Making the first decision: EGFR mutation-positive NSCLC in the advanced setting

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Maurice Mosley
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1 ELCC May 217, Switzerland Making the first decision: EGFR mutation-positive NSCLC in the advanced setting Noemí Reguart, MD, PhD Hospital Clínic de Barcelona, Spain

2 Disclosures Consultant or Advisory Role Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Guardant Health, Pfizer Grant/Trial Funding Roche 2

3 Disclaimer Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF and in the US under the brand name GILOTRIF for use in patients with distinct types of EGFR mutation positive NSCLC. In Switzerland, GIOTRIF is indicated as monotherapy for the treatment of Epidermal Growth Factor Receptor (EGFR) TKI-naïve patients with stage IIIB/IV non-small cell lung cancer (NSCLC) with common activating EGFR mutation(s) (exon 19 deletions or exon 21 L858R substitution). The recommended dose is 4 mg once daily with no possibility for dose escalation. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in uncommon mutations and SqCC of the Lung and other indications in Switzerland. 3

The journey of a patient with EGFR mutation-positive NSCLC RESISTANCE First-line therapy Second-line therapy NSCLC (Stage IV) EGFR activating mutation First generation (erlotinib, gefitinib) or

mutations in NSCLC 2 Resistance mechanisms to EGFR TKIs 4 3% EGFR 3 : ~ 15% (Western population) ~ 3% (Asian population) 5% 14% 5% 49% KRAS BRAF PIK3CA MEK AKT1 ROS1 translocation EGFR ALK

European Medicines Agency; FDA, Food and Drug Administration; HER2, human epidermal 4 growth factor receptor 2; NSCLC, non-small lung cancer; SCLC, small cell lung cancer; TKI, tyrosine kinase

4 The journey of a patient with EGFR mutation-positive NSCLC RESISTANCE First-line therapy Second-line therapy NSCLC (Stage IV) EGFR activating mutation First generation (erlotinib, gefitinib) or second generation (afatinib) TKI T79M ~5%, most common 1,4,5 MET amplification ~5 11% 1,4 Unknown 3% 4 Osimertinib (FDA, EMA approved) C-MET inhibitor (clinical trials) Chemotherapy Molecular driver mutations in NSCLC 2 Resistance mechanisms to EGFR TKIs 4 3% EGFR 3 : ~ 15% (Western population) ~ 3% (Asian population) 5% 14% 5% 49% KRAS BRAF PIK3CA MEK AKT1 ROS1 translocation EGFR ALK translocation HER2 NRAS RET translocation Other With EGFR amp MET amp PIK3CA T79M SCLC transformation Unknown mechanism ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; HER2, human epidermal 4 growth factor receptor 2; NSCLC, non-small lung cancer; SCLC, small cell lung cancer; TKI, tyrosine kinase inhibitor. 1. Arcila ME, et al. Clin. Cancer Res. 211;17(5):1169 8; 2. Baumgart M. AJHO. 215: 3. Van Assche K, et al. Front Oncol ;4:35. doi: /fonc ; 4, Sequist LV, et al. Sci Transl Med. 211;3(75):75ra26; 5. Wang S, et al. J Hematol Oncol. 216;9:34.

5 CASE 1

6 Case 1 History Female, 6 years old, healthy, no related comorbidities, non-smoker, ECOG PS 1 First diagnosis (December 214) Lung adenocarcinoma (IHC: TTF-1 and CK7 positive) Staging: ct1bnm1 (IVb, solitary brain metastasis) First treatment (January 215) Resection of the brain metastasis and lobectomy (pt1bn1) WBRT 3 Gy 1 fx plus adjuvant chemotherapy (4 cycles platinum vinorelbine) First imaging assessment (June 215) PET-CT: multiple bone metastases MRI: no evidence of recurrence in the brain Molecular characterisation Exon 19 (EGFR T751_I759delinsS) by COBAS-Therascreen 6 Case report: N. Reguart. CK7, cytokeratin 7; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; PET-CT, positron emission tomography computed tomography; TTF-1, thyroid transcription factor-1; WBRT, whole brain radiation therapy; MRI, magnetic resonance imaging.

7 Case 1: images at diagnosis MRI PET-CT ct1bnm1 (IVb, solitary brain metastasis) Radical treatment indicated (January 215). Case report: N. Reguart PET-CT, positron emission tomography computed tomography; MRI, magnetic resonance imaging. 7

8 Case 1: images at systemic relapse MRI PET-CT Early systemic metastatic bone relapse (June 215) 8 Case report: N. Reguart. PET-CT, positron emission tomography computed tomography; MRI, magnetic resonance imaging.

Currently approved EGFR-TKIs: guiding selection of treatment in the clinic First generation Erlotinib Gefitinib Second generation Afatinib Third generation Osimertinib Outcomes of TKIs (response,

9 Currently approved EGFR-TKIs: guiding selection of treatment in the clinic First generation Erlotinib Gefitinib Second generation Afatinib Third generation Osimertinib Outcomes of TKIs (response, duration, survival) Molecular: mutation type (Del19/L858R/T79M) Phenotypic features (age, gender, weight, ethnicity) Risk of toxicity Brain disease (presence/absence) 9 EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

10 EGFR-targeted TKIs: clinical benefits in EGFR mutation-positive NSCLC Randomised controlled trials TKI Studies EGFR mutation (n) PFS HR (95% CI) OS HR (95% CI) Gefitinib IPASS 1 3 EGFR M+ (n=261)* Del19 (n=14) L858R (n=111).48 (.36.64).38 (.26.56).55 (.35.87) 1. ( ).79 ( ) 1.44 (.9 2.3) Gefitinib WJTOG 4,5 Common (n=172).49 (.34.71) 1.25 ( ) Gefitinib NEJ2 3,6 EGFR M+ (n=224) Del19 (n=116) L858R (n=97).32 (.24.44).35 (.23.52).32 (.2.5).89 ( ).83 ( ).82 ( ) Erlotinib OPTIMAL 7,8 Common (n=154).16 (.1.26) 1.19 ( ) Erlotinib EURTAC 9,1 Common (n=173).34 (.23.49).93 ( ) Erlotinib ENSURE 11 Common (n=217).34 (.22.51).91 ( ) Afatinib LUX-Lung EGFR M+ (n=345).58 (.43.78).88 ( ) Afatinib LUX-Lung EGFR M+ (n=364).28 (.2.39).93 ( ) Findings from several Phase III trials demonstrate benefit in RR, PFS and QoL, but no differences observed in OS *Out of a total of 1,217 patients. CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; M+, mutation positive; OS, overall survival; NSCLC, non-small cell lung cancer; PFS, progression-free survival; QoL, quality of life; RR, response rate; TKI, tyrosine kinase inhibitor Mok TS, et al. N Engl J Med 29;361:947 57; 2. Fukuoka M, et al. J Clin Oncol 211;29: ; 3. Yang JC, et al. Eur J Cancer 211; (suppl 1):S633 (poster 9132); 4. Mitsudomi T, et al. Lancet Oncol 21;11:121 8; 5. Yoshioka H, et al. J Clin Oncol 214;32(Suppl.): Abstract 8117; 6. Inoue A, et al. Ann Oncol 213;24:54 9; 7. Zhou C, et al. Lancet Oncol 211;12:735 42; 8. Zhou C, et al. Ann Oncol 215;26: ; 9. Rosell R, et al. Lancet Oncol 212;13:239 46; 1. Khozin S, et al. Oncologist 214;19:774 9; 11. Wu YL, et al. Ann Oncol 215;26:1883 9; 12. Sequist LV, et al. J Clin Oncol 213;31: ;13. Yang JC, et al. Lancet Oncol 215;16:141 51; 14. GIOTRIF EU SmPC, as approved July 215; 15. Wu YL, et al. Lancet Oncol 214;15:

11 Estimated OS probability Estimated OS probability LUX-Lung 3 and 6: preplanned OS analysis by mutation subgroups LUX-Lung 3: Del 19 LUX-Lung 6: Del Afatinib (n=112) Cis/pem (n=57) 1. Afatinib (n=124) Cis/gem (n=62).8 Median, months HR (95% CI) p value (.36.79) p=.15.8 Median, months HR (95% CI) p value (.44.94) p= Time (months) No. at risk: Afatinib Cis/pem Time (months) No. at risk: Afatinib Cis/gem L858R LUX-Lung 3 LUX-Lung 6 Afatinib (n=91) Cis/pem (n=47) Afatinib (n=92) Cis/gem (n=46) Median, months HR (95% CI), p value 1.3 ( ), p= ( ), p= CI, confidence interval; cis, cisplatin; gem, gemcitabine; HR, hazard ratio; pem, pemetrexed; OS, overall survival. Yang JC, et al. Lancet Oncol 215;16:

12 LUX-Lung 7: Randomised trial evaluating two EGFR-directed therapies in EGFRm NSCLC Patients (N=319) Stage IIIB/IV adenocarcinoma of the lung EGFR mutation (Del19 and/or L858R) in the tumour tissue* No prior treatment for advanced/metastatic disease ECOG PS /1 n=16 1:1 n=159 Afatinib 4 mg QD Stratified by: Mutation type (Del19/L858R) Brain metastases (present/absent) Gefitinib 25 mg QD Co-primary endpoints: PFS (independent review) TTF OS Secondary endpoints: ORR Time to response Duration of response Tumour shrinkage HRQoL Treatment beyond progression allowed if deemed beneficial by investigator RECIST assessment performed at Weeks 4 and 8, and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter Primary PFS analysis conducted after ~25 events; primary OS analysis conducted after ~213 events and 32-month follow-up All statistical testing at two-sided 5% alpha level with no adjustment for multiplicity *Central or local test; Dose modification to 5, 3 or 2 mg was permitted in line with prescribing information. 12 ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QD, once daily; RECIST, Response Evaluation Criteria In Solid Tumors; TTF, time to treatment failure. Park K, et al. Lancet Oncol 216;17:

13 In your clinical practice, which outcome is the most relevant for informing treatment decisions?? 1. OS 2. TTF 3. PFS by independent review 13 OS, overall survival; PFS, progression-free survival; TTF, time to treatment failure.

14 PFS (%) LUX-Lung 7: PFS in the overall population by independent central review 1 Afatinib (n=16) Gefitinib (n=159) 8 6 Median PFS, months HR (95% CI) p value.73 (.57.95) No. at risk: Time of PFS (months) Afatinib Gefitinib CI, confidence interval; HR, hazard ratio; PFS, progression free survival. Park K, et al. Lancet Oncol 216;17:

15 Estimated OS probability LUX-Lung 7: OS in the overall population 1. Afatinib Gefitinib.8 Median, months HR (95% CI) p value.86 ( ).258* Median follow-up: 42.6 months (as of 8 April 216) Median treatment duration (afatinib vs gefitinib): 13.7 vs 11.5 months No. at risk: Time (months) Afatinib Gefitinib *Unadjusted. 15 CI, confidence interval; HR, hazard ratio; OS, overall survival. Paz-Ares L, et al. Ann Oncol 217; 28:

16 Estimated OS probability Estimated OS probability LUX-Lung 7: OS and response by EGFR mutation subtype Del 19 1 L858R 1 1. Afatinib Gefitinib Median,months Afatinib Gefitinib Median,months HR (95% CI) p-value.83 ( ) HR (95% CI) p-value.91 ( ) No. at risk: Afatinib Gefitinib Time (months) No. at risk: Afatinib Gefitinib Time (months) Exon 19 Del Leu858Arg Mutation subtype 2 Afatinib Gefitinib Afatinib Gefirinib Response rate Rate (%) (%) 73% 66% 66% 42% 16 CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; OS, overall survival. 1. Paz-Ares L, et al. Ann Oncol 217; 28:27 277; 2. Park K, et al. Lancet Oncol 216;17:

17 Case 1: early PR after 6 weeks on afatinib Pretreatment (June 215) 6 weeks on afatinib 4 mg QD (August 215) PET-CT early response with afatinib 4 mg QD 19 PET-CT, positron emission tomography-computed tomography; PR, partial response; QD, once daily. Case report: N. Reguart.

18 LUX-Lung 7: drug-related AEs (>1%) 1 Afatinib (n=16) Gefitinib (n=159) All Grade 3* All Grade 3* Any AE, n (%) 156 (97.5) 5 (31.3) 153 (96.2) 31 (19.5) Diarrhoea 144 (9.) 21 (13.1) 97 (61.) 2 (1.3) Rash/Acne 142 (88.8) 15 (9.4) 129 (81.1) 5 (3.1) Stomatitis 13 (64.4) 7 (4.4) 38 (23.9) Paronychia 9 (56.3) 3 (1.9) 28 (17.6) 1 (.6) Dry skin 52 (32.5) 59 (37.1) Pruritus 37 (23.1) 36 (22.6) Fatigue 33 (2.6) 9 (5.6) 23 (14.5) ALT increased 15 (9.4) 38 (23.9) 13 (8.2) AST increased 1 (6.3) 33 (2.8) 4 (2.5) Higher number of AEs leading to dose reduction with afatinib (42% vs 2%) 2 Four cases of drug-related ILD were observed with gefitinib (three Grade 3); none were observed with afatinib 1 *All Grade 3 unless stated; Including one (.6%) Grade 4 AE; Grouped term. 2 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease. 1. Paz-Ares L, et al. Ann Oncol 217; 28: (supplementary table S2); 2. Park K, et al. Lancet Oncol 216;17:

19 Patients (%) LUX-Lung 7: drug-related AEs leading to discontinuation in more than one patient (3.1%) 5 (3.1%) 4 (2.5%) Afatinib Gefitinib 2 3 (1.9%) 2 (1.3%) 2 (1.3%) 1 % % % % % % Diarrhoea Fatigue* Toxic skin eruption ALT increase AST increase ILD Low rate of treatment discontinuation (6%) in both arms *Grouped term. 21 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease. Park K, et al. Lancet Oncol 216;17: (supplementary material); Park K, et al. Ann Oncol 215;26(Suppl. 9): Abstract LBA2 (oral presentation).

20 Patients (%) Influence of dose adjustment on afatinib safety: post-hoc analysis LUX-Lung 3 Median treatment exposure for dose-reduced patients 1 Key treatment-related AEs in patients requiring tolerability-guided dose adjustment 1,2 Median treatment exposure (days) Grade 3 Grade 1/2 4 mg (n=122) mg (n=12) mg (n=4) Pre Post Pre Post Pre Post Pre Post Pre Post Any Diarrhoea Rash/acne* Stomatitis Nail effects* Pre: AEs before dose reduction from 4 mg Post: AEs after first dose reduction from 4 mg Despite longer treatment exposure at lower doses, tolerability-guided dose reduction led to decreases in the incidence and severity of treatment-related AEs 22 * Grouped term. AE, adverse event. 1. Yang JC, et al. J Clin Oncol 215;33(Suppl.): Abstract 873 (poster); 2. Yang JC, et al. Ann Oncol 216;27:213 1.

21 Identifying groups of risk for afatinib AEs 3 Factors associated with severe GI toxicity and DLT induced by afatinib in patients with advanced NSCLC 1 HR 95% CI p value Severe GI toxicity Female Age, years ECOG PS Weight, kg Malnourished DLT Body surface, m Malnourished Post-hoc analysis LUX-Lung 3: dose reductions more common in females, older patients, East Asian ethnicity, low body weight (<5 kg) and low body surface m 2 (BSA) 2 23 AE, adverse event; BSA, body surface area; CI, confidence interval; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; GI, gastrointestinal; HR, hazard ratio; NSCLC, non-small cell lung cancer. 1. Arrieta O, et al. Oncologist 215;2:967 74; 2. Yang J, et al. J Clin Oncol 215;33(Suppl.): abstract 873 (poster).

22 Estimated PFS probability Influence of dose adjustment on afatinib efficacy: post-hoc analysis LUX-Lung 3 Median PFS similar in patients who had afatinib dose reductions in the first 6 months and those who remained on afatinib 4 mg QD <4 mg in first 6 months (n=15) 4 mg in first 6 months (n=124) Median, months HR (95% CI) p value 1.25 ( ).175 <4 mg in first 6 months 4 mg in first 6 months.2 No. at risk in first 6 months <4 mg 4 mg Time (months) CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; QD, once daily. Yang JC, et al. Ann Oncol 216;27:213 1.

Long-term response independent of dose adjustment: Post-hoc analysis LUX-Lung 7 Long-term treatment (>3 years) was independent of tolerability-guided dose adjustment, or the presence of brain

23 Long-term response independent of dose adjustment: Post-hoc analysis LUX-Lung 7 Long-term treatment (>3 years) was independent of tolerability-guided dose adjustment, or the presence of brain metastases at time of enrolment *Patients were ordered and numbered by treatment duration, with Patient 1 being on treatment longest; At the time of enrolment. 25 LTR, long-term responders; OS, overall survival. 1. Schuler M, et al. ECCO 217 (oral presentation).

24 Approximately what proportion of your patients require tolerability-guided dose adjustment of afatinib?? 1. The majority of patients 2. About half of patients 3. Very few patients 26

25 Proactive management and close monitoring to prevent class-effect AEs Days/cycle Follow up Goal D+2/D+3 Phone call or visit* Early detection of GI toxicity D+7 First follow-up visit Early detection of possible class-effect AEs (diarrhoea and rash) D+3 and every cycle Monthly follow-up visit Monthly follow-up of patient evolution Afatinib started 4 mg QD Recommended follow-up schedule 1 Case report Afatinib reduced 3 mg QD Cycle 1 Cycle 2 Cycle 3 Day 3 Day 7 Day 38 Day 41 Bone pain opioids Oncology nurse phone call; optimal care Physician visit: afatinib 4 mg QD continued Oncology nurse phone call; optimal care Physician visit: afatinib stopped No bone pain opioids discontinued Diarrhoea G2 Diarrhoea G1 Diarrhoea G2 Diarrhoea G2 Diarrhoea G1 *By an oncologist or an oncology nurse on the basis of the hospital/centre organisation. 27 AE, adverse events; D, day; G, grade; GI, gastrointestinal; QD, once daily. 1. Arriola E, et al. Future Oncol 215;11: Case report: N. Reguart.

26 Case 1: PET-CT scans show CR after 22 months on afatinib 3 mg QD Pretreatment (June 215) 6 weeks on afatinib 4 mg QD (August 215) 22 months on afatinib 3 mg QD (April 217) Long-term and broader response with afatinib despite dose reduction 28 CR, complete response; PET-CT, positron emission tomography computed tomography; QD, once daily. Case report: N. Reguart.

27 CASE 2

28 Case 2 History Female patient, 58 years old, no past medical history, non-smoker Diagnosis April 215 Stage IVb NSCLC (ct2nm1b), gastro-hepatic ligament lymph nodes Molecular profiling: dpcr-egfr WT, ALK/ROS non-translocated Treatment evolution First line: Platinum doublet; PR as best response (October 215) Symptomatic progression at brain (January 216) Second line: Nivolumab 3 mg/kg q2w and WBRT (TD 3 Gy/1 fx) Symptomatic progression at brain and primary tumour (May 216) 3 ALK, anaplastic lymphoma kinase; dpcr, digital polymerase chain reaction; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PR, partial response; q2w, once every 2 weeks; ROS, c-ros oncogene; WBRT, whole brain radiation therapy; WT, wild type. Case report: N. Reguart.

29 Case 2: CT scans on nivolumab progression in second line Progressive disease in brain and lung after 3 cycles (May 216) Significant oedema observed 31 CT, computerised tomography. Case report: N. Reguart.

30 Case 2: Rebiopsies to guide targeted treatment April 215 Initial presentation January 216 Progression on chemotherapy May 216 Progression on nivolumab June 216 Blood sample Liquid biopsy 1 st biopsy 2 nd biopsy 3 rd biopsy Liquid biopsy 1 st Biopsy-lung EGFR WT (dpcr) no fusion ALK ROS (FISH) No tissue available for retesting 2 nd Biopsy-lung No tissue available 3 rd Biopsy-lung No tissue available Pneumothorax 32 ALK, anaplastic lymphoma kinase; dpcr, digital polymerase chain reaction; EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridisation; WT, wild type; ROS, c-ros oncogene. Case report: N. Reguart.

31 Case 2: liquid biopsy report Summary of alterations Tumour response map Alteration % cfdna cfdna amplification Somatic alteration burden 6.8% Exon 19 Deletion 6.8 EGFR AMP + PTEN E73* 2.5 BRCA1 Q78*.1 Guardant36 (v 2.1) Exon 19 deletion identified in liquid biopsy 34 AMP, amplification; BRCA1, breast cancer 1; EGFR, epidermal growth factor receptor; PTEN, phosphatase and tensin homolog. Case report: N. Reguart.

32 Does the presence of brain metastasis factor in your selection for a TKI?? 1. No 2. Yes 3. Only if asymptomatic 35 TKI, tyrosine kinase inhibitor.

33 Estimated PFS probability PFS in patients with brain metastases: combined analyses from LUX-Lung 3 and Afatinib (n=48) Chemo (n=33) Median PFS, months HR (95% CI) p value.5 (.27.95) No. at risk in first 6 months Afatinib Chemo Time (months) 17 1 Time to CNS progression in LUX-Lung 3 and 6 was superior than chemo in patients with brain metastasis (15.2 vs 5 7 months) CI, confidence interval; CNS, central nervous system; HR, hazard ratio; PFS, progression-free survival. Schuler M, et al. J Thorac Oncol 216;11:38 9.

34 Case 2: CT scans after 2 cycles of afatinib Pretreatment (June 216) 6 weeks on afatinib (August 216) 37 CT, computerised tomography. Case report: N. Reguart.

35 Summary Efficacy First-line afatinib showed a significant improvement in OS of over 1 year versus chemotherapy in EGFR Del 19 patients in two randomised trials 1 Results from LUX-Lung 7 confirm the significant benefit in PFS of afatinib over gefitinib in treatment of EGFR m+ NSCLC 2 Tolerability AEs with afatinib and gefitinib were manageable leading to equally low rates of treatment discontinuation (6.3% in both treatment arms) 1 Proactive management, close monitoring and dose adjustment can effectively manage AEs Identify groups of risk and adjust dose if necessary Brain metastasis CNS metastases negatively impact the quality of life and OS of many patients with NSCLC and continue to present a therapeutic challenge The magnitude of benefit in PFS with afatinib over chemotherapy was maintained in patients with asymptomatic brain metastases 3 38 AE, adverse event; Del, deletion; CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; OS, overall survival; M+, mutation positive; PFS, progression-free survival. 1. Yang JC, et al. Lancet Oncol 215;16:141 51; 2. Park K, et al. Ann Oncol 215;26(Suppl. 9): Abstract LBA2 (presentation); 3. Schuler M, et al. J Thorac Oncol 216;11:38 9.

36 Faculty Discussion Chair Rolf Stahel University Hospital of Zürich, Switzerland David R. Gandara University of California Davis Cancer Center, USA Noemí Reguart Hospital Clínic de Barcelona, Spain Maximilian Hochmair Otto Wagner Spital, Vienna, Austria 4

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