Nieuwe patientenselectie met longcarcinoom als rolmodel voor de medisch oncoloog

Transcription

1 Nieuwe patientenselectie met longcarcinoom als rolmodel voor de medisch oncoloog Egbert F. Smit MD PhD Dept. Pulmonary Diseases Vrije Universiteit VU Medical Centre Amsterdam, The Netherlands

2 ASCO 2013 Moleculaire pathologie EGFR-TKI s in EGFR WT NSCLC Plaats 2 de generatie EGFR TKI s? ALK: resistentie mechanisme KRAS: geen slechte prognostische-predictieve marker. Drugable? BRaf

3 Franse Benadering

4 [Franse benadering

5 Niet Kleincellig bronchuscarcinoom Moleculaire Pathologie Pathologie highlights Moleculaire Pathologie helpt LCMC 1007 pat. Adeno getest; 62% driver mutatie. 264 met mutatie gerichte behandeling vs 313 met mutatie geen gerichte behandeling: OS 3.5 vs 2.4 jaar. Frequentie driver mutaties hoog Adenocarcinoom 60% met behandelbare mutaties (off label gebruik) Breder gebruik van immunohistochemische technieken: Alk, ROS1, RET, Her2

6 Incidence (%) Incidence of Fusions Incidence of RET fusions Incidence of ROS1 fusions Never-Smokers Pan-Negative Lung AdenoCAs Pan-Negative NSCLCs Unselected NSCLCs Never-Smokers Pan-Negative Lung AdenoCAs Pan-Negative NSCLCs Unselected NSCLCs 95% CI [3 27%] n = 5/34 Lipson et al 1 Nature 2012 Wang et al 2 CCR % CI [2 27%] n = 5/33 Bergethon et al 3 J Clin Oncol Lipson et al. Nature Med 2012;18: Wang et al. J Clin Oncol 2012;30: Bergethon et al. J Clin Oncol 2012;30:863 Drilon et al. J Clin Oncol 31, 2013 (suppl; abstr 8067)

7 ASCO 2013 Moleculaire pathologie EGFR-TKI s in EGFR WT NSCLC Plaats 2 de generatie EGFR TKI s? ALK: resistentie mechanisme KRAS: geen slechte prognostische-predictieve marker. Drugable? BRaf

8 EGFR TKI s in WT EGFR 2 e lijns docetaxel vs erlotinib ASCO 2012: Tailor RPhII EGFR WT docetaxel vs erlotinib. PFS erlotinib inferieur, OS? ASCO 2013: DELTA

9 EGFR TKI s in WT EGFR PROSE: RPhIII tweede lijn erlotinib vs docetaxel na stratificatie mbv Veristrat

10 EGFR TKI s in WT EGFR PROSE: RPhIII tweede lijn erlotinib vs docetaxel na stratificatie mbv Veristrat

11 EGFR TKI s in WT EGFR PROSE: RPhIII tweede lijn erlotinib vs docetaxel na stratificatie mbv Veristrat

12 ASCO 2013 Moleculaire pathologie EGFR-TKI s in EGFR WT NSCLC Plaats 2 de generatie EGFR TKI s? ALK: resistentie mechanisme KRAS: geen slechte prognostische-predictieve marker. Drugable? BRaf

13 Lux Lung 6 Key patient inclusion criteria No prior treatment for advanced disease Afatinib 40 mg/day (n=242) PD Stage IIIB/IV lung adenocarcinoma EGFR mutation positive Asian ECOG PS 0-1 (n=364) R 2:1 Gemcitabine 1,000 mg/m 2 days 1/8 + cisplatin 75 mg/m 2 day 1 q3w (n=122) Up to 6 cycles PD Primary endpoint Secondary endpoints PFS ORR, DCR, OS, PROs Safety Wu et al. J Clin Oncol 31, 2013 (suppl; abstr 8016)

14 PFS (probability) PFS 242 patients were randomised to treatment with afatinib, 122 to treatment with GC (groups were similar with respect to gender, smoking history, exon 19 deletion and L858R) ORR and DCR were also higher with afatinib than GC (66.9% vs. 23.0%, respectively, p< for ORR; 92.6% vs. 76.2%, p< for DCR) Median PFS (months) % Afatinib n=242 HR (95% CI) Gemcitabine/cisplatin n= ( ) p< Number at risk Afatinib Gemcitabine/cisplatin % Wu et al. J Clin Oncol 31, 2013 (suppl; abstr 8016)

15 En nu? Data lijken op de andere uitkomsten in EGFR mutaties LUX-lung 6 = Lux-lung 3 = IPASS = EURTAC =. Toxiciteit? Beter dan erlotinib-gefitinib: LUX-lung 7 En T790M? HER2?

16 EGFR resistentie

17 HSP90 remmers (AUY2992) + erlotinib in EGFR TKI resistent longcarcinoom Key patient inclusion criteria EGFR mutation (T790M) Acquired resistance (n=16) AUY mg/m 2 weekly + Erlotinib 150 mg q4w Primary endpoint ORR at 8 weeks Johnson et al. J Clin Oncol 31, 2013 (suppl; abstr 8036)

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19 ASCO 2013 Moleculaire pathologie EGFR-TKI s in EGFR WT NSCLC Plaats 2 de generatie EGFR TKI s? ALK: resistentie mechanisme KRAS: geen slechte prognostische-predictieve marker. Drugable? BRaf

20 Systematic resistance to ALK inhibitors Unknown (ALK +) 13% Unknown (ALK -) 6% EGFR Mutation 12% ALK Non-Dominant ALK Mutation 31% KRAS Mutation 19% ALK Dominant ALK Mutation + CNG 6% ALK CNG 13% Doebele et al. J Clin Oncol 30, 2012 (suppl; abstr 7504)

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22 Shaw: update LDK remmer

23 Nieuwe Alk remmers Key patient inclusion criteria Advanced malignancies (except leukemia) Refractory to available therapies or none available (n=44) AP design with following doses: 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg PD Camidge et al. J Clin Oncol 31, 2013 (suppl; abstr 8031)

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26 ASCO 2013 Moleculaire pathologie EGFR-TKI s in EGFR WT NSCLC Plaats 2 de generatie EGFR TKI s? ALK: resistentie mechanisme KRAS: geen slechte prognostische-predictieve marker. Drugable? BRaf

27 KRAS studies MEK remmer alleen MEK remmer vs chemotherapie MEK remmer + chemotherapie

28 Trametinib vs Docetaxel Key patient inclusion criteria Trametinib 2 mg/day (n=89) PD Advanced KRASmutant NSCLC R 2:1 Crossover PD Previously treated with platinum-based chemotherapy ECOG PS 0/1 Docetaxel 75 mg/m 2 q3w (n=45) PD (n=134) Primary endpoint PFS Footer text left aligned (Arial 12pt roman, black) Secondary endpoints OS, 1-year, ORR, duration of response Safety Blumenschein et al. J Clin Oncol 31, 2013 (suppl; abstr 8029)

29 Proportion Alive and Progression-free Proportion Alive PFS and OS PFS OS Median PFS = 11.7 (T) vs 11.4 (D) months (HR=1.14; p=0.5) Median OS = 8.0 (T) (HR=0.97; p=0.9) n n Time from Randomization, weeks Randomised Treatment Docetaxel 0 2 Trametinib n n Randomised Treatment ?? Time from Randomization, weeks?? Docetaxel Trametinib Key conclusions Trametinib did not improve survival in patients with KRAS-mutation NSCLC compared with docetaxel However, an ORR of 12% for trametinib in KRAS-mutant NSCLC suggests that an effort to better identify responsive mutations is warranted Blumenschein et al. J Clin Oncol 31, 2013 (suppl; abstr 8029)

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33 ASCO 2013 Moleculaire pathologie EGFR-TKI s in EGFR WT NSCLC Plaats 2 de generatie EGFR TKI s? ALK: resistentie mechanisme KRAS: geen slechte prognostische-predictieve marker. Drugable? Hsp90 BRaf

34 CRA8007: A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1) Ramalingam SS et al Randomised, open-label trial Objective: To investigate safety and efficacy of the second generation Hsp90 inhibitor, ganetespib, in patients with advanced lung adenocarcinoma Key patient inclusion criteria Advanced lung adenocarcinoma One prior systemic treatment ECOG PS 0/1 (n=252) Docetaxel 75 mg/m 2 day 1 q3w + ganetespib 150 mg/m 2 days 1 and15 q3w (n=125) Stratification ECOG PS 0/1, time since diagnosis, baseline LDH, smoking Docetaxel 75 mg/m 2 day 1 q3w (n=127) PD PD Primary endpoint PFS in patients with elevated LDH or KRAS+ tumours OTR, objective tumour response Secondary endpoints OS and PFS in all adenocarcinoma patients ORR, DCR, QoL Ramalingam et al. J Clin Oncol 31, 2013 (suppl; abstr CRA8007)

35 Key efficacy data: PFS and OS in advanced disease (> 6 months after diagnosis) Key results 255 patients were enrolled to study (G+D, n=125; G, n=127; median age 60 years; ~60% male; ~40% PS 0) Patients had been diagnosed over 6 months earlier in 87 and 89 patients in the G+D and G groups, respectively Overall PFS (months) OS (months) >6 months disease PFS (months) OS (months) G + D D HR (95% CI) p-value ( ) 0.82 ( ) 0.61 ( ) 0.61 ( ) Improvement in PFS was observed in patients treated with the combination over docetaxel alone Survival benefits were most pronounced among patients that were enrolled more than 6 months after diagnosis of advanced NSCLC Key conclusions Ganetespib in combination with docetaxel improved OS and PFS compared with docetaxel alone The combination was well tolerated with an acceptable safety profile Phase 3 trial in patients with advanced disease >6 months is ongoing (GALAXY-2) Ramalingam et al. J Clin Oncol 31, 2013 (suppl; abstr CRA8007)

36 Precisie geneeskunde

37 Precisie geneeskunde

38 ASCO 2013 Moleculaire pathologie EGFR-TKI s in EGFR WT NSCLC Plaats 2 de generatie EGFR TKI s? ALK: resistentie mechanisme KRAS: geen slechte prognostische-predictieve marker. Drugable? BRaf

39 Dabrafenib in V600E BRAF mut Single-arm, 2-stage, phase II study Objective: To evaluate dabrafenib in stage IV BRAF V600E mutation positive NSCLC patients who failed at least 1 line of chemotherapy Key patient inclusion criteria NSCLC BRAF V600E mutation 1 line prior treatment (n=53) Stage 1 Dabrafenib 150 mg bid (n=20) Stage 2 Dabrafenib 150 mg bid (n=20) Primary endpoint ORR (investigator assessed) Secondary endpoints PFS, duration of response, OS Safety, tolerability Population pharmacokinetics Planchard et al. J Clin Oncol 31, 2013 (suppl; abstr 8009)

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41 Eating away the pies Oxnard et al. J. Clin. Oncol. 2013

42 Conclusie Pathologie klaar voor dagelijkse praktijk?? Veel ontwikkelingen t.a.v. EML4-ALK translokaties KRAS: fase II en III studies met combinatie MEKdocetaxel Niet alles in fase III: braf / ROS / RET waterfall-plot geneeskunde

43 WATER FALL PLOT GENEESKUNDE

44 WATER FALL PLOT GENEESKUNDE