Metastatic Colorectal Cancer Update 2015 A/Prof Jeremy Shapiro GI Medical Oncologist Cabrini Hospital, Melbourne 1
Not all pts with metastatic CRC are equal
1 st consideration can patient be cured by resection of metasatic disease? 3
Metastatic colorectal cancer 100 80 60 Unresectable 66% 48% Resectable --- Best supportive care --- 5FU --- Resectable liver mets. 40 30% 20 2 3 4 5 6 7 8 9 10 Colon Cancer Collaborative Group, BMJ 2000 and Adam, Ann Surg 2004
Liver resection can cure some pts Refs Colon Ca Collab. Group, BMJ 2000 / Tournigand, JCO 2004 / Adam, Ann Surg 2004 100 80 60 48% --- BSC --- 5-FU --- FOLFIRI/FOLFOX6 --- FOLFOX6/FOLFIRI --- resectable 40 30% 20 0 1 2 3 4 5 6 7 8 9 10 years
Is metastatic disease resectable? Full CT staging, PET +/- liver MRI And if it is, is pt fit enough for surgery? sometimes, I can make the call. 20 % pts suitable, 50 % clearly not Perhaps 30% or so unsure => Best to assess all pts with liver limited disease in MDT.. NB Bilobar disease, not necessarily a contra-indication
2 nd consideration understanding what you can/ can t do with chemo
Pts diagnosed with met CRC in 2015.. - can t be cured with chemo alone - can expect (on average) to live about 2.5 years - 15-20 % chance of living beyond 5 years
Managing Colorectal Cancer in the clinic Traditional Same treatment for all Limited options Treating doctor only 2015 Individualised treatment plan Large treatment menu Multi-disciplinary care
CRC Menu Chemotherapy 5FU Capecitabine Raltitrexed S1 Oxaliplatin Irinotecan Mitomycin C Primary tumour Leave in situ Stent Surgery Radiotherapy Biologic agents Bevacizumab Cetuximab Panitumumab Aflibercept Ramucirumab Supportive Symptom control Palliative services Clinical trial Surgery Liver Lung Peritonectomy Liver directed therapy Sirt RFA DC beads FUDR (HAI) Biomarkers
All pts suitable for Rx should have a RAS test at diagnosis of metastases (altho RAS test will not necessarily determine initial Rx..)
RAS a new predictive biomarker -a gene that encodes one of the proteins in the epidermal growth factor receptor (EGFR) signaling pathway -important in the development and progression of cancer - 40% CRC pts have a KRAS exon 2 mutation and don t benefit from EGFR-ab Rx - ** another 10-15% have a NRAS or rare type of KRAS mutation => Near perfect negative predictor of resistance
Distribution of mutations in mcrc KRAS mt (non exon 2 KRAS mt) & NRAS mt ~10% RAS wt ~50% KRAS mt (exon 2) ~40% Douillard JY. ASCO 2013. Abstract 3620; Oliner KS. ASCO 2013. Abstract 3511.
KRAS testing 2007-2010 A revolution in the clinical care of met CRC pts % met CRC pts being KRAS tested in USA (n=1188) Before EGFR inhibitor treatment At any time during clinical care Webster J Cancer Epidemiol Biomarkers Prev 2013
Which chemotherapy? Disease factors Curative v Non-curative Symptoms Burden of metastatic disease Clinical course - ie pace of disease
Which chemotherapy? Patient factors Age Performance Status Co-morbidities Patient wishes
Which chemo? Cure Aggressive Rx Rapid PD / Significant Sx Aggressive Rx No cure / no rapid PD or signif Sx (majority) Can use milder approaches
First line therapy
systemic therapy cards Additional Australian (PBS) Rules: - Can substitute X card in place of F - Must play B at start or not at all - A can not be played at all - Can only play C after O or I has been played - Only some players are given the C or P cards and they are interchangeable - New cards cannot be used without lengthy application to rules committees
First line therapy Non-intensive initial approach (suitable for > 50% but in practice used less often)
Overall survival CAIRO study: median overall survival 1.0 sequential Rx 16.3 m (14.3-18.2) combination Rx 17.4 m (15.2-19.2) 0.8 0.6 1 st line sequential capecitabine Randomisation combination capecitabine + irinotecan 0.4 2 nd line Combination (Arm B) irinotecan capecitabine + oxaliplatin 0.2 Sequential (Arm A) p = 0.33 3 rd line capecitabine + oxaliplatin n = 803 0.0 0 6 12 18 24 30 36 42 48 Months from randomisation Koopman et al. Lancet 2007
Oral Capecitabine 5FU pro-drug, with equivalent efficacy usually well tolerated Patients like the freedom! (no IV / can travel) still need regular monitoring Especially in initial stages as dose is adjusted Side effects slowly accumulate with each course Dose delays between cycles often required Compliance issues
Cape + Bev better than Cape Cape best option for most monotherapy pts can still use IV 5FU schedules if you want Concerned re compliance Unable to swallow/absorb talblets Troublesome HF syndrome adding Bev increases RR, PFS and possibly OS
AVEX Phase III Study Design Patients Previously untreated mcrc Age 70 yr Adjuvant chemo if >6 mo prior Not optimal candidates for irinotecan or oxaliplatin No cardiovascular disease, recent aspirin/nsaid use, or full-dose anticoagulants or thrombolytics N=280 Capecitabine 1000 mg/m2 BID days 1-14 + Bev 7.5 mg/kg day 1 every 3 weeks 1:1 Randomization Capecitabine 1000 mg/m2 BID days 1-14 every 3 weeks Treat to progression Cunningham et al: The Lancet Oncology, Volume 14, Issue 11, Pages 1077-1085, October 2013
AVEX: Progression-Free Survival Cunningham et al: The Lancet Oncology, Volume 14, Issue 11, Pages 1077-1085, October 2013
AVEX: Outcomes by Age 70-74 years 75-79 years 80 years Cape + Bev (n=55) Cape (n=46) Cape + Bev (n=57) Cape (n=66) Cape + Bev (n=28) Cape (n=28) Median PFS, mos 7.6 5.0 9.8 5.1 10.5 5.1 PFS HR (P value) 0.52 (p<0.001) 0.60 (p=0.016) 0.36 (p=0.003) Median OS, mos 20.7 22.2 19.8 17.4 19.7 12.6 OS HR (P value) 0.91 (p=0.55) 0.79 (p=0.37) 0.62 (p=0.24) Best ORR, % 25.5 10.9 15.8 12.1 14.3 3.6 ORR P value 0.076 0.607 0.352 Grade 3 AEs, % 63.0 41.3 54.7 40.6 59.3 57.7 Saunders M. ESMO 2013. Abstract O-0030.
Proportion not progressed AGITG MAX: Bev increases PFS 1.0 0.8 Capecitabine + Bevacizumab + Mitomycin C Median PFS C: 5.7 months CB: 8.5 months CBM: 8.4 months 0.6 Capecitabine Capecitabine + Bevacizumab Hazard ratios C vs CB: 0.63, P<0.001 C vs CBM: 0.59, P<0.001 0.4 0.2 6 12 18 Months from randomisation 24 Tebbutt, MAX AGITG study ESMO 2009
First line therapy More intensive initial approach
Oxaliplatin and Irinotecan are the most active drugs, and are similar in efficacy (when used optimally in 1st-line advanced disease)
Equivalent survival if both drugs combined with infusional 5FU in 1 st line Colucci et al. JCO Aug 2005 Tournigand et al. JCO 2004 RR 31% v 34% (NS) RR (1 st line) 56% v 54% (NS) TTP 7 m v 7 m (NS) TTP (1 st line) 8 m v 8.5 m (NS) Med survival 14 m v 15 m (NS) Med survival 21.5 m v 20.6 m (NS)
Capecitabine can replace 5FU doublet backbone Overall Survival XELOX v FOLFOX Cassidy ASCO 2007
order not important, as long as all the active drugs are used
Best survival if exposed to all active agents Median OS (mos) 22 21 20 19 18 17 16 15 14 13 12 p =.0001 0 10 20 30 40 50 60 70 80 Patients With Three Drugs (%) 11 phase III trials: 5,768 patients OS (mos) = 13.2 + (% 3 drugs x 0.1); R^2 =.85 1st-line therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV/5-FU2 FOLFOXIRI CAIRO-1 Grothey & Sargent, 2005; Falcone et al., 2007; Koopman et al., 2007.
Oxaliplatin Mode of action Oxaliplatin causes inter- and intra-strand cross-links in DNA, inhibiting DNA synthesis and cell proliferation Lesions per Mbp Monoadducts Interstrand Protein cross-links Breaks Oxaliplatin 118 0 2 44 Cisplatin 371 23 4 0
Irinotecan Mode of action Irinotecan is a topoisomerase I inhibitor, this causes DNA double strand breaks and S-phase specific cytotoxicity
5-Fluorouracil (5-FU) Mode of action 5-FU inhibits thymidylate synthase (TS) and the synthesis of thymidine nucleotides required for DNA replication It prevents cell division and is S-phase specific
Folfiri FOLFOX v FOLFIRI: different toxicity profiles nausea, diarrhoea, mucositis, alopecia fatigue Mild-moderate cytopenias low rates of hospital admission Folfox neurotoxicity is the major toxicity and is usually dose-limiting fatigue Mild-moderate cytopenias low rates of hospital admission
Biologic agents VEGF-ab (bevacizumab / aflibercept / ramucirumab) EGFR-ab (cetuximab / panitumumab)
Angiogenesis is critical for tumour growth, development, and spread Pre-malignant stage Malignant tumour Tumour growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular tumour) (Angiogenic switch) (Vascularised tumour) (Tumour cell intravasation) (Seeding in distant organs) (Secondary angiogenesis) Stages at which angiogenesis plays a role in tumour progression Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207 25
Bevacizumab (Avastin ) Blocks VEGF a key mediator in angiogenesis Recombinant humanized monoclonal IgG 1 antibody Half-life is approximately 20 days (range, 11 to 50 days) Avastin (bevacizumab) PI. October 2006; 2. Presta et al. Cancer Res. 1997;57:4593.
Proportion surviving Bevacizumab Increases OS in 1st-line mcrc 1.0 0.8 0.6 0.4 HR=0.66, P=0.00004 Med OS : 15.6 v 20.3 months 0.2 IFL + placebo IFL + bevacizumab 0 0 10 20 30 40 survival (mo) Hurwitz et al. NEJM 2004
Proportion of patients NO16966: Bev did not significantly improve OS 1.0 XELOX / FOLFOX4 + Bev XELOX / FOLFOX4 + Placebo 0.8 0.6 HR=0.89 [0.76-1.03] p=0.08 0.4 0.2 0 19.9 21.3 0 6 12 18 24 30 36 Time [months] Cassidy JCO 2008
Several studies now reported, and ALL show some benefit BUT - not as effective as we had initially thought - not as toxic as we had feared - costly - no sub-group identified that derive greater (or lesser) benefit - Doesn t work as monotherapy
Aflibercept VEGFR-1 VEGFR-2 IgG Fc Aflibercept Soluble fusion protein Consists of portion of extracellular domains of human VEGF receptors 1 and 2 fused to human IgG1 Fc portion Binds all VEGF-A isoforms, VEGF-B and PlGF High affinity: binds VEGF-A and PlGF more tightly than native receptors Half-life in humans ~17 days
VELOUR Study (World GI and ESMO 2011) R A N 600 Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks Metastatic CRC with PD post oxaliplatin Stratification factors: - ECOG PS (0 vs 1 vs 2) - Prior bevacizumab (Y/N) D O M I Z E 1:1 600 Placebo IV, day 1 + FOLFIRI q2 weeks Primary endpoint: OS Sample size: HR 0.8, 90% power and a 2-sided type I error 0.05
Overall Survival - ITT Population Cut-off date = February 7, 2011; Median follow-up = 22.28 months
Ramucirumab RAISE (n=1072) : Ph3: FOLFIRI + Ramucirumab/Placebo Med OS 13.3 v 11.7m HR 0.84 p=.02 Med PFS 5.7 v 4.5m HR 0.79 p <.05 Gr 3 toxicity increase: Neut 38 v 23%, HPT 11%v 3%
Adding EGFRab to chemo (in RAS WT patients only) Refractory pts work best in this setting either as monotherapy (OS benefit) (often given with irinotecan based on an old phii study in pts unselected for KRAS) Second line improves RR and PFS in all studies but not OS (? cross over effect) First line more consistent improvement in RR cf Bevacizumab -? a better debulker Generally improves PFS v doublet alone Crystal and PRIME studies +ve for OS (modest in KRAS popn) but also 2 ve studies (COIN, NORDIC) (?oxali?cape)
OS estimate OS estimate Crystal 1 st line: all RAS: Cetuximab improves OS Overall patient population (ITT) 1.0 0.8 0.6 0.4 18.6 19.9 Cetuximab + FOLFIRI (n=599) FOLFIRI (n=599) HR 0.88 p=0.042 0.2 0.0 0 6 12 18 24 30 36 Months 42 48 54 RAS wt population 1.0 0.8 0.6 0.4 20.2 Cetuximab + FOLFIRI (n=178) FOLFIRI (n=189) 28.4 HR 0.69 p=0.002 0.2 0.0 0 6 12 18 24 30 36 Months 42 48 54 Adapted from Van Cutsem E, et al. J Clin Oncol 2011 and Ciardiello F, et al. ASCO 2014 (#3506)
Prime (FOLFOX+/-Pan) all RAS WT HR 0.83 med OS 23.9 v 19.7 p=.07 OS BENEFIT + 4.2 months RAS WT (both) => greater OS benefit (Post removal 17% pts with mnras) HR 0.78 medos 26.0 v 20.2 p=.04 OS BENEFIT + 5.8 months
Prime (FOLFOX+/-Pan) mutant (all) RAS Mutant RAS pts may be harmed by Panitumumab
1 NCIC CTG C0.17: Overall survival in K-ras Mutant patients Study arm MS (months) 95% CI 0.8 Cetuximab + BSC 4.5 3.8 5.6 BSC alone 4.6 3.6 5.5 Proportion Alive 0.6 0.4 HR 0.98 95% CI (0.70,1.37) Log rank p-value: 0.89 0.2 Cetuximab BSC Cetuximab BSC 0 0 2 4 6 8 10 12 14 16 18 Time from Randomisation (Months) 81 69 46 27 16 11 7 4 83 69 42 28 20 13 11 7
1 NCIC CTG C0.17: Overall survival in K- ras Wild-Type patients Study arm MS (months) 95% CI Proportion Alive 0.8 0.6 0.4 Cetuximab + BSC 9.5 7.7 10.3 BSC alone 4.8 4.2 5.5 HR 0.55 95% CI (0.41,0.74) Log rank p-value: <0.0001 0.2 0 Cetuximab BSC 0 2 4 6 8 10 12 14 16 18 Time from Randomisation (Months) Cetuximab BSC 117 108 95 81 52 34 20 9 6 2 113 92 69 36 24 17 12 5 3 3
Biologics - toxicity Bevacizumab Cetuximab/Panitumumab Hypertension gr3/4 (10-15%) Proteinuria gr3 (0-2%) Arterial thrombosis (2-3%) wound healing (1-2%) Bleeding (1-2%) GI perforation (1-2%) acne-form rash (>70%) paronychia Dyspnoea - rare Infusion reaction (0-3%) No effects on wound healing/bleeding reported Long half life
EGFr Inhibitor-mediated Skin Toxicity
Proportion Alive CO17: Suvival by Worst Grade of Rash 100 80 Grade HR 95%CI p-value 2+ vs 0 0.33 (0.22, 0.50) <0.0001 1 vs 0 0.61 (0.40, 0.93) 0.021 2+ vs 1 0.54 (0.41, 0.72) <0.0001 60 40 Grade n Median Survival 0 32 2.6 mo 1 115 4.8 mo 2+ 136 8.4 mo 20 0 Landmark-type analysis excluding all pts dying within 28 days of entry 90% experienced rash by 29 days, Median time to rash = 10 days 0 6 12 Months 18
head to head comparison (only in the 40-50% of pts all RAS WT)
Primary Endpoint of FIRE-3: Overall Response Rate Endpoint FOLFIRI + Cetuximab FOLFIRI + Bevacizumab OR P Value ORR, intent-to-treat (ITT) population (N=592) 62.0% 58.0% 1.18 (0.85-1.64) 0.183 Complete response 4.4% 1.4% Partial response 57.6% 56.6% Stable disease 17.5% 28.8% Progressive disease 7.1% 5.4% Not evaluable 13.1% 7.8% ORR, Evaluable (N=526) 72.2% 63.1% 1.52 (1.05-2.19) 0.017 Heinemann V. ASCO 2013. Abstract LBA3506.
FIRE-3: Progression Free Survival Stintzing S. ASCO 2013. Abstract LBA3506
This data rocked GI oncology in 2013/ 2014 Was it true? How could a drug not increase RR (primary end point), or PFS, yet increase OS..?? large US trial (80405) eagerly anticipated
PBS Logistics 2015 PBS reimbursement dictates order of use: => Bevacizumab then Cetuximab/Panitumumab Bev PBS funded only for 1 st line Cetux/Pan PBS funded only after progression (RAS WT only) Bevacizumab not funded if given after Cetuximab
First line therapy Even more intensive initial approach FOLFOXIRI +/- biologics
Even more intensive Advantages Most like to induce a rapid and more dramatic responses Rapid symptom relief Longer disease control conversion therapy unresectable to resectable
Even more intensive Disadvantages Toxicity Played all cards upfront?? salvage Not clear that this will result in OS advantage
FOLFIRI vs FOLFOXIRI: GONO STUDY FOLFIRI (122 pts) FOLFOXIRI (122 pts) P value RR 34% 60% <0.0001 R0 surgery 6% 15% 0.033 Liver only 12% 36% 0.017 mpfs (mos) 6.9 9.9 0.0009 mos (mos) 16.7 23.6 0.042 A. Falcone et al. JCO 2007 and ASCO 2007
FOLFIRI vs FOLFOXIRI: GONO STUDY Largely ignored! (TOXICITY CONCERNS) Gr 3-4 toxicity Triplet % Doublet % neutropenia 50 28 diarrhoea 20 12 vomiting 7 2 Neuro (gr 2/3) 20 0 => DOUBLET + BIOLOGICS PREFERRED IF AVAILABLE A. Falcone et al. JCO 2007 and ASCO 2007
Since 3 drugs are better than 2... How about 4??...? Triple chemo with one biologic? Doublet chemo with 2 biologics
TRIBE Phase III Study ( 4 v 3 drugs) Patients Unresectable mcrc No prior mcrc treatment Adjuvant oxali-containing chemotherapy allowed if >12 mo between tx and relapse FOLFIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance) 1:1 Randomization FOLFOXIRI + Bev (up to 12 cycles) 5-FU/LV + Bev (Maintenance) Treat to progression Falcone A. ASCO 2013. Abstract 3505.
TRIBE: PFS (ITT Population) Falcone A. ASCO 2013. Abstract 3505.
TRIBE: Secondary Endpoint (OS) Falcone A. ASCO 2013. Abstract 3505.
Combination EGF and VEGF Abs. Seemed a good idea...pre-clinical rationale, clinical data (BOND2)... But PACCE (2007) Increased toxicity Inferior PFS Phase III ChemoBev +/- panitumumab in arm with chemo and doublet antibody trend to worse OS at interim analysis => TRIAL STOPPED CAIRO 2 (2008) Phase III XeloxBev +/- cetuximab Increased toxicity in arm with chemo and doublet antibody Inferior PFS 9.6 v 10.7 m [p=0.018]
Maintenance therapy
Chemotherapy Free Intervals - CFIs OPTIMOX 1 (JCO 06) - Similar outcomes - arm2 better tolerated FOLFOX7 x 6 FOLFOX4 until progression 5FU FOLFOX7 OPTIMOX 2 (ASCO 07) - inferior outcome in arm2 - (av break 4 mths?too long) FOLFOX7 x 6 FOLFOX7 x 6 5FU FOLFOX7 FOLFOX7 GISCAD (ASCO 06) - Similar outcomes - Less toxicity - 2 months on/off Irinotecan - continuous Irinotecan Irinotecan Irinotecan Irinotecan
Koopman, et al. ASCO 2013 CAIRO3: maintenance bev+cape v observation PFS1 PFS2 Arm A Previously untreated mcrc (n=558) bevacizumab + XELOX (x6) CR PR SD R Observation bevacizumab + capecitabine PD1 PD1 bevacizumab + XELOX bevacizumab + XELOX PD2 PD2 Arm B Primary endpoint: PFS after re-introduction = PFS2 Capecitabine 625 mg /m2 bd continuously (Bev 7.5 mg/kg q3 wks) Upon PD1, only 75% in ARM A and 47% arm B received XELOXbev
PFS1 estimate CAIRO3: PFS1 significantly improved with maintenance 1.0 0.8 0.6 Maintenance Observation Median PFS1, months 8.5 4.1 Stratified HR (95% CI) 0.44 (0.36 0.53) p<0.00001 Adjusted* HR 0.41 p <0.001 0.4 0.2 4.1 8.5 0.0 0 6 12 18 24 30 36 Time (months) Observation 279 85 18 9 6 6 3 Maintenance 279 172 89 44 29 15 9 *Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013
PFS2 estimate CAIRO3: PFS2 (1 o end point) improved with maintenance 1.0 0.8 0.6 Maintenance Observation Median PFS2, months 11.8 10.5 Stratified HR (95% CI) 0.81 (0.67 0.98) p=0.028 Adjusted* HR 0.77 p=0.007 0.4 0.2 10.5 11.8 0.0 0 6 12 18 24 30 36 Time (months) Observation 279 207 111 42 16 11 4 Maintenance 279 207 130 66 38 23 12 *Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013
OS estimate CAIRO3: OS improved* with maintenance bevacizumab 1.0 0.8 0.6 (preliminary analysis) Maintenance Observation Median OS, months 21.7 18.2 Stratified HR (95% CI) 0.87 (0.71 1.06) p=0.156 Adjusted* HR 0.80 p=0.035 0.4 0.2 18.2 21.7 0.0 0 6 12 18 24 30 36 Time (months) Observation 279 248 184 122 78 53 28 Maintenance 279 252 192 143 95 58 33 *Adjusted for covariates with imbalances at baseline; Koopman, et al. ASCO 2013
CAIRO3: safety profile during observation/ maintenance Grade 3/4 adverse event, % Observation (n=279) Maintenance (n=279) Hypertension 18 24 Neutropenia 0 2 Thrombocytopenia 0 1 Diarrhoea 1 3 Vomiting 1 0.4 Nausea 0 2 Hand-foot syndrome 0 22 Neurotoxicity 5 10 GI perforation 0 1 Venous thromboembolic events 2 3 Fatigue 2 4 Red box indicates a difference in incidence between treatment arms of 5% NB also - no drop off in % pts receiving all 4/5 drugs - reassuring
Maintenance therapy No significant survival benefit can t be too dogmatic! Does delay progression modestly (CAIR03 HR 0.44) If having breaks, need to monitor closely A FP + bev is optimal. (No role Bev mono) however 22% gr3+ HF syndrome is unacceptable Which subgroup benefit most from this approach??
Second line therapy? chemo + antivegf (more bev/aflib/ram?)? chemo + EGFR (WT)? chemo alone
Decision 1 is more systemic Rx needed? Progression may be very slow? continue to observe Sometimes non-systemic Rx is appropriate Radiotherapy for local PD Liver directed therapy
Decision 2: which chemo backbone? Change doublet Restart 1 st line Rx if did not progress on Rx. (if Optimoxing, or if on a chemo-break)
Decision 3: to add a biologic? Continue Bevacizumab Beyond Progression New data re aflibercept/ramucurimab to consider too Switch from Bev to EGFRab if WT (or vice versa) Chemo alone, (keep EGFRab in reserve for 3 rd line) NB If FOLFIRI alone in 1 st line => FOLFOX + Bev (e3200 data, but not PBS)
What about using EGFR Abs in second line
2 nd line regimens -EGFRAb Increased RR and PFS when C-Mab / P-Mab added to Irinotecan-based chemo EPIC trial - cetux Sobrero JCO 2008 181 trial - p mab Peeters ESMO 2009 BUT no survival benefit (? due to crossover)
ECCO 2011: PICCOLO: efficacy data KRAS WT Irinotecan (n=230) Irinotecan + panitumumab (n=230) Median OS (months) 10.5 10.4 HR (95% CI) 0.91 (0.73 1.14) p value 0.44 Median PFS (months) 4.7 5.5 HR (95% CI) 0.78 (0.64 0.95) p value 0.01 ORR (%) 12 34 p value <0.0001 Seymour, et al. ECCO-ESMO 2011 (abstract 6007)
ECCO 2011: PICCOLO trial Irinotecan +/- P mab in 2 nd line adv CRC Again no overall survival benefit with EGFR in 2 nd line but Not due to crossover only 6% in this study => Strengthens argument to hold EGFRAb for 3 rd line - delay toxicity - use where survival benefit clearly documented
Proportion of pts receiving Rx diminishes with subsequent lines 1st line 2nd line 3rd line
Refractory patients No significant advances for several years now modest benefit at best: Regorafenib/TAS102 several ve phase III trials: Brivanib, BBI Don t always need to rush into next line of Rx consider liver directed Rx if suitable.. consider Rx breaks if asymptomatic/slow paced
Regorafenib (BAY 73-4506), an oral multikinase inhibitor targeting multiple tumor pathways 1-3 Biochemical activity Regorafenib IC 50 mean ± SD nmol/l (n) Regorafenib VEGFR1 13 ± 0.4 (2) Murine VEGFR2 4.2 ± 1.6 (10) Inhibition of proliferation KIT PDGFR RET Inhibition of tumor microenvironment signaling PDGFR-β FGFR Inhibition of neoangiogenesis VEGFR1-3 TIE2 Murine VEGFR3 46 ± 10 (4) TIE2 311 ± 46 (4) PDGFR-β 22 ± 3 (2) FGFR1 202 ± 18 (6) KIT 7 ± 2 (4) RET 1.5 ± 0.7 (2) RAF-1 2.5 ± 0.6 (4) B-RAF 28 ± 10 (6) B-RAF V600E 19 ± 6 (6) 1. Wilhelm SM et al. Int J Cancer 2011. 2. Mross K et al. Clin Cancer Research 2012. 3. Strumberg D et al. Expert Opin Invest Drugs 2012.
Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)
Drug-related treatment-emergent adverse events occurring in 10% of patients Adverse event, % All grades Regorafenib N=500 Grade 3 Grade 4 Grade 5* All grades Grade 3 Placebo N=253 Grade 4 Hand-foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0 Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0 Hypertension 27.8 7.2 0 0 5.9 0.8 0 0 Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0 Rash / desquamation 26.0 5.8 0 0 4.0 0 0 0 Anorexia 30.4 3.2 0 0 15.4 2.8 0 0 Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0 Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0 Fever 10.4 0.8 0 0 2.8 0 0 0 Nausea 14.4 0.4 0 0 11.1 0 0 0 Bleeding 11.4 0.4 0 0.4 2.8 0 0 0 Voice changes 29.4 0.2 0 0 5.5 0 0 0 Weight loss 13.8 0 0 0 2.4 0 0 0 * Grade 5 drug-related AEs: 1.0% in regorafenib arm vs 0% in placebo arm Grade 5*
What about SIR Spheres? ASX: post SIRFLOX press release 17/3/15
Conclusions (1) consider if your stage IV pt could be resectable Even if not, med OS 2.5 yrs, 15% > 5 years. A large array of treatment options now available Early review of these patients in MDM setting
Conclusions (2) Treatment Goal Treatment Intensity Develop chemo strategy (cure v palliative v decide in 3months) (aggressive v mono v observ) (OPTIMOX/?maintenance/?CFI) Determine biologic strategy
Play your systemic therapy cards cleverly know when to hold them..
For RAS WT pts refractory to Irinotecan.. The Irinotecan Cetuximab Evaluation and the Cetuximab Response Evaluation Among Mutants (ICE CREAM) study MONO V COMBO cetux cetux + irino Study recruitment 89/100, g13d arm closed WT arm : all RAS WT now acceptable for study entry..