EGFR-Mutated Advanced NSCLC The Coming Paradigm Shift Title Slide Layout Faculty Suresh S. Ramalingam, MD Professor of Hematology/Oncology Director, Lung Cancer Program Winship Cancer Institute Emory University Atlanta, Georgia

Program 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 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

Incidence of Driver Mutations in Advanced NSCLC Lung Cancer Mutation Consortium KRAS 25% EGFR (sensitizing) 17% ALK 8% EGFR (other) 4% Mutation in > 1 gene 3% HER2 BRAF 2% PI3KCA 1% MET NRAS MEK1 <1% No oncogenic driver detected 36% Kris MG, et al. JAMA. 2014;311:1998-2006.[1]

Molecularly 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 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]

N (EGFR- mutation-positive) First-Line EGFR TKI Therapy vs Platinum-Doublet Chemotherapy in EGFR-Mutated Advanced NSCLC: PFS Study (EGFR TKI) N (EGFR- mutation-positive) ORR (EGFR TKI) Median PFS (EGFR TKI vs chemotherapy) Median OS 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 13.1 vs 4.6 mo; HR = 0.16 (0.10-0.26); P <.0001 19.3 v 19.5; P = .87 EURTACe 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 *First-line EGFR therapy licensed for use in some countries outside the United States. a. Mok TS, et al. N Engl J Med. 2009;361:947-957[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]

Treatment until disease progression First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC Study Design Afatinib (oral) 40 mg/d n = 230 Patients with treatment-naïve, stage IIIB/IV lung adenocarcinoma EGFR-activating mutation ECOG PS = 0,1 RANDOM I ZE Cisplatin 75 mg/m2 + Pemetrexed 500 mg/m2 IV every 3 d, up to 6 cycles n = 115 Treatment until disease progression 2:1 Stratification factors include EGFR mutation (exon 19 del, L858R, other) Race (Asian, non-Asian) Primary end point PFS Secondary end points include ORR; DCR; DoR; OS; PROs; safety; PK Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.[10]

First-Line Afatinib vs Chemotherapy in EGFR-Mutated Advanced NSCLC PFS 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 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 HR (95% CI) for patients with EGFR exon 19 del or L858R mutation only 0.47 (0.34-0.65) P = .001 Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.[10]

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 Diarrhea 95.2% 14.4% 15.3% 0% Rash/acne 89.1% 16.2% 6.3% Stomatitis/mucositis 72.1% 8.7% 0.9% Nausea 17.9% 65.8% 3.6% Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.[10]

Treatment until disease progression First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLC Study 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 RANDOM I ZE Treatment until disease progression 1:1 Erlotinib (oral) 150 mg/d once daily n = 77 Primary end point PFS Secondary end points include: OS, tumor response, QoL, safety Stratification factors include EGFR mutation type Seto T, et al. Lancet Oncol. 2014;15:1236-1244.[23]

First-Line Erlotinib +/- Bevacizumab in EGFR-Mutated Advanced NSCLC PFS and Safety 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]

Approximate Frequency, % 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-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 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

until disease progression* IMPRESS Study Design Treatment until disease progression* RANDOM I ZE 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 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. Mok TSK, et al. ESMO 2014. Abstract LBA2_PR.[31]

IMPRESS ORR and DCR ORR, % DCR, % n = 133 n = 132 n = 133 n = 132 OR (95% CI) = 0.92 (0.55-1.55); P = .760 OR (95% CI) = 1.39 (0.74, 2.62); P = .308 ORR, % DCR, % There was no statistical difference in ORR or DCR between treatment arms. n = 133 n = 132 n = 133 n = 132 Odds ratio >1 favours gefitinib Odds ratio and p-value from logistic regression with covariates CI, confidence interval Mok TSK, et al. ESMO 2014. Abstract LBA2_PR.[31]

IMPRESS PFS Gefitinib (n = 133) Placebo (n = 132) PFS event, n (%) 98 (73.7) 107 (81.1) Median PFS, mo 5.4 HR (95% CI) 0.86 (0.65-1.13) P value .273 OS: 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 2014. Abstract LBA2_PR.[31]

Third-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]

AURA Study 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 a. 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] ESMO 2014; Poster Discussion, Developmental therapeutics; Sunday, September 28, 2014 *cobas® EGFR Mutation Test (Roche Molecular Systems)

AURA Safety Patients With an AE, % 20 mg N = 21 40 mg N = 58 80 mg Total N = 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 2% 4% 5% 6% Selected AEs Diarrhea 24% 41% 33% 68% 76% 47% Rash 22% 32% 63% 71% 40% Nausea 17% 18% 30% Hyperglycemia 0% QT prolongation Pneumonitis-like event Sweta: I’d like to keep the “%” here if possible. Yang JC, et al. ESMO 2014. Abstract 449PD.[36]

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 mg N (Total = 127) 10 32 43 28 14 ORR 50% 59% 70% 61% Yang JC, et al. ESMO 2014. Abstract 449PD.[36]

Ongoing 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 TKI FLAURA 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 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-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]

CO-1686 Preliminary Outcomes 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)* *Reported in June 2014. Sequist L, et al. J Clin Oncol. 2014;32. Abstract 8010.[39]

CO-1686 Safety Selected AEs (%) (N = 72*) Grade 1 Grade 2 Grade 3 Diarrhea 19% 4% 0% Rash Nausea 14% 1% Hyperglycemia and IGT 11% 22% QT prolongation 7% 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.[39]

TIGER 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 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]

Summary 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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