erlotinib + Bev (n = 77)Erlotinib (n = 75)Median PFS, mo16.09.7HR (95% CI)0.54 (95% CI, )P value*.0015*Log-rank test, 2-sided.Most Common Grade 3 AEsErlotinib + Bev (n = 77)Erlotinib (n = 75)Rash25%19%Hypertension60%10%Proteinuria8%0%Serious AEsOccurred with the same frequency (~25%) in both arms.Seto T, et al. Lancet Oncol. 2014;15: 
13Approximate Frequency, % Some Characteristics of EGFR-Mutated Advanced NSCLC With Acquired Resistance to First-Line EGFR TKIMolecular AlterationApproximate Frequency, %EGFR Target Alteration (~60%)T790M alone~T790M with EGFR amplification~10Other EGFR point mutations1 - 2Bypass Tracts (~20%)HER2 amplification~8 - 13SCLC alone~6SCLC with PI3K~4MET amplification~5PI3KCA~1 - 2BRAF~1No Acquired Resistance Mechanism Identified (~15% to 20%)Camidge DR, et al. Nat Rev Clin Oncol. 2014;11: 
14EGFR T790M Mutation-Positive Advanced NSCLC in Acquired Resistance EGFR T790M-mutated advanced NSCLCOccurs on exon 20 and is found in > 50% of patients with acquired resistance to an EGFR TKIIncreases relative affinity of mutated EGFR for ATP, and may also sterically hinder binding of erlotinibMore likely to show progression in lungs/pleuraLess commonly detected in CNSPatients with disease characterized by the EGFR T790M mutation may have a better prognosis than patients with EGFR T790M mutation-negative diseaseOxnard GR, et al. Clin Cancer Res. 2011;17: 
15Rationale for Rebiopsy Following Disease Progression on First-Line EGFR TKI To determine whether transformation to SCLC has occurredTo evaluate for the presence of the EGFR T790M mutation and identify appropriate clinical trials when availableTo evaluate for the presence of other actionable mutations for which a clinical trial may be availableA rebiopsy is critically important for optimal assessment and treatment selection of patients with disease progression on first-line EGFR TKI therapy
16until disease progression* IMPRESS Study DesignTreatmentuntil disease progression*RANDOMIZECisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d (up to 6 cycles) +Gefitinib (oral) 250 mg/dn = 133Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d up to 6 cycles +Placebo (oral) 250 mgn = 132Patients with chemotherapy-naïve advanced NSCLCEGFR-activating mutationAchieved CR/PR ≥ 4 mo or SD > 6 mo with first-line gefitinibDisease progression ≤ 4 weeks prior to study randomization1:1Primary end pointPFSSecondary end points includeORR; 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.Mok TSK, et al. ESMO Abstract LBA2_PR.
17IMPRESS ORR and DCR ORR, % DCR, % n = 133 n = 132 n = 133 n = 132 OR (95% CI) = 0.92 ( );P = .760OR (95% CI) = 1.39 (0.74, 2.62);P = .308ORR, %DCR, %There was no statistical difference in ORR or DCR between treatment arms.n = 133n = 132n = 133n = 132Odds ratio >1 favours gefitinibOdds ratio and p-value from logistic regression with covariates CI, confidence intervalMok TSK, et al. ESMO Abstract LBA2_PR.
18IMPRESS PFS Gefitinib (n = 133) Placebo (n = 132) PFS event, n (%) 98 (73.7)107 (81.1)Median PFS, mo5.4HR (95% CI)0.86 ( )P value.273OS: 14.8 vs 17.2 mo, in favor of chemotherapy arm(P = .029, although OS data are not yet mature)Mok TSK, et al. ESMO Abstract LBA2_PR.
19Third-Generation EGFR TKIs Orally administered agents that block T790M-mutated EGFR and EGFR characterized by the original sensitizing mutation (eg, exon 19 deletion; L858R)*AZD9291CO-1686 (rociletinib)*HM61713 is another third-generation EGFR TKI in early-phase development.
20AURA Study DesignPhase 1, open-label, multicenter study of AZD9291 in patients with advanced NSCLC and progression on prior therapy with an EGFR TKIa,bRolling 6 study design allowing for enrollment of 2 to 6 patients concurrently on to a dose levelc5 doses evaluated: 20 mg; 40 mg; 80 mg; 160 mg; 240 mgDose administered once dailyDose escalation not preselected by EGFR T790M mutation statusExpansion study includes only patients with EGFR T790M mutation-positive disease according to central laboratory testinga. Yang J C-H, et al. J Clin Oncol. 2014;32. Abstract 8004; b. Yang JC, et al. ESMO Abstract 449PD; c. Skolnik JM, et al. Clin Oncol. 2008;26: ESMO 2014; Poster Discussion, Developmental therapeutics; Sunday, September 28, 2014*cobas® EGFR Mutation Test (Roche Molecular Systems)
21AURA Safety Patients With an AE, % 20 mg N = 21 40 mg N = 58 80 mg TotalN = 253Any AE, drug-related67%66%79%94%100%80%Any AE Grade ≥ 3, drug-related10%3%11%25%14%13%Serious AE, drug-related2%4%5%6%Selected AEsDiarrhea24%41%33%68%76%47%Rash22%32%63%71%40%Nausea17%18%30%Hyperglycemia0%QT prolongationPneumonitis-like eventSweta: I’d like to keep the “%” here if possible.Yang JC, et al. ESMO Abstract 449PD.
22AURA: Preliminary Outcomes in Patients With Centrally Tested EGFR T790M-Positive Disease ORR61%ORR by doseDisease control rate (CR+PR+SD): 95%Duration of confirmed responsePreliminary median duration of response at 80 mg: 8.2 mo (N=138)The longest duration of response to date is ongoing at > 11 moMedian PFSPreliminary median PFS: 9.6 mo (30% maturity; N=138)AZD9291 Dose20 mg40 mg80 mg160 mg240 mgN(Total = 127)1032432814ORR50%59%70%61%Yang JC, et al. ESMO Abstract 449PD.
23Ongoing Studies of AZD9291 AURA3 FLAURA 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 TKIFLAURAAZD9291 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. NCT ; b. ClinicalTrials.gov. NCT 
24CO-1686 (Rociletinib) Pre-Clinical Studies Transgenic murine model with tumor characterized by EGFR L858R/T790MDramatic tumor regression with CO-1686 in contrast to tumor progression observed with afatinibCellular viability assay using A431 model, which is characterized by high levels of EGFR wild typeLess cell inhibition observed with increasing doses of CO compared with other EGFR TKIsSuggests 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; Walter AO, et al. Cancer Discov ;3: 
25Phase 1 and Extended Phase 2 Expansion Studies of CO-1686 Formulation and dosingInitially evaluated as a free baseHydrobromide (HBr) salt formulation subsequently shown to be more efficaciousTwice-daily doses of 500 mg, 625 mg, 750 mg, 1000 mg have been evaluatedStudy designsPhase 1: Patients with advanced or recurrent NSCLC characterized by an activating EGFR mutation and prior EGFR-directed therapyCO-1686 dose escalation to MTDPrimary end points: Safety, PKPhase 2: Patients with EGFR T790M mutation-positive disease that has progressed on prior EGFR-directed therapy3 doses (500 mg, 625 mg, 750 mg twice daily) being evaluated as second- or higher-line therapy in 2 patient populations characterized by prior treatmentPrimary end points: ORR, DoRSequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.
26CO-1686 Preliminary Outcomes Evaluated in 40 patients with EGFR T790M mutation-positive disease treated with therapeutic doses of CO-1686ORR58%PFSMedian not yet reached (estimated > 12 mo)**Reported in June 2014.Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.
27CO-1686 Safety Selected AEs (%) (N = 72*) Grade 1 Grade 2 Grade 3 Diarrhea19%4%0%RashNausea14%1%Hyperglycemia and IGT11%22%QT prolongation7%Sweta: I’d like to keep the “%” here if possible.*Includes patients treated at efficacious doses.Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.
28TIGER Trials TIGER 1a TIGER 2b TIGER 3c Phase 2 randomized trial CO-1686 vs erlotinib as first-line therapy in treatment-naïve patients with disease characterized by an EGFR-sensitizing mutationTIGER 2bPhase 2 single arm trialCO-1686 as second-line therapy in patients with advanced NSCLC characterized by an EGFR T790M mutation and progression on a first-line EGFR TKITIGER 3cPhase 3 randomized trialCO-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 chemotherapya. ClinicalTrials.gov. NCT ; b. ClinicalTrials.gov. NCT ; c. ClinicalTrials.gov. NCT 
29SummaryResistance to first-line EGFR TKI therapy is a challenging clinical problemThe acquired resistance mutation, EGFR T790M, accounts for resistance to prior EGFR TKI therapy in nearly 60% of patientsThird-generation TKIs have demonstrated robust activity in patients with acquired resistance to a first-line EGFR TKITumor biopsy after disease progression on a first-line EGFR TKI is necessary to determine the mechanism(s) of acquired resistance
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