What to do after 1 st line failure?

Transcription

1 ESMO Preceptorship Programme Colorectal Cancer Valencia 21 st May 2016 What to do after 1 st line failure? Andrés Cervantes

2 ESMO Preceptorship Programme Colorectal Cancer Valencia 21 th May 2016 Dirk Arnold, Instituto CUF de Oncologia, CUF Hospitals Cancer Centre, Lisboa What to do after 1 st line failure?

3 mcrc: How to maximize survival? Improving 1st line therapy efficacy - and selecting the besttreatment for the individual patient Using the chance for cure by resection of metastases (and other local ablative treatments) Using the continuum of care with optimizing treatmentatdifferent lines Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

4 Factors that affect treatment decisions 1st line Treatment goal Disease-related factors Patient-related factors Biomarkers Anticipated toxicity 2nd and further line Pretreatment Information from pretreatment (including reported toxicity) Disease-related factors Patient-related factors Treatment goal Biomarkers

5 ESMO consensus: Sequences FOLFOX à FOLFIRI vs. FOLFIRI à FOLFOX Tournigand et al., J Clin Oncol 2004: Median OS 20.6 months Schmoll,..., Arnold, Ciardiello, Poston,... Cervantes; Ann Oncol 2012

6 2L in anti-vegf naive patients: E3200 Study; Bevacizumab with FOLFOX Probability A B C FOLFOX-Bevacizumab FOLFOX Bevacizumab alone FOLFOX vs. FOLFOX-Bevacizumab HR = 0.75; p=0.011 Median OS: 10.8 vs mos OS (months) Treatment Total Dead Alive Median A B C ESMO PRECEPTORSHIP PROGRAM Giantonio et al., J Clin Oncol 2007

7 Treatment sequences: Strategies Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

8 Antiangiogenic treatment in mcrc PIGF VEGF-B VEGF-A Bevacizumab VEGF-C, VEGF-D Ramucirumab (IMC-1121B) Aflibercept (VEGF Trap) c Cell membrane VEGFR Tyrosine kinase inhibitors (TKIs) VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangiogenesis Arnold & Tabernero, J Oncopathol 2013

9 2 nd line mcrc treatment with anti-vegf combinations E3200 TML VELOUR RAISE Bev + FOLFOX4 (n=286) FOLFOX (n=291) Bev + CT (n=410) CT (n=409) Aflib + FOLFIRI (n=612) Plac + FOLFIRI (n=614) Ramu + FOLFIRI (n=536) Bev before? none all 30% all Plac + FOLFIRI (n=536) mos, months HR=0.75 p= HR=0.81 p= HR=0.82 p= HR=0.84 p=0.022 mpfs, months ORR, % HR=0.61 p< HR=0.68 p< HR=0.76 p= HR=0.79 p= p< ns p= ns Plac = placebo Giantonio, 1. Langer, et al. ESMO J Clin2008; Oncol ; Peeters, Benounna, et al. JCO 2010; Arnold 3. Van et al, Cutsem, Lancet et Oncol al. WCGC 2012; 2011 Van Cutsem, et al. J 4. Clin Giantonio, Oncol et 2012 al. J ; Clin Tabernero Oncol 2007; et al., 5. Roche ASCO data GI 2015 on file

10 Treatment sequences: Strategies Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

11 survival difference, assuming a true HR (cetuximab and irinotecan to irinotecan) of An O Brien and Fleming type spending function was used to ensure an overall, two-sided, type I error rate of 5%. Survival was compared between treatment arms using a two-sided log-rank test stratified by ECOG PS (0 to 1 v 2). This analysis was supplemented by Kaplan-Meier curves, and estimates of OS, HR, and associated confidence intervals (HR CI level was EPIC: Phase III Trial of Cetuximabadjusted Plus for the interim Irinotecan analysis). After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer Progression-free survival (PFS; defined as time to progression or death, and evaluated similar to survival) and rates of tumor response were determined from study-investigator assessments, without independent review for these secondary end points. Tumor response was compared between treatment arms using a Cochran-Mantel-Haenszel test stratified by ECOG PS (0 to 1 v 2). The duration of treatment was the period from the first dose until the Alberto F. Sobrero, Joan Maurel, Louis Fehrenbacher, Werner Scheithauer, last plus 21 days for irinotecan Yousifand A. plus Abubakr, 7 days for cetuximab. Time to response was computed for those patients with a response (complete or partial). Manfred P. Lutz, M. Eugenia Vega-Villegas, Cathy Eng, Ernst U. Steinhauer, Jana Prausova, Heinz-Josef Lenz, European Organisation for Research and Treatment of Cancer Quality Christophe Borg, Gary Middleton, Hendrik Kröning, Gabriele Luppi, of Life Questionnaire Oliver Kisker, C-30 score changes Angela fromzubel, baseline were compared be- Christiane Langer, Justin Kopit, and Howard A. Burris III tween treatment arms by a Wei-Lachin test. Adverse events were categorized using the MedDRA dictionary, version 9.1. Analyses of survival, PFS, tumor response, and QOL were done on an intent-to-treat basis. Safety analyses were restricted to treated subjects. RES Patient Characteristics and From May 2003 to February 1,410 with EGFR-positive tumo meeting all eligibility criteria, 1, to cetuximab and irinotecan Demographic and clinical charac balanced between treatment arm Treatment Exposure Median treatment duration irinotecan combination: cetuxim irinotecan for 13.1 weeks (range irinotecan alone (range, 0.4 to 7 delay rates and median dose int Proportion Alive Cetuximab + irinotecan Censored Irinotecan Censored Proportion Without Progression Cetuximab + irinotecan Censored Irinotecan Censored f Time (months) No. patients at risk Cetuximab + irinotecan Irinotecan Cetuximab + Irinotecan N = 648, No. Dead = 445, Median = 10.7 (95% CI = ) Irinotecan N = 650, No. Dead = 429, Median = 10.0 (95% CI = ) Time (months) No. patients at risk Cetuximab + irinotecan Irinotecan Cetuximab + Irinotecan N = 648, No. progressed = 610, Median = 4.0 (95% CI = ) Irinotecan N = 650, No. progressed = 598, Median = 2.6 (95% CI = ) OS, high crossover-rate PFS by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by KLINIKUM KROELLWITZ on F Copyright 2008 by the American Society of Clinical Oncology. All rights rese Sobrero et al., J Clin Oncol 2008

12 2L FOLFIRI +/- Panitumumab, expanded RAS testing: OS Peeters, et al. Clin Cancer Res. 2015

13 2L FOLFIRI +/- Panitumumab, expanded RAS testing: ORR Peeters, et al. Clin Cancer Res 2015

14 2nd line: Sequence following FOLFIRI/bev Study conducted in 11 centers in Italy PFS BEV + FOLFIRI (n=110) PD R 1:1 Irinotecan/ CETUXIMAB FOLFOX FOLFOX Irinotecan/ CETUXIMAB 101 events were required to achieve a power of 80% of detecting a HR of 0.57 in favor of one of the two sequences, translating in an increase of median overall PFS from 4 to 7 months, with a type I error of 5%, two-sided, using the Mantel-Cox version of the logrank test. 110 assessable patients were needed to reach the target number of events. Primary endpoint Secondary endpoints Progression-free survival (PFS) Overall survival (OS) from randomisation; PFS 2 and 3 line; Overall response rate; Safety Clinicaltrials.gov: NCT Research Funding Source: AIFA (Agenzia Italiana del Farmaco) Code FARM 6XB38F Cascinu et al., ECC 2015

15 2nd line: Sequen ce following FOLFIRI/bev A: CPT-11 + Cetuximab -> Folfox-4 B: Folfox-4 -> CPT 11 + Cetuximab PFS Progression Free Survival Number of events A: 49 (90.7%) B: 48 (87.3%) Overall Arm A Arm B HR 0.83 PFS ( ); p=0.37 Log-rank: Chi2=0.79 df=1 p=0.373 Patients at Risk Time to Event (months) Time A B OS A: CPT-11 + Cetuximab -> Folfox-4 B: Folfox-4 -> CPT 11 + Cetuximab Overall Survival Number of events A: 46 (85.2%) B: 43 (78.2%) Log-rank: Chi2=1.30 df=1 p=0.255 Patients at Risk Time to Event (months) Time A B Cascinu et al., ECC 2015

16 Treatment sequences: Strategies Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

17 Following FOLFOX/bev: 2nd line FOLFIRI/P mab vs. FOLFIRI/Bev KRAS wild-type; N=182 A PFS Probability (%) Censored 10 0 Subjects at Risk Panitumumab Bevacizumab 0 Treatment Group: Panitumumab (n = 91) Bevacizumab (n = 91) Progression Free Survival (Months) Hecht et al., Clin Colorectal Cancer 2015

18 FIRE-3: 2nd line efficacy: Any treatment better after FOLFIRI/Cet Progression free survival from 2nd line on Overall survival from 2nd line on Modest et al., Poster ESMO 2014; ASCO 2015 Stintzing et al., J Clin Oncol 2015

19 2nd line treatment: Antibodies Bevacizumab-naïve should be considered for bevacizumab 2 nd line Who received bevacizumab 1 st line should be considered for treatment with: Bevacizumab post continuation (TML) strategy Aflibercept (or ramucirumab, if available) in combination with FOLFIRI when treated in first line with oxaliplatin EGFR antibodies in combination with FOLFIRI for patients with RAS wild-type (& BRAF wild-type) in 2 nd line Patients who are fast progressors should be considered for treatment with the (likely) most active treatment (anti-egfr in the RAS wild-type and aflibercept in RAS mutant). ESMO Consensus 2015; in preparation ESMO PRECEPTORSHIP PROGRAM

20 Are there «optimal sequences»? STRATEGIC-1 Phase III, GERCOR PI: Benoist Chibaudel

21 Are there «optimal sequences»? CR_Sequence trial Continued cfdna analysis (q 6-8 weeks) Int l Phase III (TTD et al.) PI: Alfredo Carrato, Ramon Salazar & Jean-Yves Douillard

22 Treatment of metastatic disease Anti-EGFR s in later lines n In RAS wild-type and BRAF wild-type patients not previously treated with EGFR antibodies cetuximab or panitumumab therapy should be considered n Cetuximab and panitumumab equally active as single agents n The combination of cetuximab with irinotecan is more active than cetuximab alone, in irinotecan refractory patients n There is no unequivocal evidence to administer the alternate anti- EGFR antibody, if a patient is refractory to one of the anti-egfr antibodies. ESMO PRECEPTORSHIP PROGRAM

23 Treatment of metastatic disease Third and further line therapy Regorafenib is recommended in patients pretreated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and in RAS wild-type patients with anti-egfr antibodies Regorafenib is superior to placebo in terms of overall survival, although there are safety / toxicity concerns in frail patients. TAS 102 is a new option for patients pretreated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and in RAS wild-type patients with anti-egfr antibodies ESMO PRECEPTORSHIP PROGRAM

24 Up to 30% of Patients Receive 3 rd line Therapy % patients Patients with mcrc 1 Analysis of the US IntelliDose database (mcrc) 53% 28% 13% % patients Patients with Ovarian Cancer 2 Follow-up of 3 1 st -line phase III Trials (N=3388) 47.8% 30.2% 20.4% 14.7% 11.7% n= n= First Second Third Fourth First Second Third Fourth Fifth Sixth % patients Patients with mbc 3 Analysis of SEER-Medicare (dx2001-5) 40.8% 24.6% 0 n= First Second Third Patients receiving targeted therapy, by line Of patients who received 1 st - line targeted therapy, % Patients with ansclc 4 Analysis of SEER-Medicare (2007) 1. Abrams T, et al. JNCI. 2014;106(2):djt371; 2. Hanker L, et al. Ann Oncol. 2012;23: and online supplement; 3. Taylor D, et al. J Clin Oncol. 2011;29(27 Sept 20 suppl):abstract 150; 4. Penrod J, et al. J Clin Oncol. 2014;32(15 May 20 suppl):abstract % 17.2% 0 n= First Second Third Patients receiving targeted therapy, by line 24

25 Goals of Treatment Change with Line of Therapy Realistic Treatment Goals Adjuvant Cure Reduce risk of recurrence Line of Systemic Treatment First-line Second-line Third-line Subsequent lines Durable Tumor response Long duration of low/no tumor burden Tumor response if needed Durable disease control Durable disease control Maintenance of QoL and PS Disease Control and Maintenance of QOL; Palliation OS Courtesy of Dirk Arnold; Prime Reports. 2014;6:108.

26 Regorafenib (BAY ): an oral multikinase inhibitor 1,2,3 Inhibition of roliferation Inhibition pf signalling In tumor microenvironment Inhibition of angiogenesis 1. Wilhelm SM, et al. Int J Cancer. 2011;1219(1): Mross K, et al. Clin Cancer Research 2012;18(9): Strumberg D, et al. Expert Opin Investig Drugs. 2012;21(6):

27 CORRECT Trial: Regorafenib or Placebo after failure of standard therapy Regorafenib + BSC (n=505) Refractory mcrc (n=760)* R 2:1 Placebo + BSC (n=255) Preceding treatment MUST have been contained Fluoropyrimidine, Oxaliplatin, Irinotecan, Bevacizumab, and (in KRAS wt) Cetuximab or Panitumumab Van Cutsem, E, et al. J Clin Oncol. 2012;30(15S): Abstract 3502

28 Baseline characteristics Regorafenib (n=505) CORRECT Placebo (n=255) Regorafenib (n=136) CONCUR Placebo (n=68) Median age, years (IQR) 61 (54 67) 61 (54 68) 58 (50 66) 56 (49 62) Male, % Race, % Asian Median body mass index, kg/m ECOG PS 0/1, % 52/48 57/43 26/74 22/78 KRAS wild-type/mutant/unknown, % 41/54/5 37/62/2 37/34/29 43/26/31 >3 prior treatment lines for metastatic disease, % Previous targeted biological treatment, % None Any (anti-vegf, anti-egfr, or both) Anti-VEGF, but not anti-egfr Anti-EGFR, but not anti-vegf Anti-VEGF and anti-egfr ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IQR, interquartile range; VEGF, vascular endothelial growth factor. Grothey A, Van Cutsem E, et al. Lancet 2013;381: ; Li J, et al. Lancet Oncol 2015;16:

29 Treatment for refractory colon cancer: Regorafenib CORRECT& CONCUR& Grothey&A,&Van&Cutsem&E,&et#al.#Lancet#2013;381: ;&Li&J,&et#al.#Lancet#Oncol#2015;16: # Grothey et al., WCGC 2015 (oral presentation)

30 Selected drug-related grade 3 adverse events* Proportion of patients (%) Regorafenib (n=500) CORRECT Placebo (n=253) Regorafenib (n=136) CONCUR Placebo (n=68) Hand foot skin reaction 17 < Fatigue Hypertension Diarrhea Hypophosphatemia 4 <1 7 0 Lipase increase 3 <1 4 1 Rash *Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 (CORRECT) and version 4.0 (CONCUR). Safety analyses are based on 753 patients who initiated treatment. Grothey A, Van Cutsem E, et al. Lancet 2013;381: ; Li J, et al. Lancet Oncol 2015;16:

31 Key factor with regorafenib: Dose adjustment Overall Survival (%) No. at Risk TAS-102 Placebo Hazard ratio for death, 0.68 (95% CI, ) P< Months since Randomization TAS-102 Placebo Subgroup All patients KRAS status Wild type Mutant Time since diagnosis of first metastases <18 mo 18 mo Geographic region Japan United States, Europe, and Australia Sex Male Female Age <65 yr 65 yr ECOG performance status 0 1 Primary tumor site Colon Rectum Disease refractory to fluoropyrimidine (as part of last prior regimen) Prior use of regorafenib Yes No No. of prior regimens No. of metastatic sites No. of Patients TAS-102 Better Hazard Ratio (95% CI) Placebo Better 0.68 ( ) 0.58 ( ) 0.80 ( ) 0.84 ( ) 0.64 ( ) 0.75 ( ) 0.64 ( ) 0.69 ( ) 0.68 ( ) 0.74 ( ) 0.62 ( ) 0.73 ( ) 0.61 ( ) 0.68 ( ) 0.64 ( ) 0.75 ( ) 0.69 ( ) 0.69 ( ) 1.05 ( ) 0.74 ( ) 0.59 ( ) 0.69 ( ) 0.68 ( ) Arnold et al., BMJ Cancer 2016 (submitted)

32 TAS-102; Mechanism of Action TPase F 3 dthd (FTD) FTY (inactive form) TPI F 3 dtmp Inhibition of tumor growth TAS-102 (Oral Combination Drug) F 3 dtdp DNA dysfunction FTD TPI F 3 dttp FTD incorporation into DNA Molar ratio = 1 : 0.5 FTD:Trifluridine TPI:Tipiracil-HCl

33 Differentiation between 5-FU and TAS FU TAS FU dump FdUMP Inhibit TS dtmp F3dTMP F3dTDP DNA duplication FTD F3dTTP Phosphorylation Incorporation into DNA dttp Inhibit DNA duplication T T FTD Thymidine(T) DNA damage

34 RECOURSE Trial: TAS-102 vs. placebo Overall Survival (%) Hazard ratio for death, 0.68 (95% CI, ) P<0.001 TAS-102 No. at Risk TAS-102 Placebo Months since Randomization Placebo Mayer et al., NEJM 2015

35 Key Subgroup Analysis of OS Subgroup Favors TAS-102 Favors Placebo Events/N HR [95% CI] Median (mos) TAS-102 : PBO All Subjects 574 / [0.58, 0.81] 7.1 : 5.3 KRAS Status Wild Type 280 / [0.45, 0.74] 8.0 : 5.7 Mutant Type 294 / [0.63, 1.02] 6.5 : 4.9 Geographic Region Japan 227 / [0.57, 1.00] 7.8 : 6.7 West (AU/EU/US) 347 / [0.52, 0.80] 6.5 : 4.8 Refractory to 5-FU when given as last therapy prior to randomization* 317 / [0.59, 0.96] 6.8 : Hazard Ratio: TAS-102 versus Placebo (95% CI) *Not prespecified subgroup Yoshino T, et al., 16 th ESMO-GI, 2014: O-0022

36 Non-Hematologic Adverse Events Occurring in >10% of Patients (as-treated population) Non-Hema Adverse events, % TAS-102 (N=533) Placebo (N=265) All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4 Nausea Decreased appetite Fatigue Diarrhea Vomiting Pyrexia Asthenia Constipation Abdominal pain Cough Dyspnoea Oedema peripheral Weight decreased One treatment-related death was observed in TAS-102 Yoshino T, et al., 16 th ESMO-GI, 2014: O-0022

37 Yoshino T, et al., 16 th ESMO-GI, 2014: O-0022 Hematologic Laboratory Abnormalities Occurring in >10% of Patients (as-treated population) Lab abnormalities, % TAS-102 (N=533) Placebo (N=265) All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4 Hematology Leukopenia Anemia * Neutropenia Lymphocytopenia Thrombocytopenia *One case of grade 4 was reported in AE

38 Yoshino T, et al., 16 th ESMO-GI, 2014: O-0022 Occurring in < 10% of Patients but Clinically Important Adverse Events (as-treated population) Adverse events, % TAS-102 (N=533) Placebo (N=265) All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4 Febrile neutropenia Stomatitis Hand-foot syndrome Cardiac ischaemia events, % Acute myocardial infarction Angina pectoris Myocardial ischaemia

39 Kavuri SM et al, CancerDiscovery 2015

40 Kavuri SM et al, CancerDiscovery 2015

41 HERACLES treatment and assessments Presented By Salvatore Siena at 2015 ASCO Annual Meeting

42 Sartore-Bianchi A, et al, Lancet Oncol 2016

43 Sartore-Bianchi A, et al, Lancet Oncol 2016

44 Response Presented By Salvatore Siena at 2015 ASCO Annual Meeting