Hacia una mayor individualización clínica en el CPNM. J.M. Sánchez Torres H.U. Princesa, Madrid

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1 Hacia una mayor individualización clínica en el CPNM J.M. Sánchez Torres H.U. Princesa, Madrid

2 Lung cancer histologic subtypes NSCLC (80-85%) SCLC (15-20%) Squamous carcinoma (25 30%) Non-squamous carcinoma (70 75%) Adenocarcinoma (75 90%)

3 CPNM: Tratamiento individualizado Características clínicas: - Edad - PS - Comorbilidades Características histológicas: - CPNM no escamoso: Pemetrexed, Bevacizumab, Nintedanib - CPNM escamoso: Necitumumab Carácterísticas moleculares: - Mutación EGFR: EGFR-TKI (Gefitinib, Erlotinib, Afatinib) - Translocación ALK y ROS1: ALK-TKI (Crizotinib, Alectinib) - Mutación BRAF : Dabrafenib plus Trametinib

4 COG 1594: Comparison Doublet regimens in 1 st of 4 First-Line -Line Advanced oublet Regimens in Advanced NSCLC NSCLC: Overall ECOG1594 Survival Platinum-based chemotherapy improves survival, symptom control and QoL r JH, et al. N Engl J Med. 2002;346(2): Schiller J, N Engl J Med 2002

5 NSCLC Management: Specific Gene Profiles Chemotherapy: efficacy / toxicity Patient characteristics Tumor characteristics Predictive Markers Histology Mutations SNPs Genomic DNA Gene expression - RNA expression - Methylation - Protein expression

6 Tratamiento de 1ª línea en no escamosos sin marcador predictivo conocido NSCLC avanzado 80% No mutados (WILD TYPE) No escamosos Escamosos Cisplatino + pemetrexed Doblete de platino + bevacizumab

7 Histology: Pemetrexed/cisplatin vs. Gem/cisplatin: Overall survival P < (noninferiority p-value) P = (superiority p-value) Scagliotti GV, et al. J Clin Oncol. 2008

8 Overall survival E4599: Phase III Paclitaxel-Carboplatin + Bevacizumab for Non-SqCC: OS & PFS 1.0 OS: 12.3 m vs m, HR = 0.79 ( ), p=0.003 PFS: 6.2 m vs. 4.5 m, HR = 0.66 ( ), p<0.001 OS CP Bevacizumab + CP Time (months) Adenocarcinoma Hystology CP + Bv CP Hazard ratio Overall Survival 14.2 months 10.3 months 0.69 ( ) Progression-free survival 6.6 months 5.0 months 0.65 ( ) Sandler et al. N Engl J Med 2006 Sandler et al J Thor Oncol 2008 abst 133

9 Meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line therapy in NSCLC OS PFS Soria J.C. et al. Ann Oncol 2013

10 Progression-free survival (%) Nintedanib: LUME Lung 1 Stage IIIB/IV or recurrent NSCLC patients (all histologies) 2 nd -line Setting Primary endpoint: PFS Randomization (n=1314) Nintedanib 200mg BID PO, D docetaxel 75 mg/m 2 IV, D1 21-day cycles (n=655) Placebo 200mg BID PO, D docetaxel 75 mg/m 2 IV, D1 21-day cycles (n=659) Median 3.4 months Median 2.7 months Hazard Ratio 0.79 (95% CI ) P= Time (months)

11 Overall survival (%) Nintedanib: LUME Lung 1: Overall Survival OS en Adenocarcinoma y progresión <9 meses desde inicio QT 1ªL Median 10.9 months Hazard Ratio 0.75 (95% CI ) P= Median 7.9 months Time (months)

12 REVEL: Study Design 1:1 - Stage IV NSCLC after one platinum- based chemo +/- maintenance - Prior Bev allowed - All histologies - PS 0 or pts R A N D O M I Z E Ramucirumab 10 mg/kg + Docetaxel 75 mg/m 2 q3wks N=628 Placebo + Docetaxel 75 mg/m 2 q3wks N=625 Treatment until disease progression or unacceptable toxicity Stratification factors: ECOG PS 0 vs 1 Gender Prior maintenance East-Asia vs. ROW Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety, patient-reported outcomes Abbreviations: Bev=bevacizumab; ECOG PS=Eastern Cooperative Oncology Group performance status; ORR=objective response rate; PFS=progression-free survival; ROW=rest of the world; q3wks=every 3 weeks. Garon EB, et al. Lancet 2014

13 REVEL trial: Progression-Free Survival ORR: 22.9% vs 13.6% p<0.001 Garon EB, et al. Lancet 2014

14 REVEL trial: Overall Survival Garon EB, et al. Lancet 2014

15 Tratamiento de 1ª línea en epidermoides sin marcador predictivo conocido NSCLC avanzado 80% No mutados (WILD TYPE) No escamosos Escamosos Cisplatino + pemetrexed Doblete de platino + bevacizumab Doblete de platino

16 Squire trial: Study design 1253 pts Randomization (R) stratified by: ECOG PS (0-1 vs. 2) and geographic region (North America, Europe and Australia; vs. South America, South Africa and India; vs. Eastern Asia) Patient selection not based on EGFR protein expression Radiographic tumor assessment (investigator read): at baseline and every 6 weeks until PD Mandatory tissue collection Primary endpoint: Overall Survival Thatcher N, et al. Lancet Oncol 2015

17 SQUIRE trial: OS and PFS OS: HR 0.84, p=0.01 PFS: HR 0.85, p=0.02 Thatcher N, et al. Lancet Oncol 2015

18 Driver mutations in lung cancer: from one-fits-all to personalized treatment

19 Selected targeted-therapy predicts outcome in advanced NSCLC (LCMC) Kris MG, et al. JAMA 2014

20 Personalized treatment: Challenges Limited biopsy tissue available to conduct genome analyses: Low tumor content by FNB Biopsy tumor specimens are usually formalin-fixed and paraffin-embedded (FFPE), leading to fragmentation of the DNA and to introduction of fixation-related artifacts: False-positive mutation when PCR amplification is involved The structural differences of the relevant genome alterations pose enormous technological challenges to their detection Distinguishing rare (mostly irrelevant) germline variants from true somatic mutations is difficult: functionally irrelevant passenger mutations that are found at high numbers in carcinogen-induced tumors from those driver mutations that are oncogenic, clinically relevant and targetable To enable a general access of the public to such comprehensive genomic testing, such tests need to be affordable Heuckmann & Thomas. Ann Oncol 2015

21 EGFR: 10-15% CPNM Terapias dirigidas a EGFR Inihibidores reversibles EGFR (1ª generación) Gefitinib Erlotinib Inhibidores irreversibles de la familia ErbB (2ª generación) Afatinib Dacomitinib Inhibidores de T790M (3ª generación) AZD9291 (Osimertinib) Rociletinib BI694

22 Randomized Phase III of EGFR-TKI in EGFRm NSCLC

23 Estimated OS probability Estimated OS probability LUX-Lung 3: Overall Survival in Mutation Subgroups Del19 L858R Afatinib Cis/Pem 0.8 Afatinib Cis/Pem Time of overall survival (months) No. at risk: Afatinib Cis/Pem Time of overall survival (months) No. at risk: Afatinib Cis/Pem Del19 L858R Afatinib (n=112) Cis/Pem (n=57) Afatinib (n=91) Cis/Pem (n=47) Median, mo HR (95% CI) P-value a HR=1.02 ( ), when adjusted for baseline imbalances ( ) P= a ( ) P= Yang et al. Lancet Oncol. 2015; 16:141-51

24 Phase IIb trial of Afatinib vs Gefitinib for the treatment of 1st-line EGFR mutation + adenocarcinoma LUX-Lung 7 - Study Design Stage IIIb/IV adenocarcinoma of the lung EGFR mutation (Del19 and/or L858R) in the tumour tissue # No prior treatment for advanced/metastatic disease ECOG PS 0-1 Randomisation 1:1 Stratified by mutation type (Del19 vs L858R) and presence of brain metastases (yes vs no) Afatinib 40 mg once daily Gefitinib 250 mg once daily Primary endpoints: PFS (independent review) #, TTF, OS Secondary endpoints: ORR, time to and duration of response, duration of disease control, tumour shrinkage, HRQoL, safety # local or central test # Tumor assessment performed at week 4, 8, every 8 weeks until w64 and every 12 weeks thereafter Treatment beyond progression allowed if deemed beneficial by investigator. Park et al. Ann Oncol. 2015;26: (suppl 9; abstract LBA2)

25 Estimated PFS probability Phase IIb trial of Afatinib vs Gefitinib for the treatment of 1st-line EGFRm adenocarcinoma LUX-Lung 7: PFS ORR: 70% vs 56%, p= DoR: 10.1 m vs 8.4 m DCR: 91% vs 87.4% Afatinib Gefitinib Median, mo HR (95% CI) P-value 0.73 ( ) Afatinib Gefitinib %* 18% % Time of progression free survival (months) No. at risk: Afatinib Gefitinib % * P= P= Park et al. Ann Oncol. 2015;26: (suppl 9; abstract LBA2)

26 Adquired resistance to EGFR-TKIs REVIEWS a Bypass tracks ~20% b EMT ~1 2% HER2 amplif cation ~8 13% BRAF ~1% MET amplif cation ~5% PIK3CA ~1 2% SCLC alone ~6% SCLC with PI3K ~4% No identif cation AR mechanism ~15 20% T790M alone ~40 55% T790M with EGFR amplif cation ~10% Other EGFR point mutations 1 2% No identif cation AR mechanism ~25% ALK mutations ~22 33% KIT amplif cation ~10% EGFR target alteration ~60% thera acqui bypas is ne studi the o MET Pat resist inclu tion o gence as an the or ALK tinib. R. Camidge, W. Pao and L.V. L1196M Sequist, Nat Rev Clin Oncol 2014 G1202R

27 T790M inhibitors in EGFRm patients after PD with an EGFR-TKI Rociletinib (Sequist, NEJM 2015) 130 p enrolled In T790M+, 59% RR In T790M-, 29% RR AZD9291 (Osimertinib) (Jänne NEJM 2015) 253 p enrolled In T790M+, 61% RR In T790M-, 21% RR BI694 (Park ASCO 2015) 63 p evaluable In T790M+, 55%

28 ALK rearrangements in NSCLC are associated with adenocarcinoma histology and signet ring cells ALK rearranged/translocated NSCLC clinical features - male/female rate of approximately 50% (male predominance when compared to EGFR mutated NSCLC); - higher frequency in never (<100 cigarettes/life) or light smokers (<15 pack-years); - patients tend to have younger age (~50 years) at diagnosis than EGFR mutated NSCLC (>65 years) Shaw, A. T. et al. J Clin Oncol; 27:

29 Phase III study: First-line crizotinib versus pemetrexed-cisplatin (or carboplatin) in patients with advanced ALK-positive non-squamous NSCLC (PROFILE 1014) ORR 74% vs. 45%; p< DoR 49 w vs w Solomon BJ, et al. NEJM 2014

30 Efficacy and safety of the ALK inhibitor alectinib in ALK+ NSCLC patients who have failed prior crizotinib: An open-label, single-arm, global phase 2 study (NP28673) Study objective To investigate the efficacy and safety of alectinib, a highly selective, CNS-active ALK inhibitor, in ALK+ NSCLC patients who have progressed on crizotinib Locally advanced or metastatic ALK+ NSCLC No response or progression on prior crizotinib Age 18 years ECOG PS 0 2 (n=138) Alectinib 600 mg bid PD Primary endpoint: ORR (assessed by IRC) RR: 50.0% DCR: 78.7% PFS: 8.9 m Patients with CNS metastases: % ORR in patients with measurable CNS metastases % CR (43.5% in untreated CNS mets) Secondary endpoints CNS ORR by IRC, DCR, DOR, PFS, safety Ou et al. J Clin Oncol 2015; 33 (suppl): abstr 8008, ASCO 2015

31 Crizotinib in ROS1 rearranged NSCLC PFS Complete Response Partial Response Stable Disease 3 (6%) 33 (66%) 9 (18%) Response Rate (CR+PR) 72% (95% CI, 58%-84%) DCR (CR+PR+SD) 90% Median DoR (months) Median PFS (months) Median OS (months) 17.6 (95% CI,14.5-NR) 19.2 (95% CI, 14.4-not reached) NR 12 months OS 85% (72-93) Shaw AT, et al. NEJM 2014

32 Dabrafenib and Trametinib Dabrafenib: ATP-competitive inhibitor that selectively inhibits BRAF V600E kinase activity Trametinib: Specifically binds to and inhibits MEK 1 and 2 Θ Θ Both have demonstrated antitumor efficacy in melanoma patients The combination of BRAF and MEK inhibition delay the resistance in preclinical models

33 BRAF V600E-mutant NSCLC Partial Response Stable Disease Progressive Disease NE Dabrafenib monotherapy 25 (32%) 19 (24%) 23 (29%) 11 (14%) Response Rate (CR+PR) 32% (95% CI, 21.9%-43.6%) DCR (CR+PR+SD) 56% (95% CI, 44.7%-67.6%) Median DoR (months) 11.8 (95% CI, 5.4-NR) Partial Response Stable Disease Progressive Disease NE Dabrafenib plus Trametinib 15 (63%) 6 (25%) 2 (8%) 1 (4%) Response Rate (CR+PR) 63% (95% CI, 40.6%-81.2%) DCR (CR+PR+SD) 88% (95% CI, ) Median DoR (months) Not Reached Planchard D. et al. ASCO 2015

34 NSCLC subtyping SqCC: FGFR Educational Book, ASCO 2014

35 OS (%) Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous cell NSCLC Key results Nivolumab was associated with a 27% reduction in risk of death OS Number of Patients at Risk Nivolumab Docetaxel 1-year OS rate=39% 1-year OS rate=51% Nivolumab (n=292) Nivolumab Docetaxel (n=290) mos, months HR 0.73 (96%CI 0.59, 0.89); p= Docetaxel Time (months) Symbols represent censored observations Paz-Ares et al. J Clin Oncol 2015; 33 (suppl): abstr LBA109, ASCO 2015

36 Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous cell NSCLC PD-L1 expressors benefitted more from nivolumab than PD-L1 non-expressors PD-L1 expression level OS Nivolumab (n) Docetaxel (n) Unstratisfied HR (95% CI) 1% (0.43, 0.82) <1% (0.66, 1.24) 5% (0.30, 0.63) <5% (0.77, 1.34) 10% (0.26, 0.59) <10% (0.76, 1.31) Not quantifiable at baseline (0.61, 1.35) PFS 1% (0.53, 0.94) <1% (0.88, 1.61) 5% (0.39, 0.76) <5% (1.01, 1.71) 10% (0.37, 0.75) <10% (0.96, 1.61) Not quantifiable at baseline (0.73, 1.56) Interaction p-value* < PD-L1 expressors PD-L1 non-expressors PD-L1 not quantifiable *Interaction p-value from Cox proportional hazard model with treatment, PD-L1 expression and treatment by PD-L1 expression interaction Conclusion Nivolumab Nivolumab improved survival vs. docetaxel in previously treated patients with advanced non-squamous NSCLC with efficacy being correlated with PD-L1 expression Docetaxel Paz-Ares et al. J Clin Oncol 2015; 33 (suppl): abstr LBA109, ASCO 2015

37 OS (%) A phase III study (CheckMate 017) of nivolumab vs docetaxel in previously treated advanced or metastatic squamous cell NSCLC Key results Nivolumab was associated with a 41% reduction in risk of death OS Number of patients at risk Nivolumab Docetaxel 1-year OS rate=24% 1-year OS rate=42% Nivolumab Docetaxel Time (months) Symbols represent censored observations mos, months (95%CI) Nivolumab (n=135) 9.2 (7.3, 13.3) Docetaxel (n=137) 6.0 (5.1, 7.3) No. of events HR 0.59 (95%CI 0.44, 0.79); p= Spigel et al. J Clin Oncol 2015; 33 (suppl): abstr 8009, ASCO2015

38 A phase III study (CheckMate 017) of nivolumab vs docetaxel in previously treated advanced or metastatic squamous cell NSCLC Key results Survival benefit with nivolumab was independent of PD-L1 expression PD-L1 Expression OS Nivolumab Patiients n Docetaxel Unstratisfied HR (95%CI) 1% (0.45, 1.05) <1% (0.37, 0.92) 5% (0.31, 0.89) <5% (0.47, 1.02) 10% (0.28, 0.89) <10% (0.48, 1.01) Not quantifiable (0.19, 0.82) PFS 1% (0.44, 1.01) <1% (0.43, 1.00) 5% (0.32, 0.90) <5% (0.52, 1.08) 10% (0.33, 1.02) <10% (0.49, 0.99) Not quantifiable (0.23, 0.89) Interaction p-value* Conclusion Nivolumab was superior to docetaxel in OS, PFS and ORR in patients with advanced or metastatic squamous NSCLC, regardless of tumour PD-L1 levels Nivolumab PD-L1 expressors PD-L1 non-expressors Not quantifiable Docetaxel Spigel et al. J Clin Oncol 2015; 33 (suppl): abstr 8009, ASCO2015

39 Conclusions Lung cancer: Several different diseases! No oncogenic driver: Treatment selection according to characteristics of the patients and histology Oncogenic driver: Individualized therapy based on predictive biomarkers increase time to progression, survival and QoL in lung cancer patients Patient selection may be critical: Molecular biomarkers are the strongest predictive marker of efficacy for antitarget agents TKIs against EGFR, ALK, ROS1 and BRAF are the first option of treatment in patients with activating alterations Objective: To treat the patient not the disease