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Tratamiento en CPCNP en 2L: IO vs quimioterapia

Tratamiento en CPCNP en 2L: IO vs quimioterapia. Mariano Provencio Servicio Oncología Médica Hospital Universitario Puerta de Hierro, Madrid. ¿HAY BENEFICIO?. 1 st line pembro FDA approved 2016. Nivolumab FDA approved 2015. Atezolizumab FDA approved 2016.

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Tratamiento en CPCNP en 2L: IO vs quimioterapia

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  1. Tratamiento en CPCNP en 2L: IO vs quimioterapia Mariano Provencio Servicio Oncología Médica Hospital Universitario Puerta de Hierro, Madrid

  2. ¿HAY BENEFICIO? 1st line pembro FDA approved 2016 Nivolumab FDA approved 2015 Atezolizumab FDA approved 2016 Pembrolizumab FDA approved 2015 Borghaei and Brahmer, NEJM 2015 Herbst, Lancet 2016 Reck, NEJM 2016 Barlesi, ESMO 2016

  3. ¿HAY BENEFICIO? Nivolumab FDA approved 2015 Nivolumab Ensayos que avalan su uso en histología escamosa CheckMate003 CheckMate 017 CheckMate 063

  4. NIVOLUMAB • Nivolumab • Ensayos que avalan su uso en histología escamosa • CheckMate003 • CheckMate 017 • CheckMate 063

  5. Phase I: Nivolumab monotherapy in ≥2nd-line NSCLC. Checkmate 003 Eligibility: advanced melanoma, NSCLC, RCC, CRC, or CRPC with PD after 1-5 systemic therapies NSCLC Expansion Cohort: Pts randomized to 3 dose levels of nivolumab (1, 3, or 10 mg/kg) Rapid PD or clinical deterioration Off study 8-wk treatment cycle Unacceptable toxicity Follow-up q8w x 6 (48 wks) Day 1* 15* 29* 43* 57 Treat to confirmed CR, worsening PD, unacceptable toxicity, or 12 cycles (96 wks) CR/PR/SD or PD but clinically stable *Dose administered IV q2w.Scans done at baseline and following each 8-wk treatment cycle. Brahmer JR. Phase I study of single-agent anti-programmed death-1 (MDX-1106)…JCO 2010; 28:3167-75

  6. Anti-PD-1 demonstrates encouraging survival in pre-treated patients: nivolumab as an example CA209-003: phase 1 follow-up study, up to 5 prior lines of therapy, stage IIIB/IV squamous and non-squamous (NSCLC cohort OS rate, % (95% CI) 100 90 Group Died/Treated Median OS, mo (95% CI) 3-year 1-year 2-year Censored 1 mg/kg 3 mg/kg 10 mg/kg 26/33 23/37 50/59 9.2 (5.3, 11.1) 14.9 (7.3, 30.3) 9.2 (5.2, 12.4) 33 (17, 49) 56 (38, 71) 38 (26, 50) 15 (5, 30) 42 (24, 58) 20 (11, 31) 15 (5, 30) 27 (12, 43) 14 (7, 25) 80 70 60 50 OS (%) 2-year OS = 42% 40 3-year OS = 27% 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 Months Since Initiation of Treatment Pts at Risk Nivolumab 1 mg/kg 33 37 59 26 34 51 21 26 35 16 21 29 9 17 22 7 14 16 6 13 14 6 12 12 4 11 11 4 9 10 4 9 9 3 7 9 1 5 6 1 2 4 0 1 2 0 1 2 0 1 2 0 1 1 0 1 1 0 1 0 0 1 0 0 1 0 0 0 0 Nivolumab 3 mg/kg Nivolumab 10 mg/kg 70% of patients had 3–5 prior lines of therapy; 46% of these patients had received 12 prior lines of therapy and 54% had received 35 prior lines of therapy. Brahmer J, et al. Poster presented at ASCO 2014 (Abstract 8112).

  7. PD-1 Inhibitor Nivolumab in Pts With Progressive Squamous NSCLC CheckMate 063. Study Design • Assessments (RECIST v1.1) performed at week 8 and Q6W • Tumor PD-L1 expression was retrospectively assessed in pretreatment (archival) tumor samples (baseline testing not required) • Updated safety and OS are reported as of June 2015 Screening • Stage IIIB/IV SQ NSCLC • ≥2 prior systemic therapies • ECOG PS 0–1 (N =140) Treatment Nivolumab 3 mg/kg IV Q2W until PDor unacceptable toxicity (N=117) Endpoints Primarya • IRC-assessed confirmed ORR Secondaryb • Investigator-assessed confirmed ORR Exploratory • Safety and tolerability • PFSa and OS • Efficacy by PD-L1 expressiona aBased on July 2014 DBL; bBased on March 2014 DBL IRC = Independent radiology review committee

  8. Stage IIIB/IV SQ NSCLC • ≥ 2 prior systemic therapies Overall Survival (All Treated Patients) 100 90 80 70 60 8.1 mos OS (%) 50 39% 40 27% 30 20 10 8.2 mos 0 0 3 6 9 12 15 18 21 24 27 41% Time Since Treatment Initiation (Months) Number of patients at risk: 0 0 0 July 2014 DBL 117 93 68 51 28 5 0 June 2015 DBL 117 93 69 54 45 38 30 24 6 0 Data are based on July 2014 and June 2015 DBLs. Symbols represent censored observations

  9. Closedwith 272 and 587 pts. Stoppedearlybecausethestudiesmettheirendpoints, demonstrating superior overallsurvival in patientsreceiving Nivolumab comparedtothe control arms

  10. Hazard Ratio 0.59% CI: 0.44, 0.79, p=0.00025] …is the only FDA-approved monotherapy to demonstrate proven superior OS compared to standard of care in more than 15 years in previously treated metastatic squamous NSCLC

  11. Hazard Ratio 0.59% CI: 0.44, 0.79, p=0.00025] …is the only FDA-approved monotherapy to demonstrate proven superior OS compared to standard of care in more than 15 years in previously treated metastatic squamous NSCLC

  12. Nivolumab • Ensayos que avalan su uso en histología escamosa • CheckMate 0003 • CheckMate 017 • CheckMate 063 • Nivolumab • Ensayos que avalan su uso en histología no escamosa • CheckMate003 • CheckMate 057

  13. CheckMate 57

  14. NEJM sept/2015

  15. Summary:NSCLC Indication (Section 4.1) • OPDIVO is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adults  • CHMP Opinion=Broad indication for NSQ NSCLC • PD-L1 testing is not required in SMPC • 3 post-hoc analyses in additional sections of the SMPC specific to NSQ NSCLC • New PD-L1 analyses including intervals and inclusion of 50% threshold level • Warning statement for early deaths in section 4.4 • Subgroup data for patients that were never smokers or had EGFR mutation

  16. Overall Survival Hazard Ratios by PD-L1 Expression All Randomized Subjects 0 1 2 Unstratified Hazard Ratio (95% CI) • Study was not designed or powered to prospectively evaluate intervals • Samples sizes are small and, at the time of the analysis, the PD-L1 IHC 28-8 pharma Dx assay was not analytically validated at the 10% or 50% expression levels http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/003985/WC500205973.pdf

  17. One-Year OS Ratesa Overall and by PD-L1 Expression Level 100 100 Overall PD-L1 expression Overall PD-L1 expression CheckMate 017 (SQ NSCLC) CheckMate 057 (non-SQ NSCLC) Nivolumab Docetaxel 80 80 60 60 OS (%) 40 40 67 66 60 51 47 45 45 44 43 42 20 20 39 39 37 32 30 26 26 25 25 24 0 0 OS (%) n 135 137 54 52 63 56 42 39 36 33 292 290 108 101 123 123 95 86 86 79 n All patients <1% ≥1% ≥5% ≥10% All patients <1% ≥1% ≥5% ≥10% HRb,3(95% CI) 0.59(0.44, 0.79) 0.58(0.37, 0.92) 0.69(0.45, 1.05) 0.53(0.31, 0.89) 0.50(0.28, 0.89) HRb,4(95% CI) 0.73(0.59, 0.89c) 0.90(0.66, 1.24) 0.59(0.43, 0.82) 0.43(0.30, 0.63) 0.40(0.26, 0.59) aKaplan–Meier estimates, with error bars indicating 95% CIsbFor the comparison of the full Kaplan–Meier survival curves for each treatment groupc96% CI

  18. One-Year OS Ratesa Overall and by PD-L1 Expression Level 100 100 Overall PD-L1 expression Overall PD-L1 expression CheckMate 017 (SQ NSCLC) CheckMate 057 (non-SQ NSCLC) Nivolumab Docetaxel 80 80 60 60 OS (%) 40 40 67 66 60 51 47 45 45 44 43 42 20 20 39 39 37 32 30 26 26 25 25 24 0 0 OS (%) n 135 137 54 52 63 56 42 39 36 33 292 290 108 101 123 123 95 86 86 79 n All patients <1% ≥1% ≥5% ≥10% All patients <1% ≥1% ≥5% ≥10% HR 0.59(0.44, 0.79) 0.58(0.37, 0.92) 0.69(0.45, 1.05) 0.53(0.31, 0.89) 0.50(0.28, 0.89) HR(95% CI) 0.73(0.59, 0.89c) 0.90(0.66, 1.24) 0.59(0.43, 0.82) 0.43(0.30, 0.63) 0.40(0.26, 0.59) aKaplan–Meier estimates, with error bars indicating 95% CIsbFor the comparison of the full Kaplan–Meier survival curves for each treatment groupc96% CI

  19. Nivolumab • Ensayos que avalan su uso en histología escamosa • CheckMate 003 • CheckMate 017 • CheckMate 063 • Nivolumab • Ensayos que avalan su uso en histología no escamosa • CheckMate 003 • CheckMate 057 • Pembrolizumab • Ensayos que avalan su uso: Keynote 010 y 001

  20. Keynote 010: OS by PD-L1 ExpressionPembrolizumabpoblación total PD-L1 > 50% HR: 0.54 SG: 14.9 m vs 8.2 m R Herbst et al. Lancet 2016

  21. Keynote 010: RR by PD-L1 ExpressionPembrolizumab Garon et al. ASCO 2016

  22. Subgroup No. of Events/ Hazard Ratio (95% CI) No. of Patients Overall 521/1033 0.67 (0.56-0.80) Sex Male 332/634 0.65 (0.52-0.81) Female 189/399 0.69 (0.51-0.94) Age <65 years 317/604 0.63 (0.50-0.79) ≥ 204/429 0.76 (0.57-1.02) 65 years ECOG performance status 0 149/348 0.73 (0.52-1.02) 1 367/678 0.63 (0.51-0.78) PD-L1 tumor proportion score 204/442 0.53 (0.40-0.70) 1%–49% 317/591 0.76 (0.60-0.96) Tumor sample Archival 266/455 0.70 (0.54-0.89) New 255/578 0.64 (0.50-0.83) Histology Squamous 128/222 0.74 (0.50-1.09) Adenocarcinoma 333/708 0.63 (0.50-0.79) EGFR status Mutant 46/86 0.88 (0.45-1.70) Wild type 447/875 0.66 (0.55-0.80) 0.1 1 10 Favors Pembrolizumab Favors Docetaxel OS in Key Subgroups, PD-L1 TPS ≥1% ≥50% aData for the pembrolizumab doses were pooled. Analysis cut-off date: September 30, 2015.

  23. Subgrupos en KN 010-ASCO 2017

  24. Nivolumab • Ensayos que avalan su uso en histología escamosa • CA 20900003 • CheckMate 017 • CheckMate 063 • Nivolumab • Ensayos que avalan su uso en histología no escamosa • CA 20900003 • CheckMate 057 • Pembrolizumab • Ensayos que avalan su uso: Keynote 010 y 001 • Atezolizumab

  25. Phase III OAK study design Locally Advanced or Metastatic NSCLC3 • N = 1225 enrolleda • 1–2 prior lines of chemo including ≥ 1 platinum-based • Any PD-L1 statusb • Stratification factors: PD-L1 expression, histology, prior chemotherapy regimens Atezolizumab (anti–PD-L1) is an engineered mAb that inhibits the PD-L1/PD-1 and PD-L1/B7.1 interactions to restore anti-tumor T-cell activity and enhance T-cell priming1,2 PD or loss of clinical benefit Atezolizumab 1200 mg IV q3w R 1:1 OAK study design PD Docetaxel 75 mg/m2 q3w Primary Endpoints (first 850 enrolled patients) • OS in the ITT population • OS in patients with PD-L1 expression on ≥ 1% TC or IC Secondary Endpoints ORR, PFS, DoR, Safety aA prespecified analysis of the first 850 patients provided sufficient power to test the co-primary endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression).bPD-L1 expression assessed with VENTANA SP142 IHC assay

  26. Histology by PD-L1 status: Overall survival Subgroup n (%) HRa Median OS, mo Atezolizumab Docetaxel Nonsquamous TC3 or IC3 0.35 22.5 8.7 96 (15%) 0.61 18.7 11.3 TC2/3 or IC2/3 188 (30%) TC1/2/3 or IC1/2/3 0.72 17.6 11.3 333 (53%) TC0 and IC0 0.75 14.0 11.2 290 (46%) All nonsquamous 0.73 15.6 11.2 628 (100%) Squamous TC3 or IC3 0.57 17.5 11.6 41 (18%) TC2/3 or IC2/3 0.76 10.4 9.7 77 (35%) TC1/2/3 or IC1/2/3 0.71 9.9 8.7 130 (59%) TC0 and IC0 0.82 7.6 7.1 89 (40%) 0.73 8.9 7.7 All squamous 222 (100%) ITT 0.73 13.8 9.6 850 0.2 1 2 Hazard Ratio In favor of atezolizumab In favor of docetaxel

  27. OS by histology Atezolizumab Docetaxel Nonsquamous Squamous Overall Survival (%) HR, 0.73a (95% CI, 0.60, 0.89) P = 0.0015b HR, 0.73a (95% CI, 0.54, 0.98) P = 0.0383b Overall Survival (%) No. at risk Atezolizumab Docetaxel Median 11.2 mo (95% CI, 9.3, 12.6) Median 15.6 mo (95% CI, 13.3, 17.6) Median 7.7 mo (95% CI, 6.3, 8.9) Median 8.9 mo (95% CI, 7.4, 12.8) Months Months Minimum follow up = 19 months. aUnstratified HRs. bP values for descriptive purpose only. Histology information from eCRF. OS, overall survival. Barlesi et al. ESMO 2016 LBA44

  28. JTO 2018

  29. IFCT‐1502 CLINIVO: Real‐life experience with nivolumab in patients with advanced NSCLC Olivier MOLINIER, Clarisse AUDIGIER‐VALETTE, Jacques CADRANEL, Isabelle MONNET, José HUREAUX, Werner HILGERS, Eric FAUCHON, Elisabeth FABRE, Benjamin BESSE, Philippe BRUN, Daniel COËTMEUR, Elisabeth QUOIX, Pierre MOURLANETTE, Fabrice BARLESI, Stéphanie BORDENAVE‐CAFFRE, Thomas EGENOD, Pascale MISSY, Franck MORIN, Denis MORO‐SIBILOT, Nicolas GIRARD

  30. Efficacy of nivolumab: survival Median OS, 95% CI: 9.9 [9.1-11.3], events = 603, censored n=299 Checkmate (s) Non-squamous: median OS 12.2 I year survival rate 51%, ORR 19% Squamous: median OS 9.2 I year survival rate 42%, ORR 20% 6-month survival rates: 64.2% (95% CI: 61.0-67.4) 12-month survival rates: 44.7% (95% CI: 41.4-48.0) 18-month survival rates: 32.7% (95% CI: 29.4-35.9) OR 19% (16.2; 21.7) SD 35.5% (32.1; 38.9) PD 44.9% (41.4-48.4) NE 0.6% (0.1;1.2)

  31. Estudio Uso Expandido en España (GECP) Supervivencia global estimada para este grupo de pacientes, con una mediana de supervivencia global de 8,97 meses (IC95% 7,69-10,24 meses). 665 pacientes 3 meses: 76.6% 6 meses: 60% 12 meses: 42.4% S global La supervivencia global estimada es del 76,6% (IC95% 73,5-76,9%) a los tres meses del inicio del tratamiento, del 60,1% (IC95% 56,4-60,5%) a los 6 meses y del 42,4% (IC95% 38,5-42,8%) a los 12 meses del inicio del tratamiento

  32. Estudio Uso Expandido Nivolumab en España La mediana de supervivencia global es de 8,93 meses (IC95% 7,42-10,44 meses) para los adenocarcinomas y de 9,00 meses (IC95% 6,55-11,45 meses) para el resto de histologías, no observándose diferencias significativas (p-valor = 0,664) en la supervivencia global 665 pacientes Supervivencia global estimada según histología (azul = adenocarcinoma, verde = resto) WLCC 2018

  33. CheckMate 384: Phase 3b/4 Trial of Nivolumab 480 mg Q4W vs 240 mg Q2W After ≤ 12 Months of Nivolumab in Previously Treated Advanced Non-Small Cell Lung Cancer Edward B. Garon,1 Niels Reinmuth,2 Lionel Falchero,3 Yolanda García,4 José Hureaux,5Ira Gore,6 Ronald P. Harris,7 Paolo Bidoli,8 Editta Baldini,9 Silverio Ros,10 Eckart Laack,11Paul Mitchell,12 Martin Wolf,13 Kenneth O’Byrne,14 Labib Zibdawi,15 Kevin Jao,16David R. Spigel,17 Ang Li,18 Sridhar K. Rabindran,18 Eric Pichon19

  34. CheckMate 384 Study Design Before study enrollment Nivolumab 240 mg Q2W Treat until disease progression or unacceptable toxicity for up to 2 years N = 363 2L+ nivolumab (3 mg/kg or 240 mg Q2W) R 1:1 ≤ 12 months Two consecutive assessments of CR, PR, or SD on nivolumab Nivolumab 480 mg Q4W Key eligibility criteria • Advanced/metastatic NSCLC • ECOG PS 0–2 Stratification factors • Tumor histology (SQ vs NSQ) • Response to prior nivolumab therapy at randomization (CR/PR vs SD) Post-randomization endpoints • Co-primary: PFS rates at 6 and 12 monthsa • Secondary: PFS rate at 24 monthsa, OS rates at 12 months and up to 36 months, safety • Database lock: June 4, 2018 for patients enrolled as of April 3, 2018 (N = 329); minimum follow-up: 2.2 months • Median follow-up (range) was 9.4 (0.0–22.7) months with 480 mg Q4W and 10.2 (0.5–21.0) months with 240 mg Q2W aAs measured by investigator-assessed response using RECIST 1.1.

  35. Post-Randomization PFS With Nivolumab Q4W vs Q2Wa 100 80 72% 60 72% 480 mg Q4W PFS (%)b 40 240 mg Q2W 20 0 0 3 6 9 12 15 18 21 24 No. at risk Months 480 mg Q4W 166 130 83 58 30 17 4 0 0 163 125 80 56 30 14 3 0 0 240 mg Q2W PFS measured by investigator-assessed response using RECIST v1.1; ~80% and ~60% of patients reached 6 months and 12 months of follow-up, respectively. aInterim analysis; bUnstratified; cAdjusted for stratification factors: tumor histology (squamous vs non-squamous) and response category at randomization (CR/PR vs SD).

  36. Safety Summary of Post-RandomizationTreatment-Related AEs • Median durationd of post-randomization study therapy was 7.5 months (480 mg Q4W) and 7.1 months (240 mg Q2W) Similar safety was observed across subgroups by weight; few patients were represented in the < 50-kg and ≥ 110-kg subgroups. aIncludes events reported between first dose and 30 days after last dose of study therapy; bTreated population; cIn either group; dDuration between first dose and treatment discontinuation/cutoff.

  37. Summary • In this descriptive analysis, nivolumab 480 mg Q4W appeared to show similar efficacy and safety to 240 mg Q2W in patients with advanced NSCLC following disease control with prior nivolumab • Post-randomization PFS rates at 6 months appeared similar in both treatment arms • No new safety signals were observed with either dose, and trends in TRAEs seemed comparable in both arms • This study offers support for the use of nivolumab Q4W dosing as a more convenient option for patients with advanced NSCLC with response or stable disease on nivolumab (≤ 12 months) • Overall, these clinical data are in agreement with pharmacokinetic modeling and provide further evidence supporting a 480-mg Q4W nivolumab dosing regimen

  38. Meta analysis PD-1/PD-L1 inhibitors over all solid tumor types • A meta-analysis to indirectly compare the safety and efficacy of PD-1 and PD-L1 antibodies across solid tumors using a Bayesian hierarchical model. • No significant difference between PD-1 and PD-L1 mAb across tumor types for ORR, PFS and Gr 3/4 AE rate. • The small magnitude of difference relative to the variability across tumor types suggests strong interchangeability of efficacy and safety profile of the antibodies targeting either PD-1 or PD-L1. • Conclusion: variability within this class of antibodies is not likely to be clinically meaningful

  39. IO Phase III Trials in pre-treated patients *850 in primary populationNR = not reached 1. Borghaei, et al. ASCO 2016 2. Herbst, et al. Lancet 2015; 3. Barlesi, et al. ESMO 2016

  40. La inmunoterapia: sí ha cambiado la supervivenciaTodos los estudios tienen puntos de crítica porque ningún ensayo puede responder todas las dudas a la vezEl futuro es imposible verlo sin la inmunoterapia

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