Erhaltungstherapie nach Ansprechen auf Erstlinientherapie: Was sind die Empfehlungen?

Transkript

1 Erhaltungstherapie nach Ansprechen auf Erstlinientherapie: Was sind die Empfehlungen?

2 Was erwarten unsere Patienten? Dass wir uns persönlich um sie kümmern und uns Zeit nehmen, die Daten zu erklären. Das Recht, Entscheidungen selbst zu treffen. Oft zu viel von onkologischen Therapien. Wir haben unterschiedliche Ansichten darüber, wie wir unsere Patienten informieren müssen. Brown, JCO 2012; Thiel, Breast Cancer Res Treat 2012; Sarradon, Soc Sci Med 2012; Barrak, Pall Support Care 2012

3 Zulassungen CH Pemetrexed: Monotherapie bei Patienten mit lokal fortgeschrittenem oder metastasiertem NSCLC nach vorangegangener Chemotherapie ausser bei überwiegender plattenepithelialer Histologie. Nach vorgängiger Kostengutsprache durch den Vertrauensarzt. Erlotinib: Zur Behandlung von Patienten mit lokal fortgeschrittenem oder metastasierendem NSCLC, bei denen mindestens eine vorgängige Chemotherapie wirkungslos geblieben ist. Nach vorgängiger Kostengutsprache durch den Vertrauensarzt. Stand: Oktober 2012

4 Erhaltung nach Radiochemotherapie bei Stadium III ist nicht indiziert Kelly JCO 2008

5 Pemetrexed-Erhaltungsstudien: Überblick JMEN PARAMOUNT AVAPERL POINTBREAK Induktion mit 4 Zyklen Platin und: Taxan oder Gemzitabine Pemetrexed Pemetrexed+ Bevacizumab Bevacizumab+ Paclitaxel vs. Pemetrexed Platin Cis / Carbo Cis Cis Carbo Erhaltung im Kontroll-Arm keine keine Pemetrexed Bevacizumab (wie E4599) Erhaltung im exp. Arm Pemetrexed "switchmaintenance" Pemetrexed "continuation maintenance" Pemetrexed+ Bevacizumab Pemetrexed+ Bevacizumab

6 Pemetrexed-Erhaltungsstudien: Publizierte Resultate JMEN Lancet 2009 PARAMOUNT Lancet 2012 AVAPERL ESMO 2011 POINTBREAK IASLC 2012 Lancet 2012 ASCO 2012 PFS *4.3 vs 2.6 *4.1 vs 2.8 *7.4 vs 3.7 *6.0 vs 5.6 OS *13.4 vs 10.6 *13.9 vs 11.0 QOL Gewisse Symptome verzögert (*16.9 vs 14.0 ab Induktion) NR vs vs 12.6 (NS) Primärer Endpunkt hervorgehoben (*P<0.05)

7 Belani, Lancet Oncol 2012 JMEN: Symptomkontrolle

8 PARAMOUNT: Study Design Randomized, placebo-controlled, double-blind phase III study Pemetrexed 500 mg/m 2 ; Cisplatin 75 mg/m 2 Folic acid and vitamin B 12 administered to both arms Induction Therapy 4 cycles, q21d Continuation Maintenance Therapy q21d until PD Previously untreated PS 0/1 Stage IIIB-IV NS-NSCLC Paz-Arez ASCO 2012 Pemetrexed + Cisplatin CR/PR/SD per RECIST R 2:1 Pemetrexed + BSC Placebo + BSC Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD)

9 Survival Probability PARAMOUNT: Final OS from Randomization Pem Placebo OS Median (mo) (95% CI) ( ) ( ) Censoring (%) Survival Rate (%) (95% CI) 1-year 58 (53-63) 45 (38-53) 2-year 32 (27-37) 21 (15-28) Time from Randomization (Months) Patients at Risk Pem + BSC Placebo + BSC

10 PARAMOUNT: Subgroup OS Hazard Ratios Hazard Ratio All Randomized Patients (N=539) Stage IV (n=490) Stage IIIB (n=49) Induction Response CR/PR (n=234) Induction Response SD (n=285) Pre-randomization ECOG PS 1 (n=363) Pre-randomization ECOG PS 0 (n=173) Non-smoker (n=117) Smoker (n=418) Male (n=313) Female (n=226) Age < 70 (n=447) Age 70 (n=92) Age < 65 (n=350) Age 65 (n=189) Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) Treatment Hazard Ratio (95% CI) Favors Pemetrexed Favors Placebo

11 PARAMOUNT: Post-discontinuation Therapy Pemetrexed (N=359) %* Placebo (N=180) %* Patients Receiving Post Discontinuation Therapy Erlotinib Docetaxel Gemcitabine 10 8 Vinorelbine 8 6 Investigational drug 6 4 Carboplatin 5 4 Paclitaxel 3 3 Pemetrexed 2 4 Cisplatin 1 2 *Data expressed as % of randomized patients. Systemic therapies used in 2% of patients in either arm are shown. Only docetaxel usage differed significantly between arms (P=0.013).

12 POINTBREAK: phase III trial of bevacizumab with pemetrexed 4 cycles Previously untreated, stage IIIB or IV, non-squamous NSCLC, treated CNS mets, PS 0 1 (n=939) R 1:1 Bevacizumab 15 mg/kg q3w + carboplatin + pemetrexed Bevacizumab 15 mg/kg q3w + carboplatin + paclitaxel Bevacizumab 15 mg/kg q3w + pemetrexed Bevacizumab 15 mg/kg q3w Treat to PD Treat to PD Primary endpoint OS Secondary endpoints ORR and DCR PFS and TTP safety and QoL Patel, et al. IASLC 2012 (Chicago)

13 OS estimate OS (primary endpoint): ITT population Pem + CP + Bev Pac + CP + Bev HR=1.00 ( ) p= Time (months) Patel, et al. IASLC 2012 (Chicago)

14 PFS estimate PFS: ITT population Pem + CP + Bev Pac + CP + Bev 0.6 HR=0.83 ( ) p= Time (months) Patel, et al. IASLC 2012 (Chicago)

15 OS estimate OS: maintenance population (exploratory) Pem + CP + Bev Pac + CP + Bev Time (months) Patel, et al. IASLC 2012 (Chicago)

16 PFS estimate PFS: maintenance population (exploratory) Pem + CP + Bev Pac + CP + Bev Time (months) Patel, et al. IASLC 2012 (Chicago)

17 POINTBREAK: CTCAEs (version 3) possibly related to a study drug (safety population) Pem + Cb + Bev (n=442) % Grade 3/4 (5) Pac + Cb + Bev (n=443) % Grade 3/4 (5) Anaemia* Thrombocytopenia* Neutropenia* Febrile neutropenia* Fatigue* Haemorrhage GI/pulmonary 1.8 (0.5) 0.5 (0.7) Thromboembolic event Neuropathy/sensory* Other grade 5 events (Pem arm/pac arm %) Includes: CNS ischaemia (0.2/0.7); Cardiac events (0.2/0.7); ARDS (0.5/0); Infection (0.2/0); Other haemorrhage (0.2/0.2) *Significant difference between arms, for grade 3/4 toxicities Patel, et al. IASLC 2012 (Chicago)

18 Laufende Studie ECOG 5508 Previously untreated stage IIIB IV non-squamous NSCLC (n=1282) Induction therapy 4 cycles, q3w Bevacizumab + carboplatin + paclitaxel R 1:1:1 Bevacizumab Pemetrexed Bevacizumab + pemetrexed Primary endpoint OS Secondary endpoints ORR PFS safety PK biomarkers Belani, NCT

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20 Traditionell oder modern? Eine interessante Studie wäre: Induktion Post-Induktion bei Progression NSCLC M1 Nicht-squamöser Subtyp Keine EGFR- oder ALK-Mutation R 6 Zyklen Platin und Pemetrexed CT alle 6 Wochen bis Progression Docetaxel zweite Linie Fit für Chemo- Therapie 4 Zyklen Platin und Pemetrexed Pemetrexed Erhaltung Docetaxel zweite Linie Primärer Endpunkt: Gesamtüberleben (OS) Gautschi, 2012

21 Auch ohne Erhaltungstherapie kann ein Tumor stabil bleiben Zustand vor der Induktion Zustand nach Induktion Nach weiteren sechs Monaten Patientin N.J.: mit Erhaltung Patientin K.M.: ohne Erhaltung

22 Molekulare Diagnostik erreicht neue Dimensionen (Sept. 2012)

23 Gezielte Erhaltung funktioniert: SATURN und INFORM Brugger, JCO 2011; Zhang, Lancet Oncol 2012

24 Gezielte Erhaltung für alle: Therapiekonzept der Zukunft? Evaluation Randomisation Induktion Erhaltung Adenokarzinom der Lunge M1 4 Zyklen Platin und Pemetrexed Pemetrexed bis zur Progression Keine EGFR- oder ALK-Mutation Material für weitere Genom- Analysen R Konventioneller Arm Experimenteller Arm 4 Zyklen Platin und Pemetrexed Gezielte Erhaltung gemäss Tumorgenom Primärer Endpunkt: progressionsfreies Überleben (PFS) ab Beginn Erhaltung Gezielte Erhaltungstherapie mit individueller Auswahl aus 4-6 molekular-gezielten Therapien, die gemäss persönlichem Tumor-Analyseresultat zum Einsatz kommen. Patienten im Kontroll-Arm erhalten die gezielte Therapie bei Progression (cross-over). Gautschi, 2012

25 Zusammenfassung Zulassungen = Möglichkeiten Richtlinien. Pemetrexed ist eine Option bei gutem Allgemeinzustand und kontrolliertem Tumor nach vier Zyklen Platin. Bei aktivierender EGFR-Mutation Umstellung auf Erlotinib oder Gefitinib. Patienten ohne Therapie engmaschig kontrollieren, um rechtzeitig mit einer neuen Therapie beginnen zu können.

26 Is there a role for targeted agents in stage I-III NSCLC? oliver.gautschi@onkologie.ch

27 Current status Targeted agents are promising for selected patients with resectable NSCLC stage I-III. If possible, patients should be enrolled in clinical trials.

28 What we want Use cancer-specific drugs that are highly active, well tolerated, and have no negative impact on surgery, radiation and chemotherapy, enhance cure rate (eradicate cancer), or at least delay tumor recurrence (control cancer).

29 What we do not want Add drugs which preclude curative standard therapy, increase (long-term) toxicity, produce secondary (lung) cancers, lead to early drug resistance.

30 The Problem: Prognosis 5-Year Survival Rates and Numbers of Cases Courtesy ETOP of Solange 4 th annual meeting Peters Amsterdam, November 11, 2011

31 The Promise: Mutations Clinical testing March 2011-June 2012 (N=105) HER2 Ampl 8.3% HER2 Mut+Ampl 1.7% BRAF 1.5% ALK 5.0% EGFR 13.0% No Aberration 29.5% KRAS 41.0% Courtesy ETOP of Joachim 4 th annual meeting Diebold Amsterdam, November 11, 2011

32 Mutations: Do they affect prognosis and adjuvant chemotherapy? Never smoked: 47% 5% 8% Marks, JTO 2008 Tsao, JTO 2011 (NCIC BR10)

33 Phase III adjuvant gefitinib (Japan) Concern about ILD in advanced NSCLC: early closure 1 ILD 2 ILDs Tsuboi, Anti-Cancer Drugs 2005

34 S0023: Maintainance gefitinib or placebo after CRT in stage III Kelly JCO 2008

35 Percentage Percentage Courtesy of G. Goss BR19: OS by EGFR Mutation Status Wild type and Treatment Placebo Gefitinib Sensitizing mutation Placebo Gefitinib # at Risk Placebo Gefitinib Time (Years) # at Risk Placebo Gefitinib Time (Years) HR (95% C.I.) Gefitinib/Placebo: 1.21 (0.84, 1.73) Log Rank: p=0.301 Median (95% C.I.) -Placebo: Not reached (5.1, inf.) -Gefitinib: 5.0 (4.3, inf.) HR (95% C.I.) Gefitinib/Placebo: 1.58 (0.83, 3.00) Log Rank: p=0.160 Median (95% C.I.) - Placebo: 5.1 (4.4, inf.) - Gefitinib: 3.7 (2.6, inf.)

36 Janjigian, JTO 2011 MSKCC-Cohort

37 MSKCC: recurrences 22/65 evaluable 15 on TKI, 7 after TKI 14 retreated with TKI ORR=73% Oxnard, Clin Cancer Res 2011

38 SELECT: Study Design Single arm Phase II study Adjuvant erlotinib following surgery and standard therapy Stage IA-IIIA NSCLC Surgically resected EGFR mutation positive Completed routine adjuvant chemotherapy and/or XRT Courtesy of L. Sequist CT surveillance: - Every 6 mo x 3 years - Annually years 4 and 5 Erlotinib 150 mg PO daily 2 years duration Observation Primary Endpoint: Disease Free Survival: Goal: 2-year >86% Secondary Endpoints: Safety and Tolerability Overall Survival

39 Survival Probability SELECT: Disease Free Survival Censored observation 94% 2-Year DFS Time from initiating adjuvant erlotinib (Years) Median follow-up time: 2.7 years Patients at Risk Courtesy of L. Sequist

40 SELECT: Treatments After Progression Initial stage Adjuvant duration (mo) Disease free interval (mo) Site(s) of progression Initial mutation Repeat biopsy Subsequent therapy PR = partial response CR = complete response PD = progressive disease NMD = no measurable disease Courtesy of L. Sequist Response to erlotinib Survival Post- Progression (mo) IB Lung nodules Ex 19 Ex19 Erlotinib Yes - PR 12+ IIB 24 3 Multiple brain, L858R - Erlotinib Yes 26+ lung nodules IB Multiple brain + L858R - Erlotinib Yes - PR 4+ bone IIIA Solitary lung Ex 19 Ex19 Lung resection - 6+ IIIA Solitary bone Ex 19 Ex19 Bone XRT -> NMD 7+ Erlotinib IIA Solitary brain L858R L858R+ Brain resection - 7+ T790M -> XRT IB 24 6 Solitary lung L858R L858R+ Lung resection PIK3CA+ b-cat IIB Lung nodules Ex 19 - Erlotinib Yes 13 (Died) IB 24 7 Solitary CNS L858R L858R Brain resection NMD 5+ -> Erlotinib IB brain + Hilar L858R L858R Brain XRT -> Yes CR 4+ node erlotinib IIIA Lung, liver, L861Q L861Q Bone XRT -> Yes 7+ adrenal, bone Erlotinib IIB 16 0 Lung, brain Ex 19 - Brain XRT - 2 (Died)

41 RADIANT Erlotinib 150mg p.o. once daily for 2 years Stage IB-IIIA EGFR +ve Complete resection No radiotherapy 4 cycles of standard platinum-based chemotherapy (optional) R Stratified by: country; adjuvant CT; histology; stage; smoking status; EGFR status Placebo Primary endpoint = disease-free survival (all patients, IHC+ve and/or FISH+ve) Status: Closed planned n=945 / actual accrual n=1252

42 CTONG1104: A national, multi center, randomized, open-label, phase III trial of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment in pathological stage II-IIIA(N1-N2) NSCLC with EGFR activating mutation (ADJUVANT) EGFR M+ Post-surgical Stage II and Stage III A NSCLC NCT FPI: Sep.15, 2011 Adjuvant gefitinib 1:1 randomisation Adjuvant Platinum based doublet chemotherapy Primary: Disease Free Survival Secondary: OS DDFS Safety QoL Sample size was estimated to be 220 when HR of DFS, the primary endpoint, was estimated to be 0.6, the enrollment period was to be 2 years, the period of follow-up after the final enrollment was to be 5 years, statistically significant level (α) was to be 0.05, and the statistical power was to be 80%. The estimated total events is 122 from 208 analysed patients Courtesy of T. Wu

43 Window of opportunity trials Short course -> rapid results Preoperative -> tissue Confined sample size -> budget Suitable to confirm predictive markers. Not suitable to define standard-of-care.

44 Preoperative gefitinib (Toronto) Lara-Guerra JCO 2009

45 Case presentation: induction therapy for stage IIIB with EGFR L858R Baseline After 3 months of EGFR-TKI After surgery and chemoradiation O. Gautschi

46 EGFR IHC on resected tumor L858R L858R +EGFR ampl Courtesy of J. Diebold

47 Intratumor heterogeneity and change over time Bai, JCO 2012

48 Perspectives Genomic characterization is feasible, let us focus on cancer-specific targets. Adjuvant TKI-therapy is promising, but promises must be fulfilled. New trial designs are important, but they are no substitute for phase III trials.

49 2013 NSCLC STUDIEN AM LUKS 49

50 NSCLC IV: SAKK19/09 Phase II N= (extended cohort EGFRwt) 1EP=PFS6m Translational research: Biomarkers for drug resistance

51 ETOP 2-11 BELIEF Rosell, Stahel Phase II N=102 1EP=PFS Translational research: EGFR T790M and gene expression

52 RANDOMIZATION 1:1 R E G I S T R A T I O N ETOP 3-12 EMPHASIS Smit, Peters, Stahel stage IIIB (non amenable to radical radiotherapy) or stage IV squamous NSCLC VeriStrat Analysis Stratum I VeriStrat Good Stratum II VeriStrat Poor Regimen A Erlotinib in standard dose. Until progression (clinical or radiological) or unacceptable toxicity Regimen B Docetaxel in standard dose. Until progression (clinical or radiological) or unacceptable toxicity Stratification Factor Performance Status VeriStrat Status Phase III N=500 1EP=PFS Predictive and prognostic value for VeriStrat

53 PROFILE 1014 Phase III Trial of Crizotinib Firstline PROFILE 1014 Key entry criteria Positive for ALK by central laboratory no prior chemotherapy for advanced disease R A N D O M I Z E N=334 Crizotinib (n=167) administered on a continuous dosing schedule Pemetrexed and cisplatin or carboplatin (n=167) infused on day 1 of a 21-day cycle