Improving outcomes for NSCLC patients with brain metastases Martin Schuler West German Cancer Center, Essen, Germany In Switzerland, afatinib is approved as monotherapy for patients with non-small cell lung cancer (stage IIIb/IV) with activating mutations of EGFR (exon 19 deletions or exon 21 L858R substitutions), not previously treated with EGFR TKIs. It is also indicated for the treatment of patients with locally advanced or metastatic squamous cell cancer of the lung whose carcinoma progressed during or after platinum-based chemotherapy and for whom immunotherapy is not suitable. Copyright:
Afatinib Indications: In Switzerland, afatinib is approved as monotherapy for patients with non-small cell lung cancer (Stage IIIb/IV) with activating mutations of EGFR (exon 19 deletions or exon 21 L858R substitutions), not previously treated with EGFR TKIs. It is also indicated for the treatment of patients with locally advanced or metastatic squamous cell cancer of the lung whose carcinoma progressed during or after platinum-based chemotherapy and for whom immunotherapy is not suitable. Posology: The recommended dose is 4 mg once daily, orally. Maximum daily dose in squamous cell carcinoma of the lung is 5 mg, orally. Not recommended in patients with an egfr <15 ml/min, in patients requiring dialysis and in severe hepatic failure. 2
Disclosures Corporate-sponsored research for Boehringer Ingelheim, S and Novartis Has been a consultant for AstraZeneca, Boehringer Ingelheim, S, Celgene, Lilly, Novartis and Roche Has received honoraria from Alexion, Boehringer Ingelheim, S, Celgene, Lilly and Novartis 3
Introduction The brain is a common site of metastasis in NSCLC, affecting 21 64% of patients 1 Patients with NSCLC defined by specific oncogenic drivers (e.g. EGFR and ALK) have a particularly high prevalence of s at primary diagnosis and at progression 2,3 ~24% at diagnosis ~3 7% at progression Intracranial responses and growth delay of CNS metastases with EGFR TKI treatment have been reported 4 Intracranially active TKI may defer the need for brain irradiation, which is associated with substantial morbidity 5 ALK, anaplastic lymphoma kinase;, brain metastasis; CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor. 1. Nguyen, Deangelis. J Support Oncol 24;2:45 1; 2. Rangachari, et al. Lung Cancer 215;88:18 11; 3. Khalifa, et al. J Thorac Oncol 216;11:1627 43; 4. Heon, et al. Clin Cancer Res 212;18:446 14; 5. Zhou, et al. J Clin Oncol 217;35:133 35. 4
Prospective data for first-generation EGFR TKIs in patients with s are limited N=28 Phase II study with either erlotinib or gefitinib 1 Systemic PR=83%; SD=11%; mpfs 6.6 months; mos 15.9 months No significant differences No information was provided on intracranial activity Phase II CTONG-83 study of erlotinib as second-line treatment 2 N=48 with asymptomatic brain metastasis after first-line CT 2 Intracranial mpfs 1.1 months; overall mpfs 9.7 months Eight patients with EGFRm+ disease No intracranial efficacy was reported CT, chemotherapy; EGFRm, epidermal growth factor receptor mutation; mpfs, median progression-free survival; mos, median overall survival; PR, partial response; SD, stable disease. 1. Park, et al. Lung Cancer 212;77:556 6; 2. Wu, et al. Ann Oncol 213;24:993 9. 5
Change in target lesion size from baseline (%) Best change in baseline target lesions (%) 3 mg LM LM LM Prospective data for CSF-permeant TKI: AZD3759 the BLOOM study BLOOM study design overview Phase I study to assess the safety, tolerability, pharmacokinetics and preliminary antitumour efficacy of AZD3759 or osimertinib in patients with EGFRm+-advanced NSCLC AZD3759 Cohort 1 5 mg BID Osimertinib 16 mg QD Cohort 2 1 mg BID TKI-pretreated LM Dose escalation Cohort 3 2 mg BID Cohort 4 3 mg BID Cohort 5 5 mg BID 2 or 3 mg BID* Dose expansion cohorts LM TKI-naïve (n=4) or pretreated (n=18) TKI-naïve (n=16) Cohort 1: T79M unselected LM (n=21) Cohort 2: T79M + LM (n=2) 2 TKI-naïve patients with advanced EGFRm+ NSCLC were enrolled (16 with and four with LM) 15 (83%) of 18 patients with measurable at baseline had confirmed objective response (14 PRs and one CR) Median best percentage change of intracranial lesions was 54% (investigator assessed) *Both AZD3759 2 and 3 mg BID were explored to evaluate long-term tolerability and efficacy; Requires stable extracranial disease if EGFR TKI pretreated; Confirmed response. BID, twice daily; CR, complete response; CSF, cerebrospinal fluid; LM, leptomeningeal metastasis; QD, once daily. Ahn, et al. J Clin Oncol 217;35(Suppl.): Abstract 26; Ahn, et al. Lancet Respir Med 217;5:891 92. 1 8 6 4 2 2 4 6 8 1 1 8 6 4 2-2 -4-6 -8-1 AZD3759 2 mg Best percent change of target lesions AZD3759 3 mg Patients Percent change of target lesion size with time Discontinued patients Continuing patients at data cut-off 1 2 3 4 5 6 7 8 9 1 11 12 Time since first dose (months) = cohort LM = LM cohort 6
Prospective data for second-generation TKI: LUX-Lung 3/6: PFS in patients with and common EGFRm Estimated PFS probability 1..8.6 Combined LUX-Lung 3/6 Afatinib (n=48) CT (n=33) Median, months 8.2 5.4 HR (95% CI) p value.5 (.27.95) p=.3.4.2 Afatinib CT No. at risk Afatinib CT CI, confidence interval; HR, hazard ratio. Schuler et al. J Thorac Oncol 216;11:38 9. 3 6 9 12 15 18 21 24 27 3 33 36 39 42 Time (months) 48 39 25 19 17 13 11 6 5 5 3 1 33 16 5 3 1 1 45 7
Prospective data for second-generation TKI: LUX-Lung 3/6: competing risk for progression in patients with baseline Estimated PFS probability 1..8 LUX-Lung 3/6/7 1 n % CNS PD 15 31.3 Censored 8 16.7 Non-CNS PD or death 25 52.1 Risk for CNS progression With (LUX-Lung 3/6, baseline common mutation) 2 6 months 15.5% 12 months 24.5% 24 months 34.4%.6.4 Non-CNS PD CNS PD.2 6 12 18 24 3 36 42 Time (months) PD, progressive disease. 1. Girard. Future Oncol 218. doi: 1.2217/fon-217-636. Epub ahead of print; 2.Boehringer Ingelheim data on File. 8
Prospective data for second-generation TKI: LUX-Lung 3/6/7: competing risk for progression in patients without baseline Cumulative incidence 1. LUX-Lung 3/6/7 1 n % CNS PD 31 6.4 Censored 74 15.3 Non-CNS PD or death 38 78.4 Risk for CNS progression Without (LUX-Lung 3/6, common baseline mutation) 2 6 months 1.3% 12 months 2.6% 24 months 5.3%.8.6 Non-CNS PD CNS PD.4.2 6 12 18 24 3 36 42 48 Time (months) 1. Girard. Future Oncol 218. doi: 1.2217/fon-217-636. Epub ahead of print; 2. Boehringer Ingelheim data on file. 9
Prospective data for second-generation TKI: dacomitinib A phase II study of dacomitinib in patients with progressive was terminated because of slow enrollment In the Phase III ARCHER 15 trial, dacomitinib demonstrated superior benefit over gefitinib (mpfs 14.7 vs 9.2 months; p<.1), but patients with CNS metastases were excluded DOR, duration of response; PO, by mouth; PRO, patient-reported outcome; TTF, time to treatment failure. Mok, et al. J Clin Oncol 217;35(Suppl. 18): LBA97; Wu, et al. Lancet Oncol 217;18:1454 66. 1
Probability Prospective data for third-generation TKI: FLAURA competing risk analysis (CNS full analysis set) Figure removed for copyright Competing risk analysis: CNS full analysis set 1. Osimertinib First-generation TKI CNS progression CNS progression.8 Non-CNS progression Non-CNS progression Death Death Figure removed for copyright Osimertinib (n=61) Firstgeneration TKI (n=67) Conditional probability of CNS progression,* 95% CI 6 months 5 (1 13) 18 (1 28) 12 months 8 (3 16) 24 (15 35).6.4.2 The probability of experiencing a CNS progression event, in the absence of non-cns progression or death, was consistently lower with osimertinib treatment than with first-generation TKI treatment* 3 6 9 12 15 18 21 Time (months) 11 FLAURA data cut-off was 12 June 217. *Conditional on the patient not experiencing a competing risk at that time. Competing risks were defined as non-cns progression and death by any cause in the absence of non-cns or CNS progression. Vansteenkiste, et al. Ann Oncol 217;28(Suppl. 1): LBA5.
PFS (%) Real-world experience: Korean patients with receiving first-line afatinib A retrospective population-based study in 165 adult patients receiving first-line afatinib at the Samsung Medical Center in South Korea 1 8 6 4 2 No Non-irradiated N=165 GKS, gamma-knife surgery; WBRT, whole brain radiation therapy. Kim, et al. J Thorac Oncol 217;12:S229. p=.21 1 2 3 4 Months since afatinib therapy N=165 No. (%) PFS (months) No 94 (57.%) Not reached before starting afatinib 71 (43.%) GKS WBRT No irradiation to brain tumour 39 (23.6%) 15.7 GKS 25 (15.2%) 15.6 WBRT 7 (4.2%) 11.5 Brain tumour response to afatinib n (%) without irradiation 39 No follow-up brain MRI 1 Nonirradiated with follow-up MRI data 29 (1) Disappeared 6 (2.7) Significantly decreased 16 (55.2) No significant change 5 (17.2) Progression 2 (6.9) Response rate to with afatinib 22 (75.9) 12
Survival (%) Survival (%) Real-world experience: Taiwanese patients with treated with afatinib WBRT 28 lung adenocarcinoma. patients with CNS imaging examinations every 3 6 months after beginning treatment; brain MRI or CT scan was also performed for follow-up CNS evaluation after a patient completed WBRT or exhibited metastatic brain symptoms 1 TTF Afatinib (n=11) Afatinib + WBRT (n=17) 1 OS Afatinib (n=11) Afatinib + WBRT (n=17) 5 5 p=.381 P=.299 5 1 15 2 Months 25 3 35 5 1 15 2 Months 25 3 35 14.5 months (afatinib + WBRT) vs 18.5 months (afatinib monotherapy), p=.381 Li, et al. Expert Rev Anticancer Ther 218;18:81 9. 18.6 months (afatinib + WBRT) vs not recorded (afatinib monotherapy), p=.299 13
Summary The first-generation, reversible EGFR TKIs erlotinib and gefitinib have limited intracranial activity in patients with NSCLC 1,2 A novel CSF-permeant, reversible EGFR TKI (AZD3759) is in early clinical development 3 The third-generation EGFR TKI osimertinib clearly has activity in patients with or LMD Osimertinib delayed onset and progression of in prospective clinical trials independent of treatment line (FLAURA, AURA-3) 4 6 Risk for CNS progression at 1 year was 8% for patients with baseline (first-line) 5 Intracranial CR rate of 41% and ORR of 66% 5 PFS was improved with osimertinib versus first-generation TKI or patient-based CT in patients with, with a similar magnitude as that observed in patients without (HR=.47 and.46, respectively, in FLAURA; HR=.32 and.4, respectively, in AURA-3) 4,6 1. Park, et al. Lung Cancer 212;77:556 6; 2. Wu, et al. Ann Oncol 213;24:993; 3. Ahn, et al. J Clin Oncol 217;35(Suppl.): Abstract 26; 4. Soria, et al. N Engl J Med 218;378:113; 5. Vansteenkiste, et al. Ann Oncol 217;28(Suppl. 1): LBA5; 6. Mok, et al. J Clin Oncol 217;35(Suppl.): Abstract 95. 14
Summary (continued) The second-generation EGFR TKI afatinib has a strong body of evidence showing efficacy in patients with EGFRm+ NSCLC with First-line afatinib delayed onset and progression of in prospective clinical trials. Risk for CNS progression at 1 year was 2.6% for patients without and 24.5% for patients with baseline 1,2 Intracranial CR rate of 21% and ORR of 76% 1 PFS was improved with afatinib versus CT or gefitinib in patients with, with the magnitude being similar to that observed in patients without (HR=.54,.47, and.76 in LUX-Lung 3, 6 and 7, respectively) 3,4 Patients with LMD showed improvement in performance status and neurological/cognitive function 5 9 Real-world data showing treatment time of ~15 months confirm the efficacy of afatinib 1,11 1. Data on file, Boehringer Ingelheim; 2. Girard. Future Oncol 218. doi: 1.2217/fon-217-636. Epub ahead of print; 3. Schuler, et al. J Thorac Oncol 216;11:38 9; 4. Park, et al. Lancet Oncol 216;17:577 89; 5. Saijo, et al. Jpn J Lung Cancer 216;56:29 6; 6. Kawaguchi, et al. Chemotherapy 217;62:147 5; 7. Hoffknecht, et al. J Thorac Oncol 215;1:156 63; 8. Ghosn, et al. Bull Cancer 217;14:385 7; 9. Lin, et al. Lung Cancer 214;85:479 8; 1. Kim, et al. J Thorac Oncol 217;12:S229; 11. Li, et al. Expert Rev Anticancer Ther 218;18:81 9. 15