Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (MRC FOCUS) - a 2135-patient randomised trial in advanced colorectal cancer Matt Seymour, on behalf of the UK NCRI Colorectal Clinical Studies Group and FOCUS Trial Investigators (Enquiries: Matt.Seymour@leedsth.nhs.uk)

Background and rationale for study Both oxaliplatin and irinotecan are well-established active agents in metastatic colorectal cancer. Each can be used in combination with fluoropyrimidines in 1st-line therapy or as 2nd-line therapy. Irinotecan may also be used as single-agent 2nd-line therapy. Phase III trials reported in 1999-2000 gave proof of improved RR and PFS, but also some additional toxicity, with 1st-line combination therapy. OS advantage was seen in irinotecan but not oxaliplatin trials, a difference which was thought to have arisen from differing usage of effective 2nd-line/cross-over therapy. From 2002, UK Health Service guidance recommended 1st-line FU alone followed by 2nd-line single-agent irinotecan for most patients (but 1st-line FU/Ox combination for patients where a response may potentially allow liver resection). QUESTION: does 1st-line combination therapy improve overall survival and/or quality of life compared with 1st-line FU plus a consistent policy of 2nd-line combination therapy or 2nd-line irinotecan?

Aims To determine if there is an advantage to the use of combination chemotherapy for colorectal cancer compared with the UK standard approach of sequential FU then Ir (“staged single agents”) To determine if combination therapy is best used 1st-line, or reserved for 2nd-line after single-agent FU (“staged combination”). To compare the efficacy and toxicity of an irinotecan-containing combination vs the equivalent oxaliplatin-containing combination

to find predictive variables Design A:(700 pts) FU until it fails, then change to Ir B(ir): (350) FU until it fails, then add Ir B(ox): (350) FU until it fails, then add Ox C(ir): (350) FU+Ir from the start until it fails C(ox): (350) FU+Ox from the start until it fails Ox+fluoropyrimidine Ox+fluoropyrimidine Ir +fluoropyrimidine Ox +fluoropyrimidine 2100 patients 3rd drug salvage introduced Feb 03; prior to that “no crossover” salvage with Mitomycin/FU time to failure of first 2 drugs. molecular pathology to find predictive variables (Adlard et al ASCO‘04 #9506) Power: 80% (α = 0.01) to detect a difference of 22.5% vs 15% in 2-year overall survival of each plan against Plan A.

Endpoints Primary - Overall survival Secondary - PFS, RECIST response, Time to failure of first two drugs Other – Quality of Life & Economic evaluation

Drug Regimens FU “MdG” Ir + FU “IrMdG” Ox + FU “OxMdG” Ir dexamethasone 8 mg iv l-LV 175 mg 2hr ivi 5FU 400 mg iv bolus 5FU 2800 mg 46-hr ivi oral dexamethasone d2-4 cycle repeat 14 days Ref: Cheeseman et al, Br J Cancer 87:393-9, 2002 Ir + FU “IrMdG” dexamethasone 8 mg iv irinotecan 180mg/m2 30 mins ivi, then l-LV 175 mg, 2hr ivi FU 400 mg/m2 iv bolus FU 2400 mg/m2 46hr ivi oral dexamethasone d2-4 cycle repeat 14 days Ref: Leonard et al, Br J Cancer 87:1216-20, 2002 Ox + FU “OxMdG” dexamethasone 8 mg iv oxaliplatin 85mg/m2 plus l-LV 175 mg, 2hr ivi (concurrent), then FU 400 mg/m2 iv bolus FU 2400 mg/m2 46hr ivi oral dexamethasone d2-4 cycle repeat 14 days Ref: Cheeseman et al, Br J Cancer 87:393-9, ‘02 Ir single-agent Ir dexamethasone 8 mg iv irinotecan 350 mg/m2, 90 mins ivi (300 mg/m2 if PS2 or age >70) oral dex d2-4 cycle repeat 21 days Reference: SPC

Eligibility Criteria Histologically confirmed adenocarcinoma of the colon or rectum Inoperable metastatic of locoregional disease No previous chemotherapy for established metastatic disease WHO performance status 0, 1 or 2 BUT: Patients with with metastases which may potentially become operable after a chemotherapy response were not entered (eligible for 1st-line Ox+FU combination under national guidance)

Results A n=701 B(ir) n=356 B(ox) n=356 C(ir) n=356 C(ox) n=357 2135 patients were entered between May 2000 and December 2003 at 61 participating oncology centres in the UK and Cyprus Pre-treatment characteristics Plan A n=701 B(ir) n=356 B(ox) n=356 C(ir) n=356 C(ox) n=357 male female 70% 30% 69% 31% 66% 34% 67% 33% Age: median (interquartiles) 63 (56-69) 64 (57-70) 64 (56-69) 64 (57-69) PS = 0 PS = 1 PS = 2 41% 50% 9% 41% 51% 8% 41% 50% 8%

Chemotherapy delivery Plan A B(ir) B(ox) C(ir) C(ox) first two drugs on FOCUS plan 1st line regimen (mean cycles) MdG 10 MdG 9.7 IrMdG 10.5 OxMdG 10.6 2nd line regimen (mean cycles Ir 4.9 IrMdG 7.7 OxMdG 7.7 - salvage: third and further drugs received any salvage chemo 24% 27% 25% 46% 41% received cross-over drug (Ox/Ir) 13% (Ox) 12% (Ox) 17% (Ir) 27% (Ox) 26% (Ir)

A,B(ir) & B(ox) C(ir) C(ox) Tolerability of 1st-line therapy: CTC grade3 toxicity A,B(ir) & B(ox) C(ir) C(ox) Treatment regimen (n) MdG (1316) IrMdG (339) OxMdG (340) neutrophils 8.6% 19.5% 27.7% platelets 0.4% 1.2% 2.4% vomiting 3.0% 7.7% diarrhoea 5.5% 12.4% 10.6% neuropathy 0.7% 2.7% 11.2% lethargy 13.0% 21.3% 23.8% alopecia 0.2%

A B(ir) B(ox) Tolerability of 2nd-line therapy: CTC grade3 toxicity Treatment regimen (n) Ir (337) IrMdG (175) OxMdG (200) neutrophils 13.1% 19.4% 23.9% vomiting 5.9% 4.6% 5.1% diarrhoea 15.7% 8.6% 8.0% neuropathy 0.6% 1.1% 3.0% lethargy 17.2% 19.9% 19.1% alopecia 9.5% 2.9% 0.0%

Overall survival (1556 events) Proportion Months Overall survival (1556 events)

Overall survival (1556 events) Proportion Months

Plan First 2 drugs schedule Median OS A FU then Ir 13.9 B(ir) B(ox) FU then FU/Ir FU then FU/Ox 14.8 15.2 C(ir) C(ox) 1st-line FU/Ir 1st-line FU/Ox 16.3 Comparison n Logrank HR (95%ci) p B vs A B(ir) vs A B(ox) vs A B(ir)+B(ox) vs A . 1066 1422 0.92 (0.60 – 1.07) 0.95 (0.82 – 1.10) 0.93 (0.82 – 1.05) 0.275 0.456 0.247 C vs A C(ir) vs A C(ox) vs A C(ir)+C(ox) vs A . 1067 1423 0.86 (0.74 – 1.00) 0.96 (0.83 – 1.11) 0.90 (0.80 – 1.02) 0.043 0.563 0.109 C vs B C(ir) vs B(ir) C(ox) vs B(ox) C(ir)+C(ox) vs B(ir)+B(ox) 712 713 1425 0.93 (0.78 – 1.12) 1.03 (0.90 – 1.29) 0.98 (0.88 – 1.14) 0.441 0.712 0.695 IrMdG vs OxMdG B(ir) vs B(ox) C(ir) vs C(ox) B(ir)+C(ir) vs B(ox)+C(ox) 0.97 (0.82 – 1.16) 0.88 (0.74 – 1.05) 0.93 (0.82 – 1.05) 0.771 0.165 0.220

Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)] Age

Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)] Performance Status

Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)] Prior Adjuvant Chemo

A,B(ir) & B(ox) C(ir) C(ox) Response to 1st line chemotherapy (RECIST) criteria A,B(ir) & B(ox) C(ir) C(ox) Treatment regimen (n) MdG (1157) IrMdG (284) OxMdG (299) CR+PR 28.5% 51.4% 56.2% SD 47.9% 37.0% 30.1% PD 23.6% 11.6% 13.7% (Measurable patients with 1 follow-up assessment)

PFS, 1st line (1969 events)

A B(ir) B(ox) Response to 2nd line chemotherapy Treatment regimen (n) IrMdG (141) OxMdG (155) CR+PR 11% 21% 23% SD 42% 44% 48% PD 47% 35% 28%

PFS, 2nd line (659 events) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 6 12 18 regimen 186 209 163 182 310 355 Events Total Plan A Ir Plan B(ir) IrMdG Plan B(ox) OxMdG

Time to failure of the first two drugs (1505 events) Median FFS HR (95%CI), p-value (versus A) A 10.5 B(ir) 11.3 0.90 (0.78, 1.06) p=0.203 B(ox) 11.6 0.90 (0.77, 1.04) p=0.163 C(ir) 9.0 1.25 (1.08, 1.45) p=0.003 C(ox) 9.2 1.19 (1.03, 1.38) p=0.020 Proportion Months

QoL - EORTC QLQ-C30 - mean global QL scores over time

Conclusions: Overall survival: No major differences: no comparisons reached p<0.01 level. “Staged single agents” (FU then Ir) tends towards inferiority compared to any other plan (reaches p=0.043 against 1st-line FU+Ir). “Staged combination” (FU then combination) is non-inferior to 1st- line combination chemotherapy (HR 0.98 [0.86-1.10]). Trend toward OS benefit for 1st-line combination in PS2 subgroup. Secondary endpoints: We confirm higher RR, PFS and toxicity of combination therapy. 1st-line combination “uses up” first 2 drugs earlier. The higher RR/PFS of 1st-line combinations does not give better QoL.

Questions and issues: Many of the best prognosis patients (“potentially down-stageable” liver metastases) were not included in this trial: explains why median OS is lower than in some other trials. conclusions don’t apply to potentially down-stageable patients. Low rate of “3rd drug salvage” in this trial (non-crossover policy up to Feb 2003). would more cross-over have affected the result? The “MdG” FU regimen is highly active (RR 28.5%, PFS >7 months). success of staged combination may depend on this high efficacy. Non-inferiority of the staged combination permits consideration of 1st-line “MdG+novel therapy” arms in future trials.