Nyt om lungekræft. Jon Lykkegaard Andersen Onkologisk Afdeling, Herlev Hospital

Transkript

1 Nyt om lungekræft Jon Lykkegaard Andersen Onkologisk Afdeling, Herlev Hospital

2 Lidt basalt om kræft. Agenda Lungekræft 2012 state of the art. Mest hot lige nu med langt navn: Vedligeholdelsesbehandling. Skånsom forebyggende strålebehandling af hjernen ved småcellet lungecancer

3 Vævsbalance Celledeling Selvmord If mitosis proceeded without cell death, an 80-year-old person would have 2000 kg of lymphoid tissue and 16 km of intestines. (Melino, Nature 412:23, 2001)

4 Konstant balance mellem dannelse af nye celler og fjernelse af gamle Celledeling Selvmord Lånt af Onkel Anders, sponsor tale hos MSD

5 Transformeret celle begår selvmord Celledeling Selvmord Lånt af Onkel Anders, sponsor tale hos MSD

6 Ny mutation hæmmer selvmord Celledeling Selvmord Lånt af Onkel Anders, sponsor tale hos MSD

7 Starten på en kræftudvikling Celledeling Selvmord Lånt af Onkel Anders, sponsor tale hos MSD

8 Det starter med en smutter

9 Somatic mutation prevalence by cancer type. Cancer type Mb of DNA Number of Mutations per samples ALL Breast Colorectal Gastric Glioma Lung Carcinoma Ovarian Renal Testis Melanoma Number of mutations Adapted from: Patterns of somatic mutaion in human cancer genomes Nature 446, (March 2007) Greenman et al

10 Typer af lungecancer Ikke småcellet NSCLC ca % Adenocarcinom, planocellulært, storcellet Småcellet ca %

11 Indtil 2000erne One size fits all

12 Potential Druggable Molecular Targets? AKT1 NRAS MEK1 MET AMP HER2 PIK3CA 2% BRAF 2% Double Mutants 3% Lung Cancer Molecular Consortium Lung Adenocarcinomas No Mutation Detected EML4-ALK 7% EGFR 17% KRAS 22% Mutations found in 54% (280/516) Emerging Druggable Targets in NSCLC-Squamous Subtype Gene Event Type Frequency, % FGFR1 Amplification FGFR2 Mutation 5 PIK3CA Mutation 9 PTEN Mutation deletion 18 CCND1 Amplification 8 CDKN2A Deletion/mutation 45 PDGFRA Amplification mutation EGFR Amplification 10 MCL1 Amplification 10 BRAF Mutation 3 DDR2 Mutation 4 ERBB2 Amplification 2 9 Kris MG, et al. ASCO CRA7506. Johnson BE, et al. IASLC WCLC Abstract O16.01 Hammerman P, et al. IASLC WCLC Abstract PRS.1

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14 Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012 Advanced-Stage NSCLC & PS 0-1 EGFR mutation positive ELM4-ALK positive EFGR mutation and ALK negative and nonsquamous histology EFGR mutation and ALK negative and squamous histology Molecular Histology: Clinical Bevacizumab appropriate Bevacizumab inappropriate Erlotinib or gefitinib first line Consider crizotinib first or second line Consider carboplatin/paclitaxel + bevacizumab or cisplatin/pemetrexed ± bevacizumab Consider cisplatin or carboplatin combined with pemetrexed, docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine ± cetuximab Consider cisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbi ne ± cetuximab Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:

15 Lung Cancer Patient in the near future Lung nodule/metastases Tumor Biopsy/ blood MOLECULAR PORTRAIT Diagnostic Prognosis Chemotherapy Targeted therapy New target sensitivity sensitivity PI3K ERCC1 FGFR1 RRM1 LKB1 Pathways Others Cancer? Yes/No Need for treatment? Which treatment and when?

16 Vedligeholdelsesbehandling Terminologi: A Rose by Any Other Name? Platin baseret dublet kemoterapi 4 behandlinger f.eks, cis/carboplatin + agent A Samme kemo A indtil PD eller bivirkninger Continuation maintenance Fortsat behandling Forskellig kemo C indtil PD eller bivirkninger Switch maintenance Skift af behandling

17 Summary of Switch Maintenance Trials Agent/Control Arm N PFS Salvage Treatment, % OS Fidias [1] Docetaxel Delayed docetaxel mos HR: mos P = HR: P =.085 Ciuleanu [2] Pemetrexed Placebo mos HR: mos P < HR: P =.012 Cappuzzo [3] Erlotinib Placebo wks HR: wks P < HR: P =.0088 Miller [4] Erlotinib + bevacizumab Placebo + bevacizumab mos HR: mos P = HR: P =.2686 Perol [5] Erlotinib Observation mos HR: mos P = NA HR:.91 NA Zhang [6] Gefitinib Placebo mos HR: mos P < HR: P = Fidias P, et al. J Clin Oncol. 2010;28: Ciuleanu T, et al. Lancet. 2009;374: Cappuzzo F, et al. Lancet Oncol. 2010;11: Miller VA, et al. ASCO Abstract LBA Perol M, et al. ASCO Abstract Zhang L, et al. ASCO Abstract LBA7511.

18 Continuation Maintenance Trials Study Yr Induction Therapy Maintenance Therapy Median PFS, Mos Median OS, Mos Main Grade 3/4 Toxicities Brodowicz [1] 2006 Gemcitabine 1250 mg/m 2 on Days 1, 8 + cisplatin 80 mg/m 2 on Day 1 x 4 Gemcitabine 1250 mg/m 2 on Days 1,8 BSC (P <.001) Maintenance Gem: ANC 14.9%, Plts 1.7%; blood transfusion: 20% gemcitabine vs 6.3% BSC Belani [2] 2010 Gemcitabine 1000 mg/m 2 on Days 1, 8 + carboplatin AUC 5 on Day 1 x 4 Gemcitabine 1000 mg/m 2 on Days 1,8 BSC (P =.575) (P =.838) ANC: 15% chemo, 2% BSC; Plts: 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC Perol [3] 2010 Gemcitabine 1250 mg/m 2 on Days 1, 8 + cisplatin 80 mg/m 2 on Day 1 x 4 Gemcitabine 1000 mg/m 2 on Days 1,8 BSC (P <.0001) NR NR At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6% Paz Ares [4] 2011 Pemetrexed 500 mg/m 2 on Day 1 + cisplatin 75 mg/m 2 on Days 1 x 4 Pemetrexed 500 mg/m 2 on Day 1 BSC (P =.00006) Fatigue: 4.2% pem, 0.6% BSC; Anemia: 4.5%, 0.6% BSC; ANC: 3.6% pem, 0 BSC 1. Brodowicz T, et al. Lung Cancer. 2006;52: Belani CP, et al. ASCO Abstract Perol M, et al. ASCO Abstract Paz-Ares LG, et al. ASCO Abstract CRA7510.

19 PARAMOUNT: Pemetrexed Maintenance in Advanced Nonsquamous NSCLC Randomized, blinded, placebo-controlled phase III trial Final survival analysis Stratified by PS 0 vs 1, stage IIIB vs IV, response to induction (CR/PR vs SD) Previously untreated patients with stage IIIB/IV nonsquamous NSCLC (N = 939) Induction 4 cycles Pemetrexed 500 mg/m 2 + Cisplatin 75 mg/m 2 on Day 1 of 21-d cycles CR/PR/SD Maintenance until progression Pemetrexed 500 mg/m 2 on Day 1 of 21-day cycle + BSC (n = 359) Placebo on Day 1 of 21-day cycle + BSC (n = 180) Paz-Ares L, et al. ASCO Abstract LBA7507.

20 PARAMOUNT: Survival Pemetrexed maintenance significantly improved survival over placebo Benefit seen in all analyzed subgroups, including disease stage, induction response, ECOG PS, age, histology Proportion of Patients With OS OS median, mos (95% CI) Censoring, % Survival rate, % (95% CI) 1 yrs 2 yrs Pemetrexed 13.9 ( ) (53-63) 32 (27-37) Patients at Risk, n Mos From Randomization Pem + BSC Placebo + BSC Placebo 11.0 ( ) (38-53) 21 (15-28) Proportion of Patients With PFS Patients at Risk, n Pem BSC Placebo BSC PFS: Primary Efficacy Endpoint Pemetrexed Placebo Unadjusted HR: 0.62 (95% CI: ) Mos Paz-Ares L, et al. ASCO Abstract LBA7507.

21 PARAMOUNT: Bivirkninger Pemetrexed vedligeholdelses behandling ens bivirkninger ift. hvad set tidligere. Behandlingsophør grundet bivirkninger 18% med pemetrexed vs 7% med placebo Grad 3/4 incidence signifikant højere med pemetrexed vs placebo: træthed, blodmangel, fald i hvide blodlegemer Event, % Pemetrexed + BSC (n = 359) Placebo + BSC (n = 180) Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Fatigue Anemia Neutropenia Paz-Ares L, et al. ASCO Abstract LBA7507.

22 Profylaktisk Cerebral bestråling (Irradiation) PCI Forebyggende strålebehandling mod hjernen 10 behandlinger nedsætter risikoen for hjernemetastaser ca. 50 %. Særligt til patienter med SCLC Som har gavn af behandlingen. Bivirkninger Hårtab Nedsat cerebralt funktionsniveau, særlig korttidshukommelse

23 PCI ved SCLC udvidet sygdom

24 Hippocampus Center for konsolidering af information Stor betydning for hukommelsesfunktionen Vigtig ved depression og Alzheimer

25 Moderne strålebehandling

26 PCI hippocampus besparende strålebehandling