Incorporating biologics in the management of older patients with metastatic colorectal cancer

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1 Incorporating biologics in the management of older patients with metastatic colorectal cancer D Papamichael MB BS MD FRCP Cyprus Oncology Centre GSK Satellite Symposium SIOG APAC Singapore July 2014

2 Outline Background anti EGFR therapies anti VEGF therapies Conclusions

3 Outline Background anti EGFR therapies anti VEGF therapies Conclusions

4 Background Median age at presentation around 70 Treatment of mcrc becoming more complex Evidence that elderly patients with colorectal cancer are: - under-staged - under-treated - under-represented in clinical trials

5 relative frequency < > 80 FOCUS patients population FOCUS: Lancet 370:143-52, 2007 UK Cancer Registry data

6 Incorporation of targeted therapies in the elderly with MCRC Three monoclonal antibodies have recently been registered for advanced colorectal cancer patients: cetuximab, panitumumab and bevacizumab Is there enough information about activity and toxicity of these drugs in the elderly population to recommend its use routinely?

7 Outline Background anti EGFR therapies anti VEGF therapies Conclusions

8 Anti-EGFR therapy in elderly patients with metastatic CRC 1.TTD 04/01: Cetuximab first-line in patients 70 years (Sastre et al. Crit Rev Oncol/Hematol 2011) 2.TTD 06/01: Cetuximab plus capecitabine in patients > 70 years (Sastre et al. The Oncologist 2012) 3.Pooled analysis of Crystal and Opus according to age (Folprecht et al. ESMO 2010) 4.NCIC CTG CO.17: Subgroup analysis according to age. (Asmis et al Ann Oncol 2011)

9 04/TTD/01: Study design Evaluation visits every six weeks Until PD Weekly cetuximab Cetuximab 400 mg/m 2 initial dose followed by 250 mg/m 2 /weekly Premedication with antihistamine was mandatory before all infusions Treatment was delayed in case of grade 3 skin toxicity

10 04/TTD/01: Related Adverse Events NCI-CTC 3.0 (n = 41) Toxicity Grade 1-2 (%) Grade 3 (%) Skin Toxicity Acne-like rash Dry skin Nail Toxicity Skin fissures Infusion-related reactions Diarrhea Vomiting Asthenia Headache Sastre J et al. Crit Rev Oncol 2011

11 04/TTD/01: Single-agent Cetuximab Progression Free Survival (ITT population) Percent Progression free survival Kaplan-Meier Method Censoring Column in censored Median PFS = 3 months Overall survival = 11.1 months Time (days) 350 Response ITT population n= 41 Complete Response Partial Response Overall Response rate Stable Disease (SD) Disease Control (%) 5% 10% 15% 36% 51% Progressive Disease Non Evaluable 44% 5% Sastre J et al. Crit Rev Oncol 2011

12 06/TTD/01: Treatment schedule Cetuximab: 400 mg/m 2 loading dose and 250 mg/m 2 weekly Capecitabine: 1250 mg/m 2 /12h (950 if CCr ml/min) days 1-14, q3w a protocol amendment became necessary due to important nail toxicity after 27 patients (Cohort 1) were treated Dose reduction: Capecitabine: 1000 mg/m 2 /12h (750 if CCr ml/min) (Cohort-2, 39 patients) Treatment was maintained until disease progression, unacceptable toxicity or patient withdrawal of consent Sastre et al The Oncologist 2012

13 06/TTD/01:Toxicity (Grade 3-4). (according to the cohort of capecitabine dose) Adverse event Cohort 1 Capecitabine 1250/950 (n =27) Cohort 2 Capecitabine 1000/750 (n =39) Number (%) Number (%) Paronychia Hand-foot syndrome Diarrhea Acneiform dermatitis Mucositis Blepharitis Conjunctivitis Keratitis Deep venous thrombosis. Pulmonary embolism 8 (29.6) 6 (22.2) 5 (18.5) 8 (29.6) 2 (7.4) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 2 (7.4) 3 (7.7) 8 (20.5) 5 (12.8) 11(28.2) 1 (2.6) (7.7) Sastre et al The Oncologist 2012

14 06/TTD/01: Response (ITT population, N=66) KRAS tumor mutation status was determined in 58/66pts (88%) Overall Response, n (%) CR PR SD PD Not evaluable Overall response rate, % (95% CI) All patients (N=66) 2 (3.0) 19 (28.8) 35 (53) 5 (7.6) 5 (7.6) 31.8 ( ) According to KRAS status KRAS WT (N=29) 2 (6.9) 12 (41.4) 13 (44.8) 1 (3.4) 1 (3.4) 48.3 ( ) KRAS mut (N=29) 0 6 (20.7) 18 (62.0) 3 (10.3) 2 (6.9) 20.7 (8-39.7) Disease control rate, % Sastre et al The Oncologist 2012

15 06-TTD-01: Cetuximab + capecitabine Progression-free survival (ITT population) All pts,n=66 According to KRAS status N= Median PFS: 7.1 m (95% CI: m) 80 KRAS wild-type Median PFS: 8.4 m Percentage Percentage HR=0.53 p KRAS mutant Median PFS: 6 m Time (days) Time (days) Sastre et al The Oncologist 2012

16 Cetuximab in the elderly: Pooled analysis of the Crystal & Opus studies Folprecht G et al ESMO 2010

17 NCIC CTG CO.17: Subgroup analysis according to age Restricting cetuximab use in the elderly or in the setting of significant comorbidities does not appear justified Asmis TR et al Ann Oncol 2011; 22:

18 ASPECCT Study Schema Patients with previously treated, WT KRAS mcrc R A N D O M I S E 1:1 Panitumumab 6.0 mg/kg Q2W Cetuximab 400 mg/m 2 loading dose, 250 mg/m 2 QW PD PD S U R V I V A L Stratification Factors: North America and Western Europe and Australia vs rest of world (ROW) ECOG PS (0 or 1 vs 2) Crossover between arms during study treatment was not allowed

19 OS Subset Analysis Favors Panitumumab Favors Cetuximab Factors N HR 95% CI All Patients Rest of World N America, Western EU and Aus ECOG PS Status: 0 or ECOG PS Status: Prior bevacizumab: No Prior bevacizumab: Yes Primary tumor: Colon Primary tumor: Rectal Metastatic: Liver only Metastatic: Other sites w/o liver Age < Age Male Female Hazard Ratio (Panitumumab / Cetuximab) Price T et al ECCO 2013

20 Outline Background anti EGFR therapies anti VEGF therapies Conclusions

21 Bevacizumab in combination with 5 FU/LV improves survival in patients with metastatic CRC: a combined analysis Probability of survival Median survival (months): 14.6 vs 17.9 HR=0.74, p= FU/LV/Avastin 5mg (n=249) 5-FU/LV or IFL (n=241) Median age 67y Range 23 90y Months since treatment initiation Kabbinavar et al. J Clin Oncol 2005;23:

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23 Safety and Effectiveness Outcomes, by age Subgroup in BRiTE All (N=1953) <65y (n=1057) y (n=533) 75y (n=363) 80y (n=161) Safety,% GI perforation Post-op bleeding or WHCs ATE Grade ¾ bleeding New/worsening HTN Survival Median PFS, months yr survival rate, % Median OS, months

24 Analysis of outcomes in older patients Trial Age yrs N Median PFS (m) Median OS (m) PFS HR (95% CI) P value OS HR (95% CI) P value AVF2107 & AVF2192 pooled analysis 1 > vs vs p< p=0.006 BRITE 3 > n/a n/a NO16966, AVF2107, AVF2192, & E3200 pooled analysis 2 > vs vs ( ) 0.80 ( ) ARIES 4 > n/a n/a 1 Kabbinavar FF, et al. J Clin Oncol. 2008;27: ; 2 Cassidy J, et al. J Cancer Res Clin Oncol. 2010;136:737 43; 3 Kozloff MF, et al. Oncology. 2010;78:329 39; 4 Kozloff MF, et al. J Clin Oncol. 2011;29 (suppl; Abst. 3625).

25 AGITG MAX study N=156 C Capecitabine 1250 mg/m 2 b.i.d. days 1 14, q21d Previously untreated mcrc, PS<2 N=471 R N=157 CB Capecitabine 1250 mg/m 2 b.i.d. days 1 14, q21d + Bevacizumab 7.5 mg/kg day 1, q21d Stratified by Age >65 and <65 yrs ECOG PS 0 vs1/2 Cape dose: 1 g bd vs 1.25 g bd Primary Endpoint: PFS N=158 CBM Capecitabine 1250 mg/m 2 b.i.d. days 1 14, q21d+ MMC 7 mg/m 2 q42d + Bevacizumab 7.5 mg/kg day 1, q21d Tebbutt N et al JCO :

26 Outcomes: PFS, OS and RRs Median Age for whole trial ~ 67 yrs C CB CBM PFS 5.7m 8.5m* P< m* p<0.001 HR OS 18.9m 18.8m 16.4 ORR 30.3% 38.1% 45.9% Post-PD Rx 68% 61% 62% All 3 active drugs received after progression 22%, 17% and 15% for C, CB and CBM *As compared to capecitabine

27 Pre-specified sub-group analyses (PFS) based on all patients in MAX

28 MAX: Bevacizumab-related AEs

29 MAX elderly sub-group: ATE risk factors Price T et al Ann Oncol

30 PFS Sub-group analysis of PFS Pts <75 yrs vs > 75yrs OS Exposure to all active drugs: <75 yrs: 20% >75 yrs 10% Price T et al Ann Oncol

31 AVEX Trial: A prospective trial in elderly patients Previously untreated mcrc, age 70 years N=280 Randomize 1:1 Capecitabine 1000 mg/m 2 b.i.d. days 1 14, q21d + Bevacizumab 7.5 mg/kg day 1, q21d Key inclusion criteria ECOG PS 0 2 Stratification factors: ECOG PS (0 1 vs 2) Geographic region Capecitabine 1000 mg/m 2 b.i.d. days 1 14, q21d Prior adjuvant chemotherapy allowed if completed >6 month before inclusion Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin Key exclusion criteria Prior chemotherapy for mcrc or prior adjuvant anti-vegf treatment Clinically significant cardiovascular disease Current or recent use of aspirin (>325 mg/day) or other NSAID Use of full-dose anticoagulants or thrombolytic agents Cunningham D GI ASCO 2013

32 Statistical considerations Primary endpoint: PFS Secondary endpoints: ORR, time to response, duration of response, OS, safety Designed to detect a 31% reduction in the risk of progression (HR 0.69) 232 events required to achieve 80% power for a 2-sided test at the 5% level PFS/OS curves estimated using Kaplan-Meier method, differences assessed using unstratified log-rank tests Stratified Cox regression model used to estimate HR HR = hazard ratio; PFS = progression-free survival; ORR = overall response rate; OS = overall survival

33 Select baseline patient characteristics Cape + BEV (n=140) Cape (n=140) Sex, % Female Median age, years (range) 76 (70 87) 77 (70 87) <75 years, % years, % ECOG performance status, % Prior adjuvant therapy, % Yes Site of metastatic disease, % Liver Lung Other Liver only Surgical resection, % Yes Location of primary disease, % Colon only Rectum Colon and rectum ITT population. Cape = capecitabine; ECOG PS = Eastern Cooperative Group performance status.

34 Progression-free survival PFS estimate Cape + BEV (n=140) Cape (n=140) HR=0.53 (95% CI: ) P< mo 9.1 mo Time (months) Number at risk Cape + BEV Cape ITT population. 113 PFS events in the Cape + BEV arm; 127 PFS events in the Cape arm. CI = confidence interval; PFS = progression-free survival

35 Subgroup analysis of PFS Cape + BEV better Cape alone better Category Subgroup N HR (95% CI) All All ( ) Sex Female ( ) Male ( ) Age <75 years ( ) Baseline ECOG performance status 75 years ( ) ( ) > ( ) Prior adjuvant therapy No ( ) Yes ( ) Liver metastases only No ( ) Yes ( ) Surgical resection No ( ) Yes ( ) Location of primary disease Colon only ( ) Rectum and colon ( ) Rectum only ( ) HR ITT population.

36 Overall survival OS estimate Cape + BEV (n=140) Cape (n=140) HR=0.79 (95% CI: ) P= mo 20.7 mo Time (months) Number at risk Cape + BEV Cape ITT population. 75 OS events in each treatment arm.

37 Subsequent therapies Subsequent therapy (selected), % Cape + BEV (n=140) Cape (n=140) Any additional treatment for malignancy Fluorouracil Capecitabine Oxaliplatin-doublet Irinotecan-doublet Bevacizumab Cetuximab Panitumumab ITT population.

38 Overall response rate Outcome, % Cape + BEV (n=140) Cape (n=140) ORR (CR + PR) P=0.042 CR PR SD PD Disease control rate (CR + PR + SD) P=0.005 Missing ITT population. CR = complete response; PD = disease progression; PR = partial response; SD = stable disease.

39 Overview of adverse events AE, % Cape + BEV (n=134) Cape (n=136) Any AE SAE Grade 3 AE Grade 5 AE Any AE leading to dose modification AE leading to discontinuation Safety population. AE = adverse event; SAE = severe adverse event.

40 AEs of special interest to BEV AE% Cape + BEV (n=134) Cape (n=136) All grades Grade 3 All grades Grade 3 Bleeding/hemorrhage Hypertension Venous thromboembolic events Proteinuria Arterial thromboembolic events Wound healing complications 1.5 Pulmonary hemorrhage/hemoptysis Fistulae 0.7 Congestive heart failure GI perforation RPLS Safety population. GI = gastrointestinal; RPLS = reverse posterior leukoencephalopathy syndrome.

41 AEs related to chemotherapy occurring in 5% of patients in the Cape + BEV arm (selected) AE,% Cape + BEV (n=134) Cape (n=136) All grades Grade 3 All grades Grade 3 Hand-foot syndrome Diarrhea Asthenia Fatigue Nausea Vomiting Stomatitis Neutropenia Safety population. Not listed: decreased appetite, abdominal pain, constipation, pyrexia, epistaxis, mucosal inflammation, lethargy, arthralgia, peripheral oedema, pain in extremity, pain, musculoskeletal pain, skin hyperpigmentation, dizziness, headache, upper abdominal pain, dyspepsia, pulmonary embolism, dry skin, paraesthesia, rhinorrhoea.

42 Analysis of outcomes in older patients Trial Age yrs N Median PFS (m) Median OS (m) PFS HR (95% CI) P value OS HR (95% CI) P value AVEX > vs vs ( ) P< ( ) P=0.182 AGITG MAX >75 99 >75 sub-group 1 (21%) 8.8 vs vs ( ) p< ( ) p=0.31 AVF2107 & AVF2192 pooled analysis 2 NO16966, AVF2107, AVF2192, & E3200 pooled analysis 3 > vs 6.2 > vs vs vs p< ( ) 0.70 p= ( ) BRITE > n/a n/a ARIES > n/a n/a 1 Price TJ, et al. Ann Oncol. 2012;23:1531 6; 2 Kabbinavar FF, et al. J Clin Oncol. 2008;27: ; 3 Cassidy J, et al. J Cancer Res Clin Oncol. 2010;136:737 43; 4 Kozloff MF, et al. Oncology. 2010;78:329 39; 5 Kozloff MF, et al. J Clin Oncol. 2011;29 (suppl; Abst. 3625).

43 Outline Background anti EGFR therapies anti VEGF therapies Conclusions

44 Conclusions Bevacizumab in combination with single agent capecitabine should be considered as a standard first-line treatment option for elderly patients (>70 yrs) with mcrc The addition of bevacizumab to capecitabine appears to be well tolerated with little additional toxicity In older patients there is a small to modest increased risk of increased ATEs Based on tolerability, bevacizumab + capecitabine could be considered an alternative to doublet therapy +/- bevacizumab in older patients where surgical resection is unlikely Those fit older patients selected for inclusion in clinical trials appear to derive a similar benefit to younger patients in terms of RR and PFS from the use of bevacizumab or anti-egfrs plus fulldose combination chemotherapy.

45 Thank you