Cáncer de pulmón no microcítico

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1 DEFINIENDO LA SECUENCIA O PTIMA DE TRATAMIENTO EN CA NCER AVANZADO Cáncer de pulmón no microcítico Enriqueta Felip Hospital Vall d Hebron, Barcelona

2 Molecular events in NSCLC Adenocarcinoma EGFR-resistance mutations 0.8% EGFR 9.5% HER2 0.9% Squamous-cell carcinoma Unknown 53.8% KRAS 27% ALK 3.7% BRAF 1.7% PI3K 2.6% Adapted from Cappuzzo F. Guide to targeted therapies: EGFR mutations in NSCLC. Basel: Springer Barlesi F, et al. Slides presented at ASCO 2013; abstract 8000.

3 First-line therapy in metastatic NSCLC (2015) Stratification for EGFR, ALK, and histology EGFR Mut + ALK rearranged ALK /EGFR wt non-squamous ALK /EGFR wt squamous EGFR TKI ALK TKI Platinum doublet + bevacizumab OR platinum + pemetrexed ± bevacizumab Platinum-based doublet Adapted from Cappuzzo F. Guide to targeted therapies: EGFR mutations in NSCLC. Basel: Springer

4 1st line EGFRm NSCLC IPASS Mok NEJM 09 WJTOG 3405 Mitsudomi Lancet Onc 10 NEJ002 Maemondo NEJM 10 EURTAC Rosell Lancet Onc 12 OPTIMAL Zhou Lancet Onc 11 LUX-LUNG 3 Sequist JCO 13 LUX-LUNG 6 Wu Lancet Onc 13 EGFR-TKI Chemo regimen PFS in TKI arm (m) Gefitinib Carboplatin + paclitaxel HR 9.5 vs Gefitinib Cisplatin + docetaxel 9.2 vs Gefitinib Carboplatin + paclitaxel Erlotinib Doublet platinum based Erlotinib Carboplatin + gemcitabine Afatinib Cisplatin + pemetrexed Afatinib Cisplatin + gemcitabine 10.8 vs vs vs vs vs

5 Acquired TKI resistance: management algorithm based on clinical factors Yang Lung Cancer 2013

6 Mechanisms of resistance in EGFR mutant NSCLC Yu HA. Clin Cancer Res 2013;19:

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8 Secuencia óptima en enfermedad avanzada, mutación EGFR Tratamiento de 1ª línea, EGFR-TKI (10-14 mo mpfs) Tratamiento resistencia adquirida Pacientes asintomáticos con PD lenta, mantener el inhibidor Pacientes sintomáticos, re-biopsia T790M+, inhibidores EGFR/T790M (>50%RR, 9-10 mo mpfs) Mecanismos de resistencia mutación C767 T790M-wt, MET? CT

9 PFS probability (%) PROFILE 1014 PFS by Independent radiologic review (all patients) All patients Crizotinib (N=172) Chemo. (N=171) Events, n (%) 100 (58) 137 (80) Median, mo HR (95% CI) 0.45 ( ) P a < At risk (ALL) Crizotinib Chemotherapy Time (months) Salomon B et al, NEJM 2015

10 ASCEND-1 PFS for ALK+ NSCLC p treated with ceritinib 750 mg/day On 26 February 2015 the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorisation for the medicinal product ceritinib, intended for the treatment of adult patients with anaplastic ALK positive advanced NSCLC previously treated with crizotinib

11 PROFILE 1014 and ASCEND-1: outcomes PROFILE 1014 Crizotinib arm (n = 172) ASCEND-1 ALKi-naïve + CT (n = 83) ASCEND-1 ALKi + CT (n = 163) mdor, mo mpfs, mo No studies directly comparing the 2 schedules Two different strategies with good outcomes mdor, median duration of response. Solomon BJ, et al. N Engl J Med. 2014;371: Felip E, et al. Ann Oncol. 2014;25 Suppl 4:abstract 1295P.

12 Activity of alectinib in advanced crizotinib naïve ALK+ NSCLC

13 Anti-tumor activity of alectinib in crizotinib pre-treated ALKrearranged NSCLC in JP28927 study Updated efficacy and safety in 28 crizotinib pretreated p who received alectinib 300 mg bid until lack of clinical benefit as assessed by the investigator Key results After a median follow-up of 141 days, 21 p continued treatment without PD Tumour shrinkage of 30% was observed in 18 of 24 patients with target lesions Response rate was 58.3% (95% CI 36.6, 77.9) and DCR was 83.3% (95% CI 62.6, 95.3) Of the 19 p with brain metastases at baseline (from 28 patients) 13 were still on alectinib without PD Alectinib had a favourable safety profile consistent with previous reports and no p discontinued treatment for safety reasons Conclusion In p with ALK-rearranged NSCLC pre-treated with crizotinib, alectinib had a good tolerability profile and demonstrated positive efficacy Seto et al. Ann Oncol 2014; 25 (suppl 4): abstr 1224O

14 PHASE 1/2 STUDY OF PF (AN ALK/ROS1 TYROSINE KINASE INHIBITOR) IN PATIENTS WITH ADVANCED NSCLC HARBORING SPECIFIC MOLECULAR ALTERATIONS In vivo, PF demonstrated marked cytoreductive activity in mice bearing tumor xenografts that express ALK or ROS1 fusion variants, including the crizotinib resistant EML4 ALKL1196M or EML4 ALKG1269A mutations PF treatment significantly reduced the tumor size and prolonged animal survival in the orthotopic brain models (EML4 ALK and EML4 ALKL1196M) in mice ALK+ NSCLC p have had disease progression after 1 or 2 previous ALK inhibitor therapy(ies), as the last therapy given

15 Secuencia óptima en enfermedad avanzada, ALK 1ª línea, crizotinib 2ª linea, inhibidor de 2 generación Tratamiento de las metástasis cerebrales, reto

16 ESMO clinical practice guidelines 2014: 1 st Line 1st-line treatment In the subgroup of non-scc tumours and in p treated with thirdgeneration regimens, including gem and taxanes, cis should be the treatment of choice [I, B] Pemetrexed is preferred to gem or docetaxel in p with non-scc tumours [II, A] The combination of bevacizumab and other platinum-based CT may be considered in eligible p with non-scc NSCLC [I, A] Maintenance Treatment Continuing pemetrexed following four cycles of 1 st -line cis plus pemetrexed CT is recommended in p with non-scc histology [I, B] Reck M, et al. Ann Oncol. 2014

17 ESMO clinical practice guidelines 2014: 2 nd -line 2 nd -line Comparable options consist of pemetrexed for a non-scc histology only or docetaxel [I, B]. Erlotinib is an additional potential option in p with unknown EGFR status or EGFR WT p with PS 0 2 [II, B] Subsequent lines of treatment Erlotinib is indicated for p with unknown EGFR status or EGFR WT p who have not yet received EGFR TKIs, with PS 0 3 [II, B] Reck M, et al. Ann Oncol. 2014

18 Nonsquamous Squamous Nivolumab in advanced NSCLC p (n=129) NSCLC responders by histology OS by dose in NSCLC OS 1 year 56% OS 2 year 45% Duration of response up to discontinuation of therapy Ongoing response Time to response Response duration following discontinuation of therapy OS by histology in NSCLC Time (Week) ORR 17% (24% in 3mg/kg) Similar RR in SCC vs non-scc (16.7 vs 17.6%) Responses in PDL1- Gettinger JCO 15

19 Nivolumab in SCC (CHECKMATE-017): OS Median OS (mo) Nivolumab: 9.2 Docetaxel: 6.0 HR=0.59 (95% Cl: ; p= ) RR 20% nivo vs 10% docetaxel 1 yr OS 42% nivo vs 24% docetaxel Estudio 2ª línea ADC: nivo vs docetaxel, ASCO 15 Nivolumab prescribing information. Available at:

20 Preliminary results from the multi-arm phase I study of nivolumab (Checkmate 012)

21 Pembrolizumab: NSCLC expansion cohorts of KEYNOTE-001, 495 patients treated Nonrandomized (N = 38) 1 PD-L1 + or PD-L1 tumors 2 previous therapies Nonrandomized (N = 33) PD-L1 + tumors 2 previous therapies Nonrandomized (N = 43) PD-L1 tumors 1 previous therapies Randomized (N = 280) PD-L1 + tumors 1 previous therapy R (3:2) Randomized (N = 101) PD-L1 + tumors Treatment naive R a (1:1) Pembro 10 mg/kg Q3W Pembro 10 mg/kg Q3W Pembro 10 mg/kg Q2W Pembro 10 mg/kg Q3W Pembro 10 mg/kg Q2W Pembro 2 mg/kg Q3W Pembro 10 mg/kg Q3W Pembro 10 mg/kg Q2W PD-L1 status assessed by a prototype IHC assay using the 22C3 antibody clone (Merck) Positivity defined as Membranous staining in 1% of cells (both neoplastic and intercalated mononuclear inflammatory cells) within tumor nests OR A distinctive band of stromal staining adjacent to tumor nests caused by mononuclear inflammatory cells infiltrating the stroma a The first 11 patients were randomized to pembrolizumab 2 mg/kg Q3W vs 10 mg/kg Q3W. The remaining 90 patients were randomized to pembrolizumab 10 mg/kg Q3W vs 10 mg/kg Q2W. 1. Garon EB et al. Presented at: 2014 AACR-IASLC on Joint Conference on Molecular Origins of Lung Cancer; January 6-9, 2014; San Diego, CA.

22 ORR a in all treated patients At the time of this analysis, 84.4% of patients with a response, PD ORR (95% CI), % ORR in total population was 19.4% (95% CI, %) Yes (n = 394) No (n = 101) Prior Therapy 10 Q2W (n = 287) Dosage b 10 Q3W (n = 202) Squamous (n = 85) Histology b Nonsquamous (n = 401) Never (n = 126) Former/Current (n = 369) Smoking History a Assessed per RECIST v1.1 by central review. b Because of small patient numbers, data for patients treated with pembrolizumab 2 mg/kg Q3W (n = 6) and those with other histology (n = 9) are not shown. Analysis cut-off date: August 29, Garon EB et al. Presented at: 2014 AACR-IASLC on Joint Conference on Molecular Origins of Lung Cancer; January 6-9, 2014; San Diego, CA.

23 ORR a by PD-L1 proportion score: CTA-evaluable validation set patients with measurable disease b Total c Previously Treated d Treatment Naive e When measurable disease is NOT required, the ORR (95% CI) in the PS 50% subgroups are: 42.3%, 41.0%, and 47.1% in the total, previously treated, and treatment-naive populations f a Assessed per RECIST v1.1 by central review. b Biomarker-evaluable population (ie, patients with measurable disease per RECIST v1.1 by central review at baseline whose slides were cut within 6 months of staining and for which a proportion score could be assigned). c n = 73, 103, and 28, respectively. d n = 57, 77, and 22, respectively. e n = 16, 26, and 6, respectively. f n = 78, 61, and 17, respectively. Analysis cut-off date: August 29, 2014.

24 Overall Survival, % OS by PD-L1 expression, all CTA-evaluable patients a PS Median (95% CI), mo 50% NR (13.7-NR) 1-49% 8.8 ( ) <1% 8.8 ( ) n at risk PS 50% PS 1-49% PS <1% Time, months a Assessed in all patients whose samples were stained within 6 months of cutting. Analysis cut-off date: August 29, 2014.

25 MPDL3280A in pre-treated NSCLC p Phase Ia expansion study ongoing, 1 prior lines of therapy, stage IIIB/IV NSCLC cohort RECIST 1.1 ORR, % SD 24 weeks, % 24-week PFS rate, % Overall (N = 175) NSCLC (n = 53) Non-squamous (n = 42) Squamous (n = 11) Herbst RS Nature 15

26 MPDL3280A phase I: RR by PDL1 IHC status Diagnostic Population (n = 53) ORR % (n/n) PD Rate % (n/n) IHC 3 83% (5/6) 17% (1/6) IHC 2 and 3 46% (6/13) 23% (3/13) IHC 1/2/3 31% (8/26) 38% (10/26) All Patients 23% (12/53) 40% (21/53) Herbst RS Nature 15

27 ASCO 2015 Fase I pembrolizumab/ipi en 2 line NSCLC; preliminar en 11 pacientes RR 55% Estudio randomizado fase II comparando MPDL3280A vs docetaxel en 2-3 línea 287 p randomizados Aumento eficacia con niveles altos de PDL1 (HR OS 0.47), mientras que niveles bajos, no beneficio Fse I/II nivo +/-IPI, RR 15% nivo vs 25% nivo/ipi

28 Selected anti-pd1 and anti-pdl1 trials Study No. Phase Indication(s) N Comparator Primary Endpoint Status Nivolumab NCT / CA NCT / CA III III Advanced/metastatic squamous NSCLC, second-line Advanced/metastatic PD-L1 positive NSCLC, firstline 264 Docetaxel OS 495 Investigator s choice chemotx PFS (IRRC) To be reported Ongoing MK-3475 Pembrolizumab NCT MK NCT MK II/III III Previously treated PD-L1 positive NSCLC Metastatic NSCLC PD-L1 strong; first-line 920 Docetaxel OS, PFS, Safety Ongoing 300 Platinum-based chemotherapy PFS Ongoing NCT BIRCH II Locally advanced or metastatic NSCLC, PD-L1 positive 635 Single arm study ORR Ongoing MPDL3280A NCT OAK III Locally advanced or metastatic NSCLC, after progression on platinumbased chemo 1100 Docetaxel OS Ongoing MEDI-4736 NCT ATLANTIC II Third-line therapy in locally advanced or metastatic NSCLC PD-L1-positiive 282 Single arm ORR Ongoing MEDI-4736 NCT Lung-MAP NCT ARCTIC II/III III Advanced squamous second line Advanced NSCLC, previously treated 10,0000 Docetaxel PFS Ongoing 900 Multiarm including tremi+medi OS, PFS Ongoing Clinicaltrials.gov. Accessed 9 th April 2015

29 Challenges with PDL1 assessment Tumor heterogeneity Small tumor sample Fresh tumor vs archival samples PD-L1 expression may change over time Different IHC mab, different cut-off for PDL1 positivity

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31 Immune-based anti-tumor therapies in advanced NSCLC Activity in different tumor types including NSCLC Toxicity profiles differ from that of CT; generally much better tolerated Impact on long-term survival Targeting PD1/PDL1 means new hope for NSCLC p Treatment algorithm, 1 st line? 2 nd line?

32 Secuencia óptima en enfermedad avanzada, EGFR/ALK wt 1º línea QT +/-bevacizumab, tto mantenimiento 2ª línea Carcinoma escamoso, inmunoterapia ADC, probablemente inmunoterapia (ASCO 15) 3ª línea Docetaxel, doctaxel/nintedanib, docetaxel/ramucirumb, ertloinib Líneas de investigación (inmuno-oncología) Definir papel PDL1 como biomarcador Anti-PD1, anti-pdl1 en 1ª línea (necesidad de biomarcador) Combinación anti-pd1, anti-pdl1/anti-ctla4

33 Gracias!!