Ashita Waterston Beatson West of Scotland Cancer Centre

Ashita Waterston Beatson West of Scotland Cancer Centre

Aim of treatment Scheduling and choice of treatments are dictated by aim: Down staging for resectability: upfront intensive Prolong survival: combination upfront Quality of life slower pace of progression: sequential and intermittent

Factors to consider when choosing treatments Age/ comorbidity Service delivery Any prior treatment Government Rate of progression Oligometastases

Primary CRC tumor localization (left vs right) is a potential biomarker Right colon (ascending) Transverse colon Small intestine Left colon (descending) Rectum Anus Sigmoid (colon) Right-sided tumors ~40% (increasing)* Associated with: Older, female patients Mucinous, signet-ring histology Microsatellite instability Poorly differentiated KRAS and BRAF mutations EGFR expression *High-incidence CRC populations Left-sided tumors ~60%* Associated with: Chromosomal instability p53 mutation COX2 expression Aneuploidy High EGFR ligand expression (COIN study) Iacopetti, B. Int J Cancer 2002;101:403 408; Brule SY, et al. ASCO 2013 (Abstract No. 3528); Adams R, et al. ASCO 2012 (Abstract No. 3516)

Chemotherapy back bone

Treatment arms: GERCOR Study R A N D O M I S A T I O N Arm A FOLFIRI irinotecan 180 mg/m 2 IV + simplified LV5FU Arm B FOLFOX6 L-OHP 100 mg/m 2 IV + simplified LV5FU until progression until progression FOLFOX6 FOLFIRI until progression until progression Tournigand et al. J Clin Oncol. 2004;22:229-237.

Efficacy: GERCOR Study Arm A FOLFIRI FOLFOX Arm B FOLFOX FOLFIRI N 109 81 111 69 Confirmed RR 56% 15% 54% 4% PFS (Months) 8.5 4.2 8.0 2.5 Survival (Months) 21.5 20.6 No statistically significant differences in 1 st or 2 nd line therapy RR or PFS and OS The study was designed for the two-sided log-rank test to have 80% power to detect a 20% difference in the proportion of patients without progression at 15 months (60% in arm A, 40% in arm B; type I error of 5%, type II error of 20%) Tournigand et al. J Clin Oncol. 2004;22:229-237.

XELOX as first-line therapy in CRC: Protocol NO16966 Large international phase III trial (n=700): first-line therapy for mcrc 3 weekly cycle Capecitabine 1000mg/m 2 bd D1-14 1 week rest Oxaliplatin 130mg/m 2 R D1 bolus 5fu D1 bolus 5fu 2 weekly cycle LV INF 5FU LV INF 5FU Oxaliplatin 85mg/m 2 Cassidy et al, JCO 2008

Toxicity % Toxicity XELOX FOLFOX Grade 3/4 neutropaenia 7 44 Febrile neutropaenia 0.9 4.8 Grade 3 diarrhoea 19 11 Grade 3 HFS 6 1

Efficacy Protocol RR (%) XELOX 47 PFS (months) 7.3 HR=1.02 OS (months) 19 HR=0.99 FOLFOX* 49 8.1 18.9 *Cassidy ASCO GI symposium 2008/9

Slower growing tumours Safety Patience preference FOCUS: sequential 5FU FOLFOX/FOLFIRI versus upfront combination. No difference Maughan Lancet 2007 CAIRO: sequential capecitabine-irinotecan-xelox versus combination Xeliri Xelox. No difference OS Koopman Lancet 2007

Targeted therapy in CRC The EGFR signaling pathway plays an essential role in colorectal carcinogenesis and progression. This makes it an attractive therapeutic target. The MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR) (www.mycancergenome.org).

Proportion alive, % Overall survival (proportion) Overall survival (proportion) CRYSTAL 1.0 0.8 0.6 0.4 n Months (95% CI) FOLFIRI 350 20.0 (17.4 21.7) Cet + FOLFIRI 316 23.5 (21.2 26.3) HR 0.796 (95% CI 0.670 0.946) p=0.0093 OPUS 1.0 0.8 0.6 0.4 n Months (95% CI) FOLFOX4 97 18.5 (16.4 22.6) Cet + FOLFOX4 82 22.8 (19.3 25.9) HR 0.855 (95% CI 0.599 1.219) p=0.39 0.2 0.2 0 0 6 12 18 24 30 36 42 48 54 Months 0 0 6 12 18 24 30 36 Months PRIME 100 90 80 70 60 50 40 30 20 10 0 n Months (95% CI) FOLFOX4 279 19.4 (17.4 22.6) Pani + FOLFOX4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Months 256 23.8 (20.0 27.7) HR 0.83 (95% CI 0.70 0.98) p=0.027 Van Cutsem E, et al. J Clin Oncol 2011;29:2011 2019; Bokemeyer C, et al. Ann Oncol 2011;22:1535 1546; Douillard J-Y, et al. ASCO 2013 (Abstract No. 3620)

Proportion alive, % Overall survival (proportion) Overall survival (proportion) Effect of EGFR inhibitor treatment in KRAS 12/13 mutant population: OS CRYSTAL 1.0 0.8 0.6 0.4 n Months (95% CI) FOLFIRI 183 16.7 (14.9 19.4) Cet + FOLFIRI 214 16.2 (14.9 17.9) HR 1.035 (95% CI 0.83 1.28) p=0.75 OPUS 1.0 0.8 0.6 0.4 n Months (95% CI) FOLFOX4 59 17.5 (14.7 24.8) Cet + FOLFOX4 77 13.4 (10.5 17.7) HR 1.29 (95% CI 0.87 1.91) p=0.20 0.2 0.2 0 0 6 12 18 24 30 36 42 48 54 60 Months 0 0 6 12 18 24 30 36 Months PRIME 100 90 80 70 60 50 40 30 20 10 0 n Months (95% CI) FOLFOX4 195 19.2 (16.2 21.5) Pani + FOLFOX4 193 15.5 (13.1 17.6) HR 1.16 (95% CI 0.94 1.41) p=0.162 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Months Van Cutsem E, et al. J Clin Oncol 2011;29:2011 2019; Bokemeyer C, et al. Ann Oncol 2011;22:1535 1546; Douillard J-Y, et al. ASCO 2013 (Abstract No. 3620)

Tested mutations K R A S e x o n 2 w i l d - t y p e s u b s e t K R A S E X O N 1 E X O N 2 E X O N 3 E X O N 4 1 2 1 3 w t 6 1 1 4 6 4. 3 % 4. 9 % N R A S E X O N 1 E X O N 2 E X O N 3 E X O N 4 12 13 59 61 117 146 3. 8 % 2 % 0 % B R A F E X O N 1 1 E X O N 1 5 6 0 0 0 % 1 0 % FIRE-3 presentation ECC September 2013

Distribution of mutations in mcrc FIRE-3 presentation ECC September 2013

FIRE-3 study design FIRE-3 presentation ECC September 2013

Overall survival: RAS* wild-type Median Duration of Treatment 5 mo (all 3 agents) Median PFS 10 mo FIRE-3 presentation ECC September 2013

Second-line treatment: RAS evaluable population (N=407) 2nd-line treatment: RAS evaluable population (N=407) Alive after 1st-line therapy Any 2nd-line therapy FOLFIRI + Cetuximab N= 205 84.9% (174/205) 78.7% (137/174) FOLFIRI + Bevacizumab N= 202 83.7% (169/202) 76.9% (130/169) 2nd-line substances, % n=137 (100) n=130 (100) Fluoropyrimidine % 91.2 86.2 Oxaliplatin % 62.0 63.1 Irinotecan % 16.1 16.2 Bevacizumab % 46.0 15.4 Anti-EGFR mab % 17.5 43.8 FIRE-3 presentation ECC September FIRE-3 Presentation ECC September 2013 Treatment with a substance not 2013 being part of 1st-line therapy

mcrc 1st-line KRAS wild type (codons 12,13) N = 1140 FOLFIRI or FOLFOX Chemo + Cetuximab Chemo + Bevacizumab 1 Endpoint: Overall Survival A Venook et al. ASCO 2014

CALGB/SWOG 80405: Eligibility Criteria Untreated Metastatic CRC Tumor KRAS wild type codons 12 & 13 > 12 months since adjuvant therapy ECOG 0-1 Preserved organ function AT ENROLLMENT CHOOSE: FOLFOX or FOLFIRI INTENT: Palliative or Part of strategy to resect all metastases

CALGB/SWOG 80405: Overall Survival Arm N (Events) OS (m) Median 95% CI Chemo + Cetux 578 (375) 29.9 27.0-32.9 Chemo + Bev 559 (371) 29.0 25.7-31.2 P=0.34 HR 0.925 (0.78-1.09)

National Clinical Trials Network NCI CANADA 3,100 Institutions 14,000 Investigators

CALGB / SWOG 80405: WHY DID IT TAKE TEN YEARS? Original Design Unselected CHEMO + BEV v. CHEMO + CETUX v. CHEMO + BEV / CETUX AMEN D CLOSE Final Design KRAS wt CHEMO + BEV v. CHEMO + CETUX 2004 2005 08 2008-09 2010-2012 2013 1/2014 DATA RELEASE [-----OPEN------- ] [------OPEN----- ] Presented by:

First-line treatment RAS wild-type PRIME Study Metastatic CRC RAS wild-type N=512 FOLFOX + Panitumumab PFS (months) OS (months) 10.1 26 FOLFOX 7.9 20.2 p=0.004 p=0.04 Duillard NEJM Sept 2013

First-line treatment RAS wild-type mcrc Approximately 50% population within FIRE-3 Study? Scottish population Therefore patients with RAS wild-type where the intention is to increase survival: FOLFIRI and cetuximab Panitimumab and FOLFOX less evidence for the combination and has not gone through SMC Duration of treatment 6 months or until progression

Treatment in patients with RAS mutation The role of anti VEGF treatment and with what chemotherapy back bone Current Practice: Bevacizumab +FOLFIRI +FOLFOX The Evidence:

Phase III trial of IFL ± bevacizumab: Study design Bolus IFL + placebo (n=411) No bevacizumab past disease progression Previously untreated metastatic CRC Bolus IFL + bevacizumab (n=402) May receive bevacizumab past disease progression IFL: 5-FU/LV + bevacizumab (n=110) May receive bevacizumab past disease progression bolus 5-FU 500mg/m 2 leucovorin 20mg/m 2 irinotecan 125mg/m 2 given 4/6 weeks 5-FU/LV: bolus 5-FU 500mg/m 2 leucovorin 500mg/m 2 given 6/8 weeks Bevacizumab: 5mg/kg every 2 weeks Hurwitz H, et al. NEJM June 2004

Phase III trial of IFL ± bevacizumab: Probability of survival Effect of bevacizumab on overall survival 1.0 0.8 Kaplan-Meier curve ARM n OS (mo) IFL 411 15.6 IFL-Bev 402 20.3 0.6 Hazard ratio = 0.66, p=0.00003 0.4 0.2 IFL + placebo IFL + bevacizumab 0 0 10 20 30 40 Survival (months) Hurwitz H, et al. NEJM June 2004

NO16966 study design

General progression free survival: chemotherapy ± bevacizumab

Open access studies Brite - USA bevacizumab + chemo Beat - European bevacizumab + chemo, n=1914 29% FOLFOX, 26% FOLFIRI, 18% Xelox, 16% monotherapy Toxicity 3% bleeding, 2% GI perf, 1% arterial thromboembolic disease, 5.3% hypertension, 1% proteinuria PFS: 10 months, OS: 22.7 months Van Cutsem Annals oncology 2009

Treatment RAS mutation In Scotland Is this dependent on second-line option Data for bevacizumab and FOLFOX E3200 study Data for aflibercept and FOLFIRI Velour study

Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: Prespecified subgroup analyses from the VELOUR trial Josep Tabernero, Eric Van Cutsem, Radek Lakomý, Jana Prausová, Paul Ruff, Guy A. van Hazel, Vladimir M. Moiseyenko, David R. Ferry, Joseph J. McKendrick, Karen Soussan-Lazard, Soazig Chevalier, Carmen J. Allegra. European Journal of Cancer 2014 50, 320-331DOI: (10.1016/j.ejca.2013.09.013)

Bevacizumab in Combination With Oxaliplatin, Fluorouracil, and Leucovorin (FOLFOX4) for Previously Treated Metastatic Colorectal Cancer: Results From the Eastern Cooperative Oncology Group Study E3200 Kaplan-Meier estimates of survival by treatment. Folfox+bev Folfox Bev Bruce J. Giantonio et al. JCO 2007;25:1539-1544 2007 by American Society of Clinical Oncology

Prognostic impact KRAS/NRAS and BRAF mutation Patients have reduced overall survival No evidence predictive of therapy Therefore should we treat patients more intensively first line

Prognostic impact of KRAS and BRAF mutations FOCUS trial Not predictive for oxaliplatin or irinotecan combination chemotherapy Richman S D et al. JCO 2009;27:5931-5937 2009 by American Society of Clinical Oncology

OS estimate CRYSTAL/OPUS pooled analysis: BRAF mt prognostic, not predictive 1.0 0.9 0.8 0.7 0.6 0.5 0.4 KRAS wt/braf wt HR (95% CI): 0.84 (0.71 1.00); p=0.048 CT + cetuximab (n=349): mos 24.8 mo CT (n=381): mos 21.1 mo KRAS wt/braf mt HR (95% CI): 0.62 (0.36 1.06); p=0.076 CT + cetuximab (n=32): mos 14.1 mo CT (n=38): mos 9.9 mo 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 CRYSTAL/OPUS: Pooled analysis of OS in patients with KRAS wt/braf wt or mt tumors Time (months) Bokemeyer C, et al. Eur J Cancer 2012;48:1466 1475

FOLFOXIRI and bevacizumab: TRIBE Folfoxiri + bevacizumab 12 cycles max 5 FU + bevacizumab Until progression PFS (months) OS (months) 12.3 29.8 mcrc N=508 Folfoxiri 12 cycles max 5 FU + Until progression 9.7 25.8 p=0.0012 p=0.125 Cremilini et al Lance Oncology vol 16 oct 2015

First-line treatment RAS mutation Phase III trial of FOLFOXIRI and bevacizumab subgroup in 28 BRAF mutated patients Median PFS 7 months and OS 13.4 months Numbers small but no difference in treatment

oligometastases Downstaging for resection-maximise intensity: RAS wild-type: cetuximab and FOLFIRI Triple therapy RAS mutation Folfoxiri +? bevacizumab Olivia ASCO 2013 Liver limited metastatic CRC (n= 80) FOLFOXIRI + bevacizumab FOLFOX + bevacizumab R0/1 21 13 p=ns Med PFS (months) 18 12 p=0.009 Fanconi Asco 2013

PS 1/0 Progressed through all current lines of treatment Whats next

Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial Med 0s 6.4 months Med os 5.0 months P=0.0052? Clinical significance Grothey et al vol 381 Lancet 2013

TAS 102 in refractory metastastic colon cancer Recourse study Med os 7.1 months Med os 5.3 months TAS 102 oral combined analogue of thymidine nucleic acid Trifluridine and a thymidine phospholrylate inhibitor tipiracil hydrochloride. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer Robert J. Mayer et al N Engl J Med 2015; 372:1909-1919May 14, 2015

Expanded Access Programmes Drug Companies can promote expanded access programmes Allows access to Novel therapies by Clinicians Limited Time frame Companies can get real life data Time consuming Inclusion/Exclusion criteria vary

+ve Phase III RCT Expanded Access Programmes FDA/EMEA Approval Expanded Access Programmes SMC Approval Expanded Access Programmes

Applications to SMC Sent by Drug company Expert Advice Templates include Current practice Any guidelines on treatment Unmet Need Service implications

SMC Process On EMEA approval Drug Companies can apply to SMC New drugs committee Can ask for End of life drugs includes PACE process Also Orphan and extra Orphan status

PACE Process Panel made up of pharmacists, SMC personnel, Patient advocate-charity, Patients, Oncology expert. Template sent prior looking: Severity of condition, unmet need, effect on patient and family SMC New drugs committee reject Drug Pace Meeting

Approval Process SMC meet with PACE Information Final decision outcome published 4 weeks later During 4 weeks need Protocol to PASG Meet to approve and send to Drugs therapeutic committee Update Clinical management guideline

New kid on the block PD-1 Blockade in Tumors with Mismatch-Repair Deficiency Dung T. Le, et al N Engl J Med Volume 372(26):2509-2520 June 25, 2015

CTLA-4 and PD-1/L1 Checkpoint Blockade Priming phase (lymph node) Effector phase (peripheral tissue) Dendritic cell T cell T-cell migration T cell Cancer cell MH C TCR TCR MHC Dendritic cell B7 CD28 CTLA-4 T cell T cell PD-1 PD-L1 Cancer cell Ribas A. N Engl J Med. 2012;366:2517-2519.

Study design Phase 2 to evaluate immune checkpoint blockade in Pts tumours with or without DNA MMR deficiency Recruited patients with HNPCC One of the germline mismatch genes is defective plus a second somatic mutation & recruited pts with sporadic MMR-deficiency Both alleles inactive through somatic mutation 3 cohorts A- MMR-deficient colorectal adenocarcinomas B- MMR-proficient colorectal adenocarcinomas C- MMR-deficient cancers of types other than colorectal

Study design: Eligibility Inclusion Age >18 CRC >2 treatment Other cancers >1 treatment ECOG 0-1 Life expectancy >3 months Adequate liver, kidney and marrow function Exclusion >50% of liver involved Unstable CNS mets ( no steroids) Chemo in last 14 days Patients with a history of prior treatment with anti- PD-1, anti-pd-l1, anti- PDL2,anti-CD137, anti- OX-40, anti-cd40, or anti-ctla-4 antibodies. (chronic steriods were allowed)

Study design Pembrolizumab was administered iv at a dose of 10mg/kg every 14 days Safety assessments were performed before each treatment Tumour markers were measured at the start of each cycle Radiographic assessment was performed at 12 weeks and every 8 weeks thereafter Mismatch repair status was assessed by assessing the level of microsatellite instability Primary tumour samples and matched blood samples were collected to examine potential for mutant peptide binding A total estimate of the total number of mutation-associated neoantigens in each tumour was made

Clinical Responses to Pembrolizumab Treatment. Le DT et al. N Engl J Med 2015;372:2509-2520

Clinical Benefit of Pembrolizumab according to MMR Status. Le DT et al. N Engl J Med 2015;372:2509-2520

Results: tumour markers / genomic analysis Mutational burden 9 deficient tumours analysed Mean of 1782 somatic mutations per tumour 578 neoantigens 6 proficient tumours analysed Mean of 73 somatic mutations per tumour 21 neoantigens High number of somatic mutations was associated with longer PFS and a trend to OS CEA measured in cohorts A and B 29/32 above the upper limit of normal Cohort A 7/10 CEA fell Cohort B 0/19 CEA fell Cohort C 4 patients had measurable tumour marker 3/4 fell Degree of fall of CEA after 1 dose was predictive of PFS (p=0.01) and OS (p=0.02) Preceded radiographic response

Discussion & Conclusion Supports hypothesis MMR deficient tumours are more responsive to PD-1 treatment Supported by previous evidence of Th-1 infiltration in tumour microenvironment MMR deficient tumours previously shown to strongly express other checkpoint ligands Suggests the greater the neoantigens the greater the response MMR status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. Changes in CEA corresponded with clinical benefit Evaluation of tumour genomics can help guide immunotherapy Phase III trial awaited

Over all Conclusion Biomarker analysis of all Stage IV patients Analyse KRAS, NRAS and BRAF (MMR) Clarify aims of therapy Down staging for resection Reduced survival-intensive Prolong survival Minimal toxicities RAS wild-type: cetuximab and FOLFIRI RAS mutation: doublet and antiangiogenic (second line)