PROGRESSION AFTER THIRD GENERATION TKI

Transcription

1 PROGRESSION AFTER THIRD GENERATION TKI What next? National Cancer Center Hospital Yuichiro Ohe, MD

2 Name of lead presenter Yuichiro Ohe employee of company and/or profit-making organization adviser of company and/or profit-making organization profit of stock No lecturer fees Institution or company/position Deputy-director National Cancer Center Hospital If yes, please specify the name of company and/or organization, your status. AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi-Sankyo, Nipponkayaku, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Clovis, Sanofi manuscript fees research expenses AstraZeneca, Chugai, Lilly, ONO, BMS, Kyorin, Dainippon-Sumitomo, Pfizer, Taiho, Novartis, Merck Serono contributions fees of testimony, judgment, comment, etc. AstraZeneca, representative of organization for clinical study receiving research expenses from company presents or any payment 2 2

3 Metastatic Non-small-cell Lung Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up First-line treatment with an EGFR TKI (erlotinib, gefitinib or afatinib) is the standard of care for tumours bearing an activating (sensitising) EGFR mutation [I, A]. Patients with EGFR mutation and PS 3-4 may also be offered an EGFR TKI [II, A]. If information on an EGFR-sensitising mutation becomes available during first-line platinum-based chemotherapy, continue chemotherapy for up to four cycles and offer the EGFR TKI as maintenance treatment in patients achieving disease control, or as second-line treatment at the time of progression [I, A]. In patients who progress after an EGFR TKI, rebiopsy is strongly encouraged to look for EGFR T790M mutation, relevant for therapeutic strategy. An alternative to tissue rebiopsy is represented by liquid biopsy [III, A]. Osimertinib is recommended in patients who have developed the EGFR T790M resistance mutation after EGFR TKI treatment [III, A]. When a rebiopsy is not feasible, or when the EGFR T790M mutation is not detected in patients who progress after an EGFR TKI, the standard of care is platinum-based doublet chemotherapy. No data support the concurrent use of EGFR TKI and platinum-based doublet chemotherapy [I, A]. 3 3

4 Possible Treatment of EGFR-mutation Positive NSCLC after 3 rd Generation EGFR-TKI Platinum-based doublets with/without bevacizumab Docetaxel with/without ramucirumab Immune check point inhibiters Others 4 4

5 Platinum-based Doublets for EGFR-mutation Positive NSCLC IPASS: ORR IMPRESS CDDP+PEM alone ORR: 34% mpfs: 5.4 months NEJ002 ORR: 25.4% 5 5

6 Platinum-based Doublets for EGFR-mutation Positive NSCLC IPASS: ORR Median: 41.7 vs 16.8 m ESMO Asia

7 Platinum-based Doublets for EGFR-mutation Positive NSCLC IPASS: ORR Median: 5.9 vs 5.4 m Median: 21.3 vs 15.4 m ESMO Asia

8 Japanese Clinical Practice of The Treatment of EGFRmutation Positive NSCLC EGFR-mutation positive NSCLC The treatment were started between Jan 2008 and Dec hospitals (Cancer Center: 3, University Hospital: 5, General Hospital: 9) Exclude patients treated with IND As of Dec 2014, Alive: 380(23%); Dead: 965 (58%); Lost follow-up: 312 (19%); Total 1657 Jpn J Clin Oncol 46: 462,

9 Japanese Clinical Practice of The Treatment of EGFRmutation Positive NSCLC EGFR-TKI±α % Platinum doublet±bev % Other Chemo±Bev % Other 0.07 % Non-treatment % Initial Treatment EGFR-TKI: 1060 Platinum-based: 509 Others: 88 Jpn J Clin Oncol 46: 462,

10 Japanese Clinical Practice of The Treatment of EGFRmutation Positive NSCLC 31.7% Treatment frequency EGFR-TKI 54 (3.3%) 956 (57.7%) 453 (27.3%) 194 (11.7%) Gefitinib ± α 269 (16.2%) 1221 (73.7%) 138 (8.3%) 29 (1.8%) Other EGFR-TKI ± α 922 (55.6%) 589 (35.5%) 114 (6.9%) 32 (2.0%) Platinum doublet ± BV 825 (49.8%) 701 (42.3%) 113 (6.8) 18 (1.1%) Other chemotherapy ± BV 1024 (61.8%) 378 (22.8%) 148 (8.9%) 107 (6.5%) Other 1630 (98.4%) 26 (1.6%) 1 (0.1%) 0 (0%) Jpn J Clin Oncol 46: 462,

11 Japanese Clinical Practice of The Treatment of EGFRmutation Positive NSCLC JSMO

12 Docetaxel Plus Ramucirumab for EGFR-mutation Positive NSCLC REVEL Lancet 384: 665,

13 Docetaxel Plus Ramucirumab for EGFR-mutation Positive NSCLC JVCG Lung Cancer 99: 186,

14 Docetaxel Plus Ramucirumab for EGFR-mutation Positive NSCLC All patients in REVEL EGFR-mutation positive patients in JVCG Lung Cancer 99: 186,

15 Platinum-based Chemotherapy and Pemetrexed or Docetaxel May Prolong Survival of EGFR-mutation Positive NSCLC Data from NEJ002 Ann Oncol 24: 54,

16 Anti-PD-1 Antibody for EGFR-mutation Positive NSCLC CheckMate057 N Engl J Med 373: 1627,

17 Anti-PD-1 Antibody for EGFR-mutation Positive NSCLC KEYNOTE 010 Lancet 387: 1540,

18 Anti-PD-L1 Antibody for EGFR-mutation Positive NSCLC OAK ESMO

19 Anti-PD-1/PD-L1 Antibody for EGFR-mutation Positive NSCLC Study PD-L1 status Total patients CheckMate 057 All 582 KEYNOTE 010 TPS 1% 1034 OAK All 850 OS HR for all patients 0.73 ( ) 0.67 ( ) 0.73 ( ) OS HR for EGFR-mutation positive patients 1.18 ( ) 0.88 ( )

20 Possible Treatment Sequence After Progression of 3 rd Generation EGFR-TKI Platinum-based doublets with/without bevacizumab Docetaxel with/without ramucirumab Immune check point inhibiters nivolumab, pembrolizumab, atezolizumab 20 20

21 Resistance Mechanism of 3 rd Generation EGFR-TKIs Change of target Alternative signal EGFR mutation EGFR loss/ amplification Bypass Downstream Morphological change C797S (all) L718Q, L844V (Rocil, WZ 2 ) T790M loss (Osim) EGFR amplification (Rosil 1 ) HER2 amplification (Osim 6 ) MET amplification (Osim 6, 7 ) IGF1R activation (WZ 8 ) BRAF V600E (Osim 6 ) ERK1/2 activation (WZ 3 ) NRAS mutation (Osim 4 ) EMT (Rosil 5 ) SCLC (Rosil 1 ) 15/67 (22%) against Osim by ddpcr (13/43 in Del 19, 2/24 in L858R) 6 in vitro (not resistant to Osim) 32/67 to Osim, despite presence of sensitizing mu, suggesting an alternate resistance mechanism 6 1/ Piotrowska, Cancer Discov, 2015, 2. Ercan et al., Clin Cancer Res., 2015, 3.Tricker et al., Cancer Discov, 2015, 4.Eberlein et al., Cancer Res, 2015, 5. Walter et al., Cancer Discov, 2013, 6. Oxnard, WCLC 2015, 7 Ou, Lung cancer 2016, 8 Park, Oncotarget 2016 Osim: osimertinib, Rocil: rociletinib, WZ: WZ

22 73-year never-smoker Asian female Stage IV adenocarcinoma Exon 19 del Erlotinib 14months CBDCA+PEM x 2 CBDCA+GEM x 2 Afatinib 10 months Osimertinib High level of MET amplification of 30 copies was observed after osimertinib. Lung Cancer 98: 59,

23 Kinase inhibitory activities (single point) of the most potent new compounds in a triple-mutant EGFR enzyme assay. A rational approach to the design of two compound seriesderived from 1 and 2, supported by computer-aided drug design. Angew Chem Int Ed Engl 55: 10890,

24 Nature 534: 129,

25 Nature 534: 129,

26 Conclusions 3 rd generation EGFR-TKI is a standard treatment for T790M EGFR-mutation positive NSCLC. Platinum-based chemotherapy should be used after progression of 3rd generation EGFR-TKI. Docetaxel with/without ramucirmab and immune check point inhibitors are also treatment options. Development of C797S is most common mechanism of 3rd generation EGFR- TKI resistance. New agents overcome C797S resistant mutation are under the development

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