DEFINIENDO LA SECUENCIA O PTIMA DE TRATAMIENTO EN CA NCER AVANZADO Cáncer de pulmón no microcítico Enriqueta Felip Hospital Vall d Hebron, Barcelona
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. 2014. Barlesi F, et al. Slides presented at ASCO 2013; abstract 8000.
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. 2014.
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 6.3 0.48 Gefitinib Cisplatin + docetaxel 9.2 vs 6.3 0.49 Gefitinib Carboplatin + paclitaxel Erlotinib Doublet platinum based Erlotinib Carboplatin + gemcitabine Afatinib Cisplatin + pemetrexed Afatinib Cisplatin + gemcitabine 10.8 vs 5.4 0.30 9.7 vs 5.2 0.37 13.1 vs 4.6 0.16 11.1 vs 6.9 0.58 11.0 vs 5.6 0.28
Acquired TKI resistance: management algorithm based on clinical factors Yang Lung Cancer 2013
Mechanisms of resistance in EGFR mutant NSCLC Yu HA. Clin Cancer Res 2013;19:2240-2247
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
PFS probability (%) PROFILE 1014 PFS by Independent radiologic review (all patients) All patients 100 80 60 Crizotinib (N=172) Chemo. (N=171) Events, n (%) 100 (58) 137 (80) Median, mo 10.9 7.0 HR (95% CI) 0.45 (0.35 0.60) P a <0.0001 40 20 At risk (ALL) Crizotinib Chemotherapy 0 0 5 10 15 20 25 30 35 Time (months) 172 120 65 38 19 7 1 0 171 105 36 12 2 1 0 0 Salomon B et al, NEJM 2015
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
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 11.3 17.02 8.25 mpfs, mo 10.9 18.40 6.93 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;371:2167-77. Felip E, et al. Ann Oncol. 2014;25 Suppl 4:abstract 1295P.
Activity of alectinib in advanced crizotinib naïve ALK+ NSCLC
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
PHASE 1/2 STUDY OF PF-06463922 (AN ALK/ROS1 TYROSINE KINASE INHIBITOR) IN PATIENTS WITH ADVANCED NSCLC HARBORING SPECIFIC MOLECULAR ALTERATIONS In vivo, PF-06463922 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-06463922 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
Secuencia óptima en enfermedad avanzada, ALK 1ª línea, crizotinib 2ª linea, inhibidor de 2 generación Tratamiento de las metástasis cerebrales, reto
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
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
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 0 8 16 24 32 40 48 56 64 72 80 88 96 104112 120128 136144 152160 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
Nivolumab in SCC (CHECKMATE-017): OS Median OS (mo) Nivolumab: 9.2 Docetaxel: 6.0 HR=0.59 (95% Cl: 0.44-0.79; p=0.00025) 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: http://packageinserts.bms.com/
Preliminary results from the multi-arm phase I study of nivolumab (Checkmate 012)
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.
ORR a in all treated patients At the time of this analysis, 84.4% of patients with a response, PD ORR (95% CI), % 100 90 80 70 60 50 40 30 20 10 0 ORR in total population was 19.4% (95% CI, 16.0-23.2%) 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, 2014. 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.
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.
Overall Survival, % OS by PD-L1 expression, all CTA-evaluable patients a 100 90 80 70 60 50 40 30 20 10 PS Median (95% CI), mo 50% NR (13.7-NR) 1-49% 8.8 (6.8-12.4) <1% 8.8 (5.5-12.0) n at risk PS 50% PS 1-49% PS <1% 0 0 4 8 12 16 20 24 28 Time, months 119 92 56 22 5 4 3 0 161 119 58 15 6 4 0 0 76 55 33 8 0 0 0 0 a Assessed in all patients whose samples were stained within 6 months of cutting. Analysis cut-off date: August 29, 2014.
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) 21 19 42 NSCLC (n = 53) 23 17 45 Non-squamous (n = 42) 21 17 44 Squamous (n = 11) 27 18 46 Herbst RS Nature 15
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
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
Selected anti-pd1 and anti-pdl1 trials Study No. Phase Indication(s) N Comparator Primary Endpoint Status Nivolumab NCT01642004/ CA209-017 NCT02041533/ CA209-026 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 NCT01905657 MK-3475-010 NCT02142738 MK-3475-024 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 NCT02031458 BIRCH II Locally advanced or metastatic NSCLC, PD-L1 positive 635 Single arm study ORR Ongoing MPDL3280A NCT02008227 OAK III Locally advanced or metastatic NSCLC, after progression on platinumbased chemo 1100 Docetaxel OS Ongoing MEDI-4736 NCT02087423 ATLANTIC II Third-line therapy in locally advanced or metastatic NSCLC PD-L1-positiive 282 Single arm ORR Ongoing MEDI-4736 NCT02154490 Lung-MAP NCT02352948 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
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
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?
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
Gracias!! efelip@vhebron.net