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New TKI in Lung cancer

R6 洪逸平 Supervisor 顏厥全醫師. New TKI in Lung cancer. Some slide revised from Boehringer Ingelheim Afatinib Launch Meeting . Actionable targets in lung adenocarcinomas. 1999. 2005 – 2013. Selumetinib Trametinib. Unknown 75%. NRAS. 2004. Gefitinib Erlotinib Afatinib Dacomitinib

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New TKI in Lung cancer

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  1. R6洪逸平 Supervisor 顏厥全醫師 New TKI in Lung cancer Some slide revised from BoehringerIngelheimAfatinib Launch Meeting

  2. Actionable targets in lung adenocarcinomas 1999 2005–2013 Selumetinib Trametinib Unknown 75% NRAS 2004 Gefitinib Erlotinib Afatinib Dacomitinib CO1686, AZD9291 RET Crizotinib ROS1 MEK Selumetinib? HER2 ALK MET EGFR PIK3CA BRAF Unknown 60% Afatinib? Dacomitinib? MK2206? BKM120? Crizotinib, LDK378, CH5424802, AP26113 Dabrafenib, vemurafenib regorafenib, MEK inhibitors MetMab?

  3. Actionable targets in lung adenocarcinomas 2005–2013 1999 HSP90 client oncoprotein AUY922, IPI504, ganetespib PD1/PD-L1 expression Lambrolizumab, nivolumab, MPDL3280A, BMS936559 Antiangiogenesis Bevacizumab, nintedanib*, motesanib Selumetinib Trametinib Unknown 75% NRAS 2004 Gefitinib Erlotinib Afatinib Dacomitinib CO1686, AZD9291 RET Crizotinib ROS1 MEK Selumetinib? HER2 ALK MET PIK3CA BRAF EGFR Unknown 60% MK2206? BKM120? Afatinib? Dacomitinib? Crizotinib, LDK378, CH5424802, AP26113 Dabrafenib, vemurafenib regorafenib, MEK inhibitors MetMab? *Nintedanib is an investigational compound and is not yet approved. Its safety and efficacy have not yet been fully established.

  4. Austin Hospital surgical series: TxN0 only Main mutations and survival in N0 patients

  5. 你相信有平行世界嗎？ 那些年，我們一起追的女孩 九把刀

  6. Conversations in Oncology 2009 – Vienna EGFR mutation + EGFR mutation – EGFR TKI Chemotherapy Tony Mok, Vienna, 2009.

  7. Conversations in Oncology in Asia – 2013, Taipei K-ras ROS1-- HER-2 EGFR mut Alk-EML4 ?? RET-- B-Raf

  8. Conversations in Oncology in Asia – 2013, Taipei Chemotherapy Antiangiogenesis HSP90 inhibitors PD1/PD-L1 antibodies cMET/HGF inhibition IGF/IGFR inhibition

  9. IPASS: Progression-free survival in EGFR mutation positive and negative patients EGFR mutation-positive EGFR mutation-negative HR: 0.48 p<0.001 HR: 2.85 p<0.001 1.0 1.0 Carboplatin/paclitaxel (n=85) Gefitinib (n=132) 0.8 0.8 Carboplatin/paclitaxel (n=129) 0.6 0.6 Probability PFS Probability of PFS 0.4 0.4 Gefitinib (n=91) 0.2 0.2 0.0 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Months Months 91 21 4 2 1 0 0 85 58 14 1 0 0 0 At risk: Gefitinib 132 108 71 31 11 3 0 C/P 129 103 37 7 2 1 0 Treatment by subgroup interaction test, p<0.0001Qualitative interaction!!! Mok TS, et al. N Engl J Med 2009;361:947–57.

  10. EGFR mutations in NSCLC geographical map India (2527) 25–40% (36%) France (1227) 14% Italy (860) 5% (10%) Qatar (25) (32%) Korea (513) 20–36% (38–48%) China (1068) 24–39% (41–50%) Spain (2105) 17% Japan (1498) 26–40% (41–49%) USA (456) 2–14% (15–25%) Taiwan (267) 34% (56–62%) The Philippines (65) (52%) Brazil (2017) 30% Hong Kong (161) (47%) Thailand (403) (54%) Vietnam (120) (64%) Australia (83) 7% (14%) Key: Country (N=) % mutation NSCLC (% mutation in adenocarcinoma). Parikh PM, Puri T. Ind J Cancer2013.

  11. Developing a targeted agent that irreversiblyblockssignalling from the ErbB Family receptors ...from the bench to the clinic

  12. Afatinib: An ErbB Family Blocker Erlotinib and gefitinib Afatinib

  13. Afatinib • Oral, small molecule TKI • Covalently binds to and is highly specific for EGFR, HER2, ErbB4 (ErbB family) • Retains activity in erlotinib/gefitinib-resistant models Li D, et al. Oncogene2008;27:4702–4711.

  14. ErbB-dependent tumours Mutation NSCLC Breast Head and neck Gastric Oesophageal Pancreatic Biliary Endometrial Ovarian Glioblastoma Melanoma EGFR HER2 Over-expression Gene amplification ErbB3 ErbB4 Chromosomal polysomy

  15. LUX trial programme NSCLC/adenocarcinoma NSCLC / SCC HNSCC Locally advancedadjuvant Erlotinib/gefitinib pretreated EGFRmutation positive Metastatic/ recurrent Head-to-head trials LUX-Lung 1 LUX-Lung 2 LUX-Lung 7 LUX-Lung 8 LUX-HN 1 LUX-HN 2 LUX-Lung 4 LUX-Lung 3 LUX-HN 3 LUX-HN 4 LUX-Lung 5 LUX-Lung 6 Yang JC, Taipei, August 2013.

  16. Afatinib in NSCLC: Key trials Improve outcomes in (EGFR M+) 3rd/4th line LL1 & 4 LL2, 3 & 6 Improve outcomes in EGFR M+ 1st/2nd line LL5 LUX-Lung Programme Continued EGFR inhibition LL7 & 8 Irreversible vs. reversible EGFR blockade LL8 Squamous cell NSCLC Afa + Cet Improve on monotherapy effect in EGFR M+ 3rd/4th line EGFR-TKI pretreated EGFR-TKI naïve

  17. LUX-Lung 1: Post erlotinib/gefitinib – third/fourth line Stage IIIB/IV adenocarcinoma of the lung Progressed after one or two lines of chemotherapy (including one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib ECOG PS 0–2 Randomization 2:1 (double blind) Oral afatinib 50 mg once daily + BSC Oral placebo once daily + BSC Primary endpoint: OS Secondary endpoints:PFS, ORR, QoL (LC13/C30), safety Miller V, et al. Lancet Oncol 2012;13:528–538.

  18. LUX-Lung 1: OS and PFS PFS (independent review) Updated OS analysis (February 2012) Miller V, et al. Lancet Oncol 2012;13:528–538.

  19. LUX-Lung 1: OS and subsequent systemic treatment Afatinib=5.8 months Placebo=4.6 months HR=0.66; p=0.027 Afatinib=12.7 months Placebo=14.4 months HR=1.09; p=0.535 Patients with no subsequent therapy (n=191) Patients with ≥1 subsequent therapy (n=394) 100 100 80 80 60 60 Estimated survival probability (%) Estimated survival probability (%) 40 40 20 20 0 0 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Time since randomization (months) Time since randomization (months) Miller V, et al. Lancet Oncol 2012;13:528–538.

  20. LUX-Lung 1: PFS and likelihood of EGFR mutation Afatinib=4.4 months Placebo=1.0 months Afatinib=2.8 months Placebo=1.8 months 1.0 1.0 0.8 0.8 0.6 0.6 Estimated PFSprobability (%) Estimated PFSprobability (%) 0.4 0.4 0.2 0.2 0.0 0.0 0 3 6 9 12 15 0 3 6 9 12 15 Time since randomization (months) Time since randomization (months) Number at riskPlacebo Afatinib Number at riskPlacebo Afatinib 134 6 2 1 0 0 257 111 49 10 7 3 61 9 2 1 0 0 133 41 16 6 2 0 • CR or PR to prior EGFR-TKI or ≥48 weeks duration of prior EGFR-TKI YES High (>80%) likelihood of mutant EGFR NO Lower (<30%) likelihood of mutant EGFR Boehringer Ingelheim. Data on file.

  21. LUX-Lung 1: Key learnings • Afatinib significantly improved PFS compared to placebo • Post erlotinib/gefitinib failure • EGFR mutation-positive patients do better • Predictive for afatinib efficacy • Prognostic (longer OS in the trial population) • Impact of subsequent therapy on OS • Was OS an appropriate endpoint for this setting?

  22. LUX-Lung 4: Phase I/II single arm in Japan Japanese NSCLC patients Failure of conventional treatment or no therapy of proven efficacy ECOG PS 0 or 1 Progressed after one or two lines of chemotherapy (including one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib (Phase II) • Population and results: Similar to LUX-Lung 1 Afatinib N=90 in Phase I/II; MTD: 50 mg/day Results (Phase II, n=62) ORR=8.2% Median PFS 4.4 months Median OS 19 months Murakami H, et al. Cancer Chemother Pharmacol2012;69:891–899; Katakami N, et al. J Clin Oncol2013 Jul 1; [Epub ahead of print].

  23. LUX-Lung 5: Continued EGFR inhibition Phase III trial, Part B blinded and still recruiting PFS OS PRO

  24. LUX-Lung 5: PFS in Part A By histology Overall (n=1154) mPFS: 3.3 months Adenoca (n=985 ): 3.3 months Squamous(n=91): 3.7 months Lower (n=556): 2.8 months Higher(n=598): 4.2 months Schuler M, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7557. Kim J-H, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7558. Schuler M, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7557. By likelihood of EGFR mutation

  25. LUX-Lung 2: Phase II in EGFR M+ first/second line Adenocarcinoma of the lung Stage IIIB/IV EGFR mutation Chemotherapy naïve or progressive disease following first-line chemotherapy EGFR-TKI naïve ECOG PS 0–2 Oral afatinib; starting dose 50 mg/day or 40 mg/day Primary endpoint: ORR Secondary endpoints: PFS, OS Yang CH, et al. Lancet Oncol2012;13:539–548.

  26. LUX-Lung 2: PFS, ORR, tumour shrinkage, OS 100 80 60 Progression free survival (%) 40 20 0 • Comparable activity in first-/second-line treatment of EGFR mutation-positive NSCLC Yang CH, et al. Lancet Oncol2012;13:539–548; BoehringerIngelheim. Data on file.

  27. LUX-Lung 3 and 6: First-line EGFR M+ NSCLC Stage IIIB(wet)/IV NSCLC adenocarcinoma EGFR mutation positive tumour (central test) ECOG PS 0‒1 Randomization 2:1 Afatinib 40 mg once daily continuously Cisplatin + pemetrexed (LL3) Cisplatin + gemcitabine (LL6) up to 6 cycles Primary endpoint: PFS (independent review) Secondary endpoints: ORR, DCR, OS, PRO Yang CH, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Oral presentation LBA7500; Sequist LV, et al. J Clin Oncol2013 Jul 1; [Epub ahead of print]; Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract/Poster 8016.

  28. LuX-LUNG 3

  29. LUX-Lung 3: Study design Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6) EGFR mutation in tumour (central lab testing; Therascreen EGFR29* RGQ PCR) Randomization 2:1 Stratified by: EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian) Afatinib 40 mg/day† Cisplatin + pemetrexed 75 mg/m2 + 500 mg/m2i.v. every 21 days, up to 6 cycles Primary endpoint: PFS (RECIST 1.1, independent review)‡ Secondary endpoints: ORR, DCR, DoR, tumour shrinkage, OS, PRO§, safety, PK *EGFR29: 19 deletions in exon 19, three insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I; †Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related Grade 3 or prolonged Grade 2 AE; ‡Tumour assessments: every 6 weeks until Week 48 and every 12 weeks thereafter until progression/start of new therapy; §Patient-reported outcomes: Q-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and every 3 weeks until progression or new anti-cancer therapy. Sequist LV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  30. LUX-Lung 3: The largest global trial in the EGFR mutation-positive NSCLC population 345 patients from 133 sites in 25 countries EUROPE Austria, Belgium, France, Germany, Hungary, Ireland, Italy, Romania, Russia, Ukraine, UK NORTH AMERICA USA Canada ASIAHong Kong Japan Korea Malaysia Philippines Taiwan Thailand SOUTH AMERICA Argentina, Brazil, Chile, Peru • Australia

  31. LUX-Lung 3: Patient demographics/characteristics Sequist LV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  32. Primary endpoint: Afatinib improved PFS versus chemotherapy Independent review – all randomized patients 1.0 0.8 0.6 Progression-free survival (probability) 47% 0.4 0.2 22% 0.0 0 3 6 9 12 15 18 21 24 27 Progression-free survival (months) Number at riskAfatinib 230 180 151 120 77 50 31 10 3 0Cis/Pem 115 72 41 21 11 7 3 2 0 0 Median follow-up: 16.4 months; 221 independently reviewed PFS events. At the time of data cut-off for primary analysis of PFS, 45 (20%) patients in the afatinib arm and three (3%) patients in the chemotherapy arm were known to be alive and progression-free. SequistLV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  33. LUX-Lung 3: PFS subgroup analysis Independent review – all randomized patients Favours afatinib Favours cis/pem Sequist LV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  34. LUX-Lung 3: Updated OS analysis *At the time of cutoff, only 98 (28%) had died. Hence, OS data are considered preliminary. Median OS has not yet been reached for any group. BoehringerIngelheim International GmbH; July 2013. Available online: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf [Last accessed 24/07/13]

  35. Afatinib improved PFS versus chemotherapy in patients with common mutations (Del19/L858R) Independent review – patients with Del19/L858R (n=308) 1.0 0.8 0.6 Progression-free survival (probability) 51% 0.4 0.2 21% 0.0 0 3 6 9 12 15 18 21 24 27 Progression-free survival (months) Number at riskAfatinib 204 169 143 115 75 49 30 10 3 0Cis/Pem 104 62 35 17 9 6 2 2 0 0 Sequist LV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  36. Afatinib improved rates of response versus chemotherapy All patients Common mutations (Del19/L858R) p<0.001 p<0.0001 p<0.0001 p<0.001 Patients, % Patients, % Median duration of response: 11.1 vs. 5.5 months (all patients; independent review) Sequist LV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  37. LUX-Lung 3: Most frequent related adverse events >20% difference between treatment arms *Grouped term;†No Grade 5 events for the presented AEs. SequistLV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  38. Afatinib delayed the worsening of lung cancer-related symptoms Cough Dyspnoea Pain NE, not estimated. Yang J.C-H, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  39. Quality of life: EORTC QoL C-30 Difference in mean scores over time (longitudinal analysis) Treatment difference 3.28 3.52 3.13 4.83 4.50 0.85 3.24 1.18 Global health status/QoL Overall health Quality of life Physical functioning Role functioning Emotional functioning Cognitive functioning Social functioning 10 5 0 –5 Favours afatinib Favours cis/pem Yang J.C-H, et al. J ClinOncol2013 Jul 1; [Epub ahead of print].

  40. LUX-LUNG 3:Asian patients

  41. Primary endpoint: PFS – Asian patients Independent review All Asian patients Asian patients with Del19/L858R 1.0 1.0 0.8 0.8 0.6 0.6 PFS (probability) PFS (probability) 52% 49% 0.4 0.4 0.2 0.2 22% 20% 0.0 0.0 0 3 6 9 12 15 18 21 24 27 0 3 6 9 12 15 18 21 24 27 PFS (months) PFS (months) Number at riskAfatinib 166 137 113 91 60 40 26 8 3Cis/pem 83 50 30 16 8 5 2 1 0 Number at riskAfatinib 149 130 108 87 58 39 25 8 3 Cis/pem 75 43 26 13 6 4 1 1 0 MokT, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

  42. LUX-Lung 3: Objective response All patients Asian patients p<0.0001 p<0.0001 p<0.0001 p<0.0001 74.7 Patients, % Patients, % 43.4 Median duration of response: 11.1 vs. 5.5 months (independent review) Median duration of response:11.2 vs. 4.2 months (independent review) MokT, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

  43. LUX-Lung 3: Most frequent related AEs – Asian patients *Grouped term; †No Grade 5 events for the presented AEs. MokT, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

  44. LUX-Lung 3: Summary

  45. LUX-Lung 3: Summary • LUX-Lung 3 is the largest* global prospective trial in EGFR mutation-positive lung cancer and the first using cisplatin and pemetrexed as the comparator • LUX-Lung 3 met its primary endpoint with median PFS (independent review): • Overall population: 11.1 vs. 6.9 months • Common mutations: 13.6 vs. 6.9 months • Consistent efficacy in all relevant subgroups • Afatinib significantly improved rates of response versus chemotherapy • Efficacy findings from the Asian subgroup are in line with those from the overall trial population *n=345. Sequist LV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print]; Mok T, et al. Presented at the 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

  46. LUX-Lung 3: Summary (continued) • First-line afatinib significantly prolonged PFS, with associated delay in worsening of lung cancer-related symptoms and improvement in quality of life • Safety profile of afatinib consistent with previous studies • Overall population: Diarrhoea and rash were the most frequent AEs; manageable with low treatment discontinuation rate • Asian patients: Diarrhoea and rash were the most frequent AEs; no treatment discontinuations for rash and only one Asian patient discontinued for diarrhoea Sequist LV, et al. J ClinOncol2013 Jul 1; [Epub ahead of print]; Mok T, et al. Presented at the 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

  47. LuX-LUNG 6

  48. LUX-Lung 6: Study design Asian patients (China, South Korea, Thailand)Stage IIIB (wet)/IV lung adenocarcinoma EGFR mutation in tumour (central lab testing; Therascreen EGFR29* RGQ PCR) Randomization 2:1 Stratified by: EGFR mutation (Del19/L858R/other) Afatinib 40 mg/day† Gemcitabine + cisplatin 1000 mg/m2 D1, D8 + 75 mg/m2 i.v. q21 days, up to 6 cycles Primary endpoint: PFS (RECIST 1.1, independent review)‡ Secondary endpoints: ORR, DCR, DoR, tumour shrinkage, OS, PRO§, safety *Central lab testing; Therascreen EGFR29 RGQ PCR detecting 19 deletions in exon 19, three insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I; †Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related Grade 3 or prolonged Grade 2 AE; ‡Tumour assessments: every 6 weeks until Week 48 and every 12 weeks thereafter until progression/start of new therapy; §Patient-reported outcomes: EQ-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and every 3 weeks until progression or new anti-cancer therapy. Wu Y-L, et al. J ClinOncol2013; 31 (suppl): Abstract 8016 and poster.

  49. LUX-Lung 6: Patient disposition 910 screened 471 EGFR mutation (+) 107 did not meet eligibility criteria or did not enter 364 randomized • 242 assigned to afatinib • 3 did not receive treatment • 122 assigned to cisplatin + pemetrexed • 9 did not receive treatment 113 (100%) stopped or completed treatment 182 (76%) stopped treatment • PFS event at data cut-off • 169 (70%) by investigator assessment • 157 (65%) by independent assessment • PFS event at data cut-off • 78 (64%) by investigator assessment • 64 (53%) by independent assessment 57 (24%)on treatment 0 on treatment Wu Y-L, et al. J ClinOncol2013;31(Suppl.):Abstract 8016 and poster.

  50. LUX-Lung 6: Patient demographics/characteristics Wu Y-L, et al. J ClinOncol2013;31(Suppl.):Abstract 8016 and poster.

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