Sequencing in EGFR-Mutated NSCLC: Does Order Matter?

Sequencing in EGFR-Mutated NSCLC: Does Order Matter? Maximilian J. Hochmair, MD Otto Wagner Hospital Vienna, Austria

Disclosures Honoraria: AstraZeneca, AbbVie, Pfizer, Boehringer Ingelheim, Roche, MSD, BMS, Takeda, Lilly 2

In the 1990s, a thoracic oncologist s life was simple Lung cancer Platinum + etoposide Very few treatment options! 3

now it s much more complex STAGE IV DIAGNOSIS Nonsquamous cell Molecular tests Squamous cell EGFR positive ALK/ROS1 positive BRAF pos. EGFR negative/alk negative Targeted Therapy (1st/2nd EGFR TKI or 1st ALK) Treat to progression Dabrafenib/ Trametinib Treat to progression Testing IHC PD-L1 Expression Pembrolizumab in PD-L1 50% Chemotherapy in PD-L1 <50% Targeted Therapy (2nd/3rd-Gen EGFR or ALK) Poor PS (2) Treat to progression Good response Platinum Doublet (+/- bevacizumab) 4-6 cycles Maintenance: Pem or Bev (or erlotinib) Single-Agent Chemo Treat to progression Platinum Doublet +/-Necitumumab 4-6 cycles Maintenance: erlotinib Stable Disease Progression Chemotherapy Testing for MET?/PD-L1 Expression? EGFR = epidermal growth factor receptor; ALK = anaplastic lymphoma kinase; ROS1 = c-ros oncogene 1; TKI = tyrosine kinase inhibitor; IHC = immunohistochemistry; PD-L1 = programmed death ligand 1; PS = performance status; Pem = pembrolizumab; Bev = bevacizumab. Chemotherapy Taxol +/- nintedanib Taxol +/- ramucirumab Platinum doublet (reind.) Gemcitabine/navelbine Pemetrexed Erlotinib/Afatinib More likely if PS bad/ patient s wish Immunotherapy Experimental drug SOP OWS 2018 according to Hochmair. 4

Case Woman, aged 45 years Healthy 10 pack years Coughing + headache 5

X-ray: June 2014 6

CT Scan 7

MRI of the Brain MRI = magnetic resonance imaging. 8

Case (cont d) Woman, aged 45 years Healthy 10 pack years Coughing + headache NSCLC (adenocarcinoma) right lower lobe T4 N2 M1b EGFR status: exon Del19 (pleural effusion) 9

6 Weeks With Afatinib 10

6 Weeks With Afatinib 11

6 Weeks With Afatinib 12

Conclusions Treatment decision was afatinib based on its efficacy data, brain-penetrating ability, and personal experience With the introduction of osimertinib, the decision would remain unchanged because of a lack of treatment options after osimertinib failure 13

First-, Second-, and Third-Generation EGFR TKIs Are Not Equal: Activity Against EGFR Mutations Wild-type EGFR Intrinsic mutant EGFR ErbB heterodimers eg, Her2: ErbB3 Acquired T790M EGFR K Kinase domain K K K K K K K Drug Metabolised by CYP Enzymes Possible Drug-Drug Interactions Erlotinib Gefitinib 1st-generation TKI EGFR inhibition Activity range Reversible binding to wild-type and mutant EGFR Inactive on T790M mutant Erlotinib yes yes Gefitinib yes yes Afatinib Dacomitinib 2nd-generation TKI ErbB family blockade Activity range Irreversible covalent binding to EGFR, ErbB2, and ErbB4 to inhibit all ErbB family signalling Broader activity to overcome EGFR TKI resistant mutations Afatinib no limited Dacomitinib yes yes Osimertinib 3rd-generation TKI EGFR mutant specific inhibitor Activity Irreversible covalent binding to mutant EGFR Specificity for EGFR T790M mutant; EGFR wild-type sparing Range Osimertinib yes yes CYP = cytochrome. Girard. Future Oncol. 2018;14:1117; Cross et al. Cancer Discov. 2014;4:1046; Li et al. Oncogene. 2008;27:4702; Peters et al. Cancer Treat Rev. 2014;40:917; TAGRISSO Prescribing Information. March 2017. 14

First- and Second-Generation TKIs Improve PFS Compared With Chemotherapy RR (%) PFS (mo) OS (mo) TKI Study TKI Chemo TKI Chemo TKI Chemo Gefitinib IPASS 1,2 71 47 9.5 6.3 21.6 21.9 Gefitinib F-Signal 3 55 46 5.8 6.4 22.3 22.9 Gefitinib WJTOG 4 62 32 9.2 6.3 30.9 NR Gefitinib NEJ002 5,6 73 31 10.8 5.4 27.7 26.6 Erlotinib EURTAC 7 58 15 9.7 5.2 19.3 19.5 Erlotinib ENSURE 8 63 34 11.0 5.5 26.3 25.5 Erlotinib OPTIMAL 9,10 83 36 13.7 4.6 22.8 27.2 Afatinib a LL3 11,12 56 23 13.6 6.9 31.6 28.2 Afatinib a LL6 12,13 66 23 11.0 5.6 23.6 23.5 a Data for patients with common mutations only. PFS = progression-free survival; RR = response rate; OS = overall survival. 1. Fukuoka et al. J Clin Oncol. 2011;29:2866; 2. Mok et al. N Engl J Med. 2009;361:947; 3. Han et al. J Clin Oncol. 2012; 30:1122; 4. Mitsudomi et al. Lancet Oncol. 2010;11:121; 5. Maemondo et al. N Engl J Med. 2010;362:2380; 6. Inoue et al. Ann Oncol. 2013;24:54-59; 7. Rosell et al. Lancet Oncol. 2012;13:239; 8. Wu et al. Ann Oncol. 2015;26:1883; 9. Zhou et al. Lancet Oncol. 2011;12:735; 10. Zhou et al. Ann Oncol. 2015;26:1877; 11. Sequist et al. J Clin Oncol. 2013;31:3327; 12. Yang et al.lancet Oncol. 2015;16:141; 13. Wu et al. Lancet Oncol. 2014;15:213. 15

Estimated OS probability Estimated OS probability Mutational Subgroup Impacts Treatment Choice: OS in Del19 Subgroups in LUX-Lung 3 and 6 LUX-Lung 3 LUX-Lung 6 1.0 Afatinib (n=112) Cis/Pem (n=57) Median, mo 33.3 21.1 1.0 Afatinib (n=124) Cis/Gem (n=62) Median, mo 31.4 18.4 0.8 HR (95% CI) P value 0.54 (0.36-0.79) P=0.0015 0.8 HR (95% CI) P value 0.64 (0.44-0.94) P=0.0229 0.6 Afatinib Cis/Pem 0.6 Afatinib Cis/Gem 0.4 0.4 0.2 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Months No. at risk Afatinib 112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 0 Cis/Pem 57 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 0 No. at risk Afatinib Cis/Gem Months 124 122 118 115 106 99 90 80 73 69 59 39 16 8 1 0 62 58 53 49 44 35 30 28 26 21 18 11 4 3 0 0 Cis = cisplatin; Gem = gemcitabine; HR = hazard ratio; CI = confidence interval. Yang et al. Lancet Oncol. 2015;16:141. 16

ORR (%) PFS (%) First- and Second-Generation EGFR TKIs Are Not Equal: Antitumour Activity Afatinib vs gefitinib as first-line treatment of patients with EGFR mutation positive NSCLC (LUX-Lung 7): a phase IIB, open-label, randomised, controlled trial 80% 60% 40% P=0.002 P=0.150 P=0.003 100 Afatinib (n=160) 73% 75% 56% 66% 69% 42% 80 60 40 27% Gefitinib (n=159) Median, mo 11.0 10.9 HR (95% CI) P value 0.74 (0.57-0.95) 0.0178 Afatinib Gefitinib 20% 0% ITT Del19 L858R Afatinib Gefitinib 16% 20 16% 0 7% 0 3 6 9 12 15 18 21 24 27 30 33 26 39 42 45 48 51 Months Afatinib 160 142 113 94 67 47 34 26 20 13 10 8 4 3 0 0 0 0 Gefitinib 159 132 105 82 51 21 15 10 7 5 5 3 3 3 0 0 0 0 Corral et al. Ann Onc. 2017;28 (suppl 2):ii28. 17

Probability of PFS First- and Second-Generation EGFR TKIs Are Not Equal: Antitumour Activity ARCHER 1050: Dacomitinib vs Gefitinib (excluding CNS metastases) ARCHER 1050: Study Design PFS: Blinded Independent Review (ITT population) Phase III, randomised, open-label study to evaluate dacomitinib as an alternative first-line treatment for patients with advanced NSCLC with an EGFR-activating mutation 1.0 Dacomitinib (n=227) Gefitinib (n=225) Advanced NSCLC with EGFR-activating mutation(s) No prior systematic treatment of advanced NSCLC No CNS metastasis No prior EGFR TKI or other TKI ECOG PS 0, 1 R 1:1 (N=452) Dacomitinib 45 mg PO qd (N=227) Gefitinib 250 mg PO qd (N=225) Primary endpoint PFS by blinded independent review 256 PFS events PFS HR 0.667 (50% ) 90% power 1-sided ɑ=0.025 mpfs: 14.3 vs 9.5 months 0.8 0.6 0.4 0.2 0 Number of events, n (%) 136 (59.9%) 179 (79.6%) Median PFS (95% Cl) 14.7 (11.1-16.6) 9.2 (9.1-11.0) HR (95% Cl) PFS rate 30.6% vs 9.6% 0.59 (0.47-0.74) P<0.0001 Dacomitinib Gefitinib ++ Censored 0 6 12 18 24 30 36 42 No. at risk Months Dacomitinib Gefitinib 227 225 154 155 106 69 73 34 20 7 6 1 0 0 0 0 CNS = central nervous system; ECOG PS = Eastern Cooperative Oncology Group performance status; PO = orally; QD = once daily; mpfs = median progression-free survival. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/nct01774721. Accessed October 3, 2018; Mok et al. J Clin Oncol. 2017;35(suppl; abstr LBA9007); Wu et al. Lancet Oncol. 2017;18:1454. 18

Safety Second- or Third-Generation TKIs vs First-Generation TKIs LUX-Lung 7 1,2 ARCHER 1050 3 FLAURA 4 Afatinib (n=160) Gefitinib (n=159) Dacomitinib (n=227) Gefitinib (n=225) Osimertinib (n=279) Gefitinib/ Erlotinib (n=277) Treatment discontinuation rate 6.3% 6.3% 10.0% 7.0% 13.0% 18.0% Most common grade 3 AEs Diarrhoea: 12% Rash/acne: 9% Liver enzyme elevation: 9% Rash/acne: 3% Acne: 14% Diarrhoea: 9% Paronychia: 8% Liver enzyme elevation: 9% Paronychia: 1% Diarrhoea: 2% Pneumonia: 2% Decreased appetite: 3% Diarrhoea: 3% Pneumonia: 2% Decreased appetite: 2% AEs = adverse events. 1. Park et al. Lancet Oncol. 2016;17:577; 2. Paz-Ares et al. Ann Oncol. 2017;28:270; 3. Wu et al. Lancet Oncol. 2017;18:1454; 4. Soria et al. N Engl J Med. 2018;378:113. 19

Estimated PFS probability Dose Reduction of Afatinib Decreased Drug-Related AEs Without Impacting Efficacy The effects of afatinib dose modification on safety and efficacy were assessed in the LUX-Lung 3 trial 1.0 0.8 <40 mg for First 6 mo (n=105) 40 mg for First 6 mo (n=124) Median PFS, mo 11.3 11.0 HR (95% CI) P value 1.25 (0.91-1.72) 0.175 0.6 0.4 <40 mg for first 6 mo 40 mg for first 6 mo 0.2 No. at risk <40 mg in first 6 mo 40 mg for first 6 mo 0 0 3 6 9 12 15 18 21 24 27 Months 105 124 87 93 75 76 58 62 41 36 26 24 15 16 6 4 2 1 0 0 As in the LUX-Lung trials, real-world afatinib dose adjustments reduced the frequency and intensity of ADRs without impacting efficacy (RealGiDo study) Median time on treatment was 18.7 months and was not impacted by reduced starting dose or dose modification (19.4/17.7/19.5 for patients who started on 30 mg/reduced to <40 mg/remained on 40 mg) 1. Halmos et al. WCLC 2018. P1.01-28; 2. Yang et al. Ann Oncol. 2016;27:2103-2110. 20

TKI Resistance: Tissue + ctdna EGFR T790M Is the Most Common Resistance Mechanism to First- and Second-Generation EGFR TKIs Piotrowska et al. Multidisciplinary Thoracic Cancers Symposium 2017. Abstract 1. 21

Assessment of T790M Mutation Status in Cell-Free Plasma DNA 25% 71% 4% 76% Buder et al. J Thorac Oncol. 2018;13:821. 22

Probability of PFS Osimertinib vs Chemotherapy in T790M+ NSCLC AURA3 Female, 64% Asian, 65% Never smoker, 68% CNS metastases, 34% 1.0 0.8 0.6 0.4 Median PFS (mo) (95% Cl) Osimertinib Platinum/pemetrexed 10.1 (8.3-12.3) 4.4 (4.2-5.6) No. of patients 279 140 BICR: PFS 11.0 months HR for disease progression or death, 0.30 (95% CI, 0.23-0.41) P<0.001 0.2 Osimertinib Plat/pem AEs grade 3: 6% 34% 0 0 3 6 9 12 15 18 No. at risk Osimertinib 279 240 162 Months 88 50 13 0 Platinum/pemetrexed 140 93 44 17 7 1 0 BICR = blinded independent central review. Mok et al. N Engl J Med. 2017;376:629. 23

Estimated Probability Time on Osimertinib: First-line Afatinib Followed by Osimertinib Pooled Analysis LUX-Lung 3, 6, 7 1.0 0.8 0.6 0.4 0.2 Sequist et al. Ann Oncol. 2017;28(suppl 2):ii28. 0 Median time on treatment: 20.2 mo 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Osimertinib treatment (mo) 72% were 3rd line No. at risk: Afatinib 37 35 28 23 20 14 8 6 5 4 3 1 1 0 Post-hoc analysis from LUX-Lung 3/6/7 (n=37), corresponding to 6% of patients treated with afatinib in the trials. Osimertinib was not yet approved at time of recruitment. Based on approval and evidence it could be assumed that all patients were T790M positive. 24

FLAURA Study Design Patients with locally advanced or metastatic NSCLC Key inclusion criteria Aged 18 years a WHO performance status 0/1 Exon 19 deletion/l858r (enrollment by local b or cental c EGFR testing) No prior systemic anticancer/ EGFR-TKI therapy Stable CNS metastases allowed Endpoints Stratification by mutation status (Exon 19 deletion/l858r) and race (Asian/non- Asian Osimertinib (80 mg PO qd) (n=279) Randomised 1:1 Gefitinib (250 mg PO qd) or Erlotinib (150 mg PO qd) (n=277) d Primary endpoint: PFS based on investigator assessment (according to RECIST 1:1) The study had 90% power to detect an HR of 0.71 (representing an improvement in median PFS from 10 months to 14.1 months) at a 2-sided alpha level of 5% Secondary endpoints: objective response rate, duration of response, disease control rate, depth of response, OS, patient-reported outcomes, safety RECIST 1:1 assessment every 6 weeks e until objective progressive disease Crossover was allowed for patients in the erlotinib or gefitinib arm who could receive open-label osimertinib upon central confirmation of progression and T790M positivity FLAURA data cut-off: 12 June 2017, NCT02296125. a 20 years in Japan, b With central laboratory assessment performed by sensitivity; c Cobas EGFR Mutation Test (Roche Molecular Systems); d Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation; e Every 12 weeks after 18 months. WHO = World Health Organization; RECIST 1.1: Response Evaluation Criteria In Solid Tumors version 1.1. Soria et al. N Engl J Med. 2018;378:113. 25

Probability of PFS Probability of OS First- and Third-Generation EGFR TKIs Are Not Equal: Antitumour Activity 1.0 0.8 PFS in FLAURA Median PFS (95% Cl) HR (95% Cl) P value Osimertinib (n=279) Erlotinib or gefitinib (n=277) 17.7 (15.1-21.4) 9.7 (8.5-11.0) 0.45 (0.36-0.57) P<0.001 1.0 0.8 FLAURA OS Data Are Immature (25% Maturity) Osimertinib Erlotinib or gefitinib No. of patients 279 277 Median OS (95% CI), mo NC (NC-NC) NC (NC-NC) 0.6 0.6 0.4 Osimertinib 0.4 Osimertinib Erlotinib or gefitinib No. at risk 0.2 Months Osimertinib 279 259 229 200 170 132 66 22 3 0 Erlotinib or 277 235 192 138 101 69 28 5 1 0 gefitinib NC = not calculated. Data cut-off 12 June 2017. Tick marks indicate censored data. Soria et al. N Engl J Med. 2018;378:113. Erlotinib or gefitinib 0 0 3 6 9 12 15 18 21 24 27 No. at risk Osimertinib 279 276 269 253 243 232 154 87 29 4 0 0 Erlotinib 277 263 252 237 218 200 126 64 24 1 0 0 or gefitinib 0.2 0.0 HR for death, 0.63 (95% CI, 0.45-0.88) P=0.007 0 3 6 9 12 15 18 21 24 27 30 33 Months 26

Probability of PFS Subsequent Therapies in FLAURA 100 90 80 70 60 50 40 30 20 10 0 29 12 56 8 51 Osimertinib (n=279) 35 Received FST (n=82) 29% received subsequent therapy after osimertinib, mostly chemotherapy 46 17 14 23 1st gen EGFR TKI (n=277) 21 43 33 Received FST (n=129) Patient Disposition Received first subsequent (second-line) therapy No subsequent therapy (dead) No subsequent therapy (alive) Still on study treatment First Subsequent (Second-Line) Therapies Other targeted therapy Non platinum based chemotherapy Platinum-based chemotherapy Osimertinib EGFR-TKI containing regimen, other than osimertinib FST = First subsequent therapy. Soria et al. N Engl J Med. 2018;378:113 27

Acquired Resistance Mechanisms After First-Line Osimertinib (FLAURA) (N=91) EGFR mutations Unknown MET amplifications Other The most frequent resistance mechanisms for osimertinib were MET amplification (15%) and EGFR C797S mutation (7%) Rudin C, discussant of Ramalingam et al. ESMO 2018. LBA50. 28

Treatment Sequences in EGFR-Mutant NSCLC After First-Line EGFR TKI Except if molecular target First-/Second-Generation TKI T790M+ Osimertinib Chemotherapy T790M- Other Chemotherapy MET/HER2 inhibitor TKI rechallenge? Chemotherapy? Immunotherapy Osimertinib Chemotherapy Except if molecular target Need Mature OS and Treatment Sequences From FLAURA Girard. Future Oncol. 2018;14:1117. 29

Afatinib Followed by Osimertinib: A Real-World Study (GioTag) REAL-WORLD STUDY ON SEQUENTIAL THERAPY IN PATIENTS WITH EGFR MUTATION POSITIVE ADVANCED NSCLC STUDY OBJECTIVES Primary objective A retrospective review to determine the time on treatment a of afatinib as first-line therapy in EFGR mutation positive (M+) followed by osimertinib for T790M resistance mutation patients in a real-world setting Secondary objective To collect data on the acquired resistance mechanism to osimertinib 204 PRESELECTED PATIENTS EGFR M+ (Del19, L858R) advanced NSCLC Based on existing data from medical records Data collection between Q4 2017 and Q2 2018 a Time on treatment defined from the start of first-line treatment until the end of second-line treatment or death date by any cause. b Randomised controlled trials (RCTs) are designed to assess the efficacy and safety of study drugs under well-defined conditions and in selected patient populations. In contrast, real-world studies include everyday patients with characteristics which might preclude their participation in a RCT. Real-world studies are complementary to RCTs, and explore patient outcomes in populations more representative of clinical practice than perspective clinical trials. Real-world studies are essential for capturing clinically relevant data at the point of care, and providing clinically meaningful insights which can be applied to patient care. https://clinicaltrials.gov/ct2/show/nct03370770. Accessed October 9, 2018; Hochmair M et al. Future Oncol. 2018 Oct 19; doi:10.2217/fon-2018-0711. 30

Baseline Characteristics (N=204) Median (range) Ethnicity ECOG EGFR Start of afatinib n (%) Female 110 (53.9) Age (years) 60.0 (30 86) Weight (kg); BMI (kg/m²) 70.2 (37-116); 25.3 (15.0 45.2) Caucasian 120 (58.8) African-American 18 (8.8) Asian 50 (24.5) Stage IV 197 (96.6) Brain mets 21 (10.3) 0 43 (21.2) 1 110 (54.2) 2/3 31 (15.3) T790M 0 (0.0) Del19 150 (73.5) L858R 53 (26.0) Del19 + L858R 1 (0.5) Hochmair M et al. Future Oncol. 2018 Oct 19; doi:10.2217/fon-2018-0711. 31

Treatment probability Time on Treatment for the Sequence Afatinib-Osimertinib 1.0 0.8 0.6 Afatinib followed by osimertinib Median time (mo), 90% CI N=204 Events 106 27.6 (25.9-31.3) 0.4 0.2 48% still on treatment 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) No. at risk Afa-Osi 204 204 179 150 106 43 25 14 3 1 1 Hochmair M et al. Future Oncol. 2018 Oct 19; doi:10.2217/fon-2018-0711 CI = confidence interval. 32

Survival probability Survival Rates (from Start of Afatinib) 1.0 0.8 0.6 79% Afatinib followed by osimertinib 2-year survival rate (maturity) N=204 Events 63 79% (50%) 0.4 0.2 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) No. at risk Afa-Osi 204 204 194 176 127 64 35 16 4 1 1 Hochmair M et al. Future Oncol. 2018 Oct 19; doi:10.2217/fon-2018-0711. 33

Treatment probability Time on Treatment for the Sequence by EGFR Subgroup 1.0 0.8 0.6 Median time (mo), 90% CI Del19 (n=150) L858R (n=53) Events 69 37 30.3 (27.6-44.5) 19.1 (16.8-25.1) Del 19 L858R 0.4 0.2 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) No. at risk Del19 150 150 141 121 84 36 21 10 1 0 L858R 53 53 37 28 21 7 4 4 2 1 1 Hochmair M et al. Future Oncol. 2018 Oct 19; doi:10.2217/fon-2018-0711. 34

Time on Treatment for the Sequence by Baseline ECOG Hochmair M et al. Future Oncol. 2018 Oct 19; doi:10.2217/fon-2018-0711. 35

Conclusion Afatinib and osimertinib are highly effective in EGFR mutation positive patients However, there are limited treatment options after osimertinib failure and no mature OS data so far The sequence of afatinib followed by osimertinib for T790M+ patients is feasible and delivers a combined time on treatment of 28 months as assessed in a real-world setting Sequencing should be considered for all patients 36