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

Nyt om lungekræft Jon Lykkegaard Andersen Onkologisk Afdeling, Herlev Hospital

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

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)

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

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

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

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

Det starter med en smutter

Somatic mutation prevalence by cancer type. Cancer type Mb of DNA Number of Mutations per samples ALL 0.57 8 2 Breast 2.70 16 56 Colorectal 1.21 28 44 Gastric 2.1 18 49 Glioma 22.37 9 69 Lung Carcinoma 4.21 20 109 Ovarian 1.85 25 60 Renal 0.74 23 22 Testis 0.12 13 2 Melanoma 18.54 6 144 Number of mutations Adapted from: Patterns of somatic mutaion in human cancer genomes Nature 446, 153-158 (March 2007) Greenman et al

Typer af lungecancer Ikke småcellet NSCLC ca. 80-85 % Adenocarcinom, planocellulært, storcellet Småcellet ca. 15-20%

Indtil 2000erne One size fits all

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 20-25 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 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01 Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

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;10:392-394.

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?

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

Summary of Switch Maintenance Trials Agent/Control Arm N PFS Salvage Treatment, % OS Fidias [1] Docetaxel Delayed docetaxel 309 5.7 mos HR: 0.63 2.7 mos P =.001 63 12.3 HR: 0.80 9.7 P =.085 Ciuleanu [2] Pemetrexed Placebo 663 4.0 mos HR: 0.50 2.6 mos P <.0001 67 13.4 HR: 0.79 10.6 P =.012 Cappuzzo [3] Erlotinib Placebo 889 12.3 wks HR: 0.71 11.1 wks P <.0001 72 12.0 HR: 0.81 11.0 P =.0088 Miller [4] Erlotinib + bevacizumab Placebo + bevacizumab 768 4.8 mos HR: 0.72 3.8 mos P =.001 55.5 15.9 HR: 0.90 13.9 P =.2686 Perol [5] Erlotinib Observation 310 2.9 mos HR: 0.82 1.9 mos P =.002 81.9 NA HR:.91 NA Zhang [6] Gefitinib Placebo 296 4.8 mos HR: 0.42 2.6 mos P <.0001 58.8 18.7 HR:.84 16.9 P =.2608 1. Fidias P, et al. J Clin Oncol. 2010;28:5116-5123. 2. Ciuleanu T, et al. Lancet. 2009;374:1432-1440. 3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 4. Miller VA, et al. ASCO 2009. Abstract LBA8002. 5. Perol M, et al. ASCO 2010. Abstract 7507. 6. Zhang L, et al. ASCO 2011. Abstract LBA7511.

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 6.6 5.0 (P <.001) 13.0 11.0 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 7.4 7.7 (P =.575) 8.0 9.3 (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 3.8 1.9 (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 4.1 2.8 (P =.00006) 13.9 11 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;52:155-163. 2. Belani CP, et al. ASCO 2010. Abstract 7506. 3. Perol M, et al. ASCO 2010. Abstract 7507. 4. Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.

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 2012. Abstract LBA7507.

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 1.0 0.8 0.6 0.4 0.2 0 OS median, mos (95% CI) Censoring, % Survival rate, % (95% CI) 1 yrs 2 yrs Pemetrexed 13.9 (12.8-16.0) 28.7 58 (53-63) 32 (27-37) 0 3 6 9 12 15 18 21 24 27 30 33 36 Patients at Risk, n Mos From Randomization Pem + BSC 359 333 272 235 200 166 138105 79 43 15 2 0 Placebo + BSC 180 169 131 103 78 65 49 35 23 12 8 3 0 Placebo 11.0 (10.0-12.5) 21.7 45 (38-53) 21 (15-28) Proportion of Patients With PFS 1.0 0.8 0.6 0.4 0.2 0 0 Patients at Risk, n Pem + 359 BSC Placebo 180 + BSC PFS: Primary Efficacy Endpoint Pemetrexed Placebo Unadjusted HR: 0.62 (95% CI: 0.49-0.79) 3 6 9 12 15 Mos 132 52 57 15 21 5 4 0 0 0 Paz-Ares L, et al. ASCO 2012. Abstract LBA7507.

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 17.5 4.7 10.6 1.1 Anemia 11.7 6.4 4.4 0.6 Neutropenia 5.0 5.8 0.6 0 Paz-Ares L, et al. ASCO 2012. Abstract LBA7507.

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

PCI ved SCLC udvidet sygdom

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