Carcinoma microcítico y otros tumores. Natividad Martínez Banaclocha Servicio Oncología Médica Hospital General Universitario de Alicante

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1 Carcinoma microcítico y otros tumores Natividad Martínez Banaclocha Servicio Oncología Médica Hospital General Universitario de Alicante

2 I have not conflict of interest

3 Carcinoma microcítico de pulmón

4 N=107 16% stable brain metastases 23% 3 prior therapies 70% male Age 63 (24-84) ASCO 2018

5 KEYNOTE-158 ASCO 2018 Baseline Biomarker Status Presented By Hyun Chung at 2018 ASCO Annual Meeting

6 KEYNOTE-158: RESULTS ASCO 2018 ORR (RECIST v1.1) central review At data cutoff date (Aug 23, 2017), 36 pts continuing on study Median follow-up 10.1m ( ) Presented By Hyun Chung at 2018 ASCO Annual Meeting

7 KEYNOTE-158: RESULTS ASCO 2018 Duration of Response<br />(RECIST v1.1, Independent Central Review) 12 patients has DOR>12m (73%) Median range NR (2.1+ to 18.7+) Presented By Hyun Chung at 2018 ASCO Annual Meeting

8 KEYNOTE-158: RESULTS ASCO % 14.3% 28.5% 8.2% Progression-Free Survival by Tumor PD-L1 Status<br />(RECIST v1.1, Independent Central Review) mpfs 2m Presented By Hyun Chung at 2018 ASCO Annual Meeting

9 KEYNOTE-158: RESULTS ASCO % 48.3% 53.1% 30.7% Overall Survival by Tumor PD-L1 Status<br />(RECIST v1.1, Independent Central Review) mos 9.1m Presented By Hyun Chung at 2018 ASCO Annual Meeting

10 KEYNOTE-158: RESULTS ASCO 2018 Slide 17 Presented By Hyun Chung at 2018 ASCO Annual Meeting

11 Conclusions KEYNOTE 158 ASCO 2018 Promising antitumor activity ORR 19% 37.7% PD-L1 + mdor not reached 73% >12m PFS/OS better in PD-L1 + Consistent safety profile Phase 2 basket study of 11 cancer types few patients KEYNOTE-604-Phase III ED SCLC Double blindplacebo controlled Pembrolizumab+EP vs Placebo+EP (NCT )

12 TRINITY Study ASCO 2018 Interim analysis 199 Presented By David Carbone at 2018 ASCO Annual Meeting

13 TRINITY: RESULTS ASCO 2018 Presented By David Carbone at 2018 ASCO Annual Meeting

14 TRINITY: RESULTS ASCO 2018 Presented By David Carbone at 2018 ASCO Annual Meeting

15 TRINITY: RESULTS ASCO 2018 Presented By David Carbone at 2018 ASCO Annual Meeting

16 Conclusions TRINITY ASCO 2018 Rova-T demonstrated antitumor activity and a favorable in 3L SCLC pts Better in DLL3 high (CBR 72%) mos 5.6m Significant toxicity Grade 3/4 Aes: thrombocytopenia (15%), photosensitivity (7%), pleural effusion (7%), fatigue (5%) Phase III ongoing, Phase 1/2 in combination with nivolumab, nivo/ipi and chemotherapy (EP)

17 IMpower133 WLCC 2018 Inclusion: Measurable ES-SCLC (RECIST v1.1) ECOG PS 0 or 1 No prior systemic treatment for ES- SCLC Patients with treated asymptomatic brain metastases were eligible R 1:1 Induction (4 x 21-dy cy) Atezolizumab (1200 mg IV, Day 1) N=201 + carboplatin + etoposide Placebo N=202 + carboplatin + etoposide Maintenance Atezolizumab Placebo Treat until PD or loss of clinical benefit Survival follow-up Stratification: Sex (male vs. female) ECOG PS (0 vs. 1) Brain metastases (yes vs. no) a Carboplatin: AUC 5 mg/ml/min IV, Day 1 Etoposide: 100 mg/m 2 IV, Days 1 3 Co-primary end points: Overall survival Investigator-assessed PFS PCI per local standard of care Key secondary end points: Objective response rate Duration of response Safety N= 403 a Only patients with treated brain metastases were eligible. ECOG PS, Eastern Cooperative Oncology Group Performance Status; IV, intravenous; PCI, prophylactic cranial irradiation; PD, progressive disease; PFS, progression-free survival; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumors.

18 IMpower133: RESULTS WLCC 2018 Atezolizumab + CP/ET (N = 201) Placebo + CP/ET (N = 202) OS events, n (%) 104 (51.7) 134 (66.3) Median OS, months (95% CI) HR (95% CI) 12.3 (10.8, 15.9) 10.3 (9.3, 11.3) 0.70 (0.54, 0.91) p = Median followup, months a 13.9 Atezolizumab + CP/ET (N = 201) Placebo + CP/ET (N = 202) PFS events, n (%) 171 (85.1) 189 (93.6) Median PFS, months (95% CI) HR (95% CI) 5.2 (4.4, 5.6) 4.3 (4.2, 4.5) 0.77 (0.62, 0.96) p = Median follow-up, months a 13.9 N Engl J Med Sep 25

19 IMpower133:RESULTS WLCC 2018 N Engl J Med Sep 25

20 IMpower133:RESULTS WLCC 2018 a Censored. b At clinical cutoff date: April 24, CR, complete response; EFS, event-free survival; PD, progressive disease; PR, partial response; SD, stable disease.

21 IMpower133: iraes WLCC 2018 Immune-related AEs no. (%) > 1% Grade 3 4 AEs in either treatment group Atezolizumab + CP/ET (N = 198) Grade 1 2 Grade 3 4 Grade 5 Grade 1 2 Placebo + CP/ET (N = 196) Grade 3 4 Grade 5 Rash 33 (16.7) 4 (2.0) 0 20 (10.2) 0 0 Hepatitis 11 (5.6) 3 (1.5) 0 9 (4.6) 0 0 Infusion-related reaction 7 (3.5) 4 (2.0) 0 9 (4.6) 1 (0.5) 0 Pneumonitis 3 (1.5) 1 (0.5) 0 3 (1.5) 2 (1.0) 0 Colitis 1 (0.5) 2 (1.0) Pancreatitis 0 1 (0.5) (1.0) 0 Clinical data cutoff date: April 24, 2018.

22 Conclusions: IMpower133 WLCC 2018 First study in 20 y with improvement in OS mos: 12.3 vs months; HR: 0.70 (p = ); 12- month OS: 51.7% vs. 38.2% mpfs: 5.2 vs. 4.3 months; HR: 0.77 (p = 0.017); 12- month PFS: 12.6% vs. 5.4% Safety profile as expected: ir-aes similar to atezolizumab monotherapy New standard of care for the first-line treatment of ES-SCLC

23 IFCT-1603 Trial ESMO 2018

24 ESMO 2018

25 ESMO 2018

26 Conclusions: IFCT ESMO 2018 Atezoluzumab did not showed better RR than conventional Chemo RR was not dependent on the expression of PD-L1 PFS/OS no difference No unexpected safety signal was observed with atezolizumab A genotype analysis of available tumor specimens from these patients is in progress. Phase III part of the study has been precluded

27 ESMO 2018 TIRACICLIB* DOSE SELECTED: 240mg/m2 *Trialaciclib: a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). Induces transient, reversible G1 cell cycle arrest in both murine and human BM haematopoeitic stem progenitor cell (HSPCs)

28 Trilaciclib Phase 1b/2: Results ESMO 2018

29 Trilaciclib Phase 1b/2: Results ESMO 2018

30 Trilaciclib Phase 1b/2: Results ESMO 2018

31 Conclusions: Trilaciclib Phase 1b/2 ESMO 2018 Trilaciclib 240 mg/m2 significantly reduced clinical impacts of Chemo on neutrophils and lymphocytes, and trended to reduce RBC transfusion requirements. Better response rate and a trend toward longer PFS Further studies will evaluate trilaciclib with other myelo-suppressive chemo such as topotecan.

32 Mesotelioma pleural maligno

33 DREAM Trial design ASCO/IASLC 2018 DuRvalumab with first line chemotherapy in Mesothelioma Single-arm, multicentre phase II trial with a safety run-in Population Induction Maintenance End Points 1 st line MPM N=54 Primary: PFS6* Nonsurgical No prior RT (MD) PS 0-1 Cisplatin 75mg/m 2 + Pemetrexed 500mg/m 2 + Durvalumab 1125mg q3w Durvalumab 1125mg q3w x 52 w Secondary: ORR (CR + PR)* Toxicity PFS* OS No PD-L1 selection 6 cycles To total 17 cycles durvalumab * mrecist for MPM, mirrc Median age 68 (42-82) Male 82% ECOG 0 60% Epitheioid 82% Anna K. Nowak, Peey Sei Kok, Willem Joost Lesterhuis, Brett G.M. Hughes, Chris Brown, Steven Chuan-Hao Kao, Deme Karikios, Tom John, Nick Pavlakis, Kenneth O Byrne, Sonia Yip, Wei-Sen Lam, Karen Briscoe, Christos S. Karapetis, Martin R. Stockler on behalf of ALTG (Australasian Lung Cancer Trials Group and NHMRC Clinical Trials Centre)

34 DREAM: RESULTS ASCO/IASLC 2018 Median PFS, mo (95% CI) Chemo+Dur va 6.9 ( ) PFS6 31/54 (57%) mrecist (%) irecist (%) CR 0 0 PR 26 (48) 27 (50) SD 20 (37) 20 (37) Probability progression free PD 8 (15) 7 (13) Total ORR 48%;DCR 85% Months mdor 6.5m

35 DREAM: RESULTS ASCO/IASLC 2018 Overall Survival Immune related AEs Any grade n (%) Grade 3 n (%) Probability alive 12m OS estimate 64.5% (52.9,78.7) Hypothyroidism 5 (9%) 0 Increased amylase/ lipase 2 (4%) 1 (2) Pneumonitis 2 (4%) 0 Adrenal insufficiency 1 (2%) 1 (2) Months Hyperthyroidism 1 (2%) 0 Renal impairment 11 (20%) 1 (2) 4 patients still to hit 12 month follow-up. Median follow-up 14.4 months

36 Conclusions: DREAM study ASCO/IASLC 2018 Durvalumab, cisplatin and pemetrexed was active and tolerable as first line treatment in advanced mesothelioma PFS6m 57% ORR(mRECIST) 48% DCR 85% Adverse events comparable to chemotherapy and immunotherapy alone: chemotherapy and durvalumab dose intensity maintained Ongoing randomised phase 3 trial.

37 Phase II Trial of Pembrolizumab (NCT ) KINDLER StudY IASLC 2018 Single institution, single arm, phase II trial Part A (N=35) Elegibility Criteria: Pleural or peritoneal mesothelioma Disease progression to Cis-Pem Ch 2 prior lines Measurable disease Archival or fresh tissue ECOG PS 0-1 No immunodeficiency, autoimmune disease, or chronic steroid use No pneumonitis or interstitial lung disease Pembrolizumab dose: 200 mg IV/21 days RR of pembrolizumab in PD-L1 unselected Optimal PD-L1 cutoff biomarker enrichment At WCLC 2016* 7 responses in Part A. No PD-L1 cutoff was established. Part B Expansion Cohort (N=30) Part B recruited patients unselected for PD-L1 Primary end point: ORR Secondary: DCR, PFS, OS A Desai, T Karrison, B Rose, E Pemberton, B Hill, A Mendoza, CM Straus, Y-H Carol Tan, TY Seiwert, HL Kindler. University of Chicago, Chicago, IL, USA

38 KINDLER: RESULTS (N=64) IASLC 2018 N (%) Partial response 14 (22%) Treatment beyond progression (N=30) N (%) Stable disease 26 (41%) Disease control rate 40 (63%) Median duration of response 11.7 months Median progression-free 4.1 months survival Median overall survival 11.5 months Partial response Disease control Disease Progression Nonevaluable 2 (7%) 9 (30%) 19 (63%) 2 (7%)

39 KINDLER: RESULTS IASLC 2018 Response rate and PD-L1 expression by histology and disease site Histology N RR (N=64) PD-L1 expression (N=62) No (0%) Low (1-49%) High ( 50%) Epithelioid 49 22% 46% 40% 14% Outcomes by PD-L1 expression PD-L1 TPS None (0%) Low (1-49%) High ( 50%) P value N ORR Sarcomatoid 5 40% 20% 0% 80% Biphasic 10 10% 70% 10% 20% Disease site Pleural 56 23% 49% 29% 22% Peritoneal 8 13% 25% 50% 25% Median PFS (months) Median OS (months)

40 KINDLER: RESULTS PFS and OS by PD-L1 expression IASLC 2018 Progression-free survival P=0.019 Overall survival P=0.43 PD-L1 Low/None High Median PFS 3.8 mo 4.9 mo 1 year PFS 9.3% 40.2% PD-L1 Low/None High Median OS 10.1 mo 12.5 mo 2 year OS 19.1% 33.6%

41 Conclusions: KINDLER Study (NCT ) IASLC 2018 Robust activity in PD-L1 unselected mesothelioma patients: Response rate: 22% Disease control rate: 63% Responses were observed in patients with no, low, and high PD-L1 expression PD-L1 expression( 50%) Higher RR (p=0.021) mpfs (p=0.034) PFS 1y (p=0.019) PD-L1 can be used as a biomarker to predict response in mesothelioma patients treated with pembrolizumab

42 MERIT study Design IASLC 2018 Single-arm, open-label, phase 2 trial (JapicCTI-No ) Key Eligibility Criteria 2nd- 3rd-line advanced or metastatic MPM Prior platinum-based combination therapy with pemetrexed No prior surgery for MPM ECOG PS 0-1 Available tumor tissue for PD-L1 analysis PD-L1 all comers Nivolumab 240 mg IV, Q2W (N=34) Until disease progression or unacceptable toxicity Primary endpoint: ORR* Select secondary endpoints: PFS and OS Safety Data cut-off: March 14, 2018 (median follow-up: 16.8 months [min. 1.8 max. 20.2]) *Efficacy analyses by central assessment according to mrecist criteria

43 MERIT study: RESULTS IASLC 2018 Percent change from baseline in target lesions (%) Tumor Response*, n (%) [95% CI] Histological ORR (n=34) 10 (29.4%) [16.8, 46.2] Epithelioid (n=27) 7 (25.9%) [13.2, 44.7] Biphasic (n=4) 1 (25.0%) [4.6, 69.9] Sarcomatoid (n=3) 2 (66.7%) [20.8, 93.9] DCR (n=34) 23 (67.6%) [50.8, 80.9] Tumor Response*, n (%) [95% CI] PD-L1 status ORR (n=34) 10 (29.4%) [16.8, 46.2] Male 85% Age 68 (43-78) PS1 61.8% E/S/B 79.4%/8.8%/11.8% PD-L1 1% (n=20) 8 (40.0%) [21.9, 61.3] PD-L1 <1% (n=12) 1 (8.3%) [1.5, 35.4] Not evaluable (n=2) 40 weeks later 1 (50.0%) [9.5, 90.5]

44 MERIT study: RESULTS IASLC 2018 PFS / OS by PD-L1 status p= p=0.2021

45 Conclusions: MERIT Study IASLC 2018 Nivolumab showed substantial clinical activity in 2 nd -3 thr - line MPM patients. Median PFS and OS were 6.1 months and 17.3 m, respectively mdor 11.1m Efficacy regardless of histological subtype and PD-L1 status. PD-L1 expression ( 1%) in the tumor could favor better response (NS) No safety concerns were detected Approved on Aug 21 st in Japan for unresectable advanced or recurrent MPM which has progressed after chemotherapy.

46 LUME-Meso trial ELCC/IASLC/ESMO 2018 Study design Scagliotti GV, Gaafar R, Nowak AK, Nakano T, Van Meerbeeck J, Popat S, Vogelzang NJ, Grosso F, Aboelhassan R, Jakopovic M, Ceresoli GL, Taylor P, Orlandi F, Fennell DA, Novello S, Scherpereel A, Von Wangenheim U, Kim M, Barrueco J and Tsao AS

47 LUME-Meso trial: RESULTS PFS by investigator ELCC/IASLC/ESMO 2018

48 LUME-Meso trial: RESULTS OS interim analysis ELCC/IASLC/ESMO 2018 Median duration follow up 9.2m

49 LUME-Meso trial: RESULTS Overal frecuency of AEs ELCC/IASLC/ESMO 2018

50 Conclusions: LUME-Meso Trial ELCC/IASLC/ESMO 2018 Primary endpoint was not met PFS (HR=1.01) OS no difference between treatment groups The study has been discontinued per protocol Safety profile manageable and consistent with previous nintedanib studies No biomarkers showed clear and significant association with nintedanib efficacy

51 Carcinoma Tímico

52 KOSMIC (NCT ) IASLC 2018 N=25 Se Hyun Kim, Yu Jung Kim, Chan-Young Ock, Miso Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo, Jong Seok Le, Seoul National University Bundang Hospital & Seoul National University Hospital, Seoul National University College of Medicine, Republic of Korea

53 KOSMIC : RESULTS IASLC 2018 Objective response (n=23) Waterfall plot (n=23) RECIST v 1.1 N 0. of pts % (95%CI) PR ( ) PR SD PD SD ( ) PD ( ) 2 patients were excluded for efficacy analysis d/t early withdrawal 3 PRs observed at 1 st stage DCR>6m 56.5 % Median Age 62 Male 76% Sunitinib as 2ndL 80%

54 KOSMIC: RESULTS IASLC 2018 Progression-free survival Adverse Events* mpfs: 15.2m (95%CI, ) ANC decrease G1-4 G3/4 12 (48%) 3 (12%) Hb decrease 4 (16%) 2 (8%) PLT decrease 16 (64%) 4 (16%) Mucositis 12 (48%) 0 Fatigue 9 (36%) 2 (8%) HFS 9 (36%) 0 Anorexia 6 (24%) 0 Diarrhea 6 (24%) 0 6 Pts: ongoing response at time analysis 11 Pts: PD (including one unrelated death) 8 Pts: withdrawal Nausea 3 (12%) 0 *68% at least 1 dose reduction due to adverse events

55 KOSMIC: RESULTS IASLC 2018 Patient C-KIT BOR PFS YG002 c g>a -23%, SD 21.3m BD007 c.1671 G>C -52%, PR 9.3m (PD) c-kit mutation: 2 patients TMB (n=15) 30/MB (n=9) Median PFS: Not reached < 30/MB (n=6) Median PFS: 3.45m Log-rank, P=0.03

56 Conclusions: KOSMICTrial IASLC 2018 Sunitinib with 2/1 schedule is an active treatment for TC after platinum-based chemotherapy. Median PFS: 15.2m (95%CI, ) 2nd prospective study 1st trial with asian ethnicity Is PFS influenced by? c-kit mutation (c g>a) High TMB

57