Niall C. Tebbutt International randomised phase III study of capecitabine, bevacizumab, and mitomycin C in first-line treatment of metastatic colorectal cancer: Final results of AGITG MAX study

The MAX study: final results Authors: Niall C. Tebbutt, Val Gebski, Kate Wilson, Michelle Cummins, YuJo Chua, Bridget Robinson, Adam Broad, David Cunningham, John Simes, Timothy Price; on behalf of the Australasian Gastro-Intestinal Trials Group (AGITG) Funding: MAX was an investigator-initiated study sponsored by AGITG, supported by Roche Products Pty Ltd, and coordinated independently at the NHMRC Clinical Trials Centre, University of Sydney.

Background Adding bevacizumab to oxaliplatin- or irinotecan-based doublet chemotherapy has shown benefit for patients with advanced colorectal cancer (CRC). Some patients may not be suitable for oxaliplatin or irinotecan based regimens because of comorbidities. Other patients may not require initial treatment with combination chemotherapy. Capecitabine ± mitomycin C (MMC) is an alternative, convenient chemotherapy regimen with a generally favourable toxicity profile in the Australasian population. This study evaluated the impact of the addition of bevacizumab ± MMC to capecitabine in patients with advanced CRC.

MAX study objective To identify a low-toxicity regimen suitable for a broad population of patients with previously untreated metastatic colorectal cancer.

Study schema C CB CBM capecitabine* Age, ≥65 vs <65 PS, 0,1 vs 2 Metastatic CRC (suitable for capecitabine monotherapy) stratified by: d1 d8 d15 d22 R A N D O M I S E C capecitabine* Age, ≥65 vs <65 PS, 0,1 vs 2 Capecitabine dose Institution CB capecitabine* Disease progression bevacizumab† bevacizumab† CBM capecitabine* bevacizumab† + mitomycin C‡ bevacizumab† * 1.25 or 1 g/m2 bd q3w; † 7.5 mg/kg q3w; ‡7 mg/m2 q 6w max 4 doses Interim safety analysis by IDSM after 60 and 150 patients completed 2 cycles.

Eligibility Histologically confirmed, unresectable metastatic colorectal cancer no prior chemotherapy, other than adjuvant therapy with no relapse for 6 months suitable for capecitabine monotherapy adequate organ function life expectancy at least 12 weeks ECOG PS 0-2 informed consent

Primary endpoint Progression-free survival The study was designed to detect a difference in median progression-free survival from 5.5 months in arm C to 8 months arm CB or CBM at P<0.025 with 80% power (450 patients required). Analysis was by intention-to-treat.

Secondary endpoints response rate overall survival toxicity quality of life Response RECIST assessed every 6 weeks. Toxicity (NCIC CTCAE v 3.0) analyses by treatment received. Quality of life assessed at 3, 6, 9, 12 weeks, then 6 weekly, with UBQ-C, CAQ, EQ-5D.

Patient enrolment and progress 471 randomised C CB CBM 156 157 158 No protocol treatment Ineligible Lost to follow-up Did not complete QOL 2 7 1 12 1 5 16 3 1 15 Treatment not received: Chicken pox and died; declined; unable to tolerate oral medication [1 patient in Arm A with pending eligibility status not mentioned here. ] Included in analysis 156 157 158

Baseline characteristics C CB CBM Median age (range, years) 69 (37–86) 67 (32–85) 67 (33–84) Male (%) 63 65 60 Performance status 0–1 (%) 96 92 93 Capecitabine 1000 mg/m2 bd (%) 66 67 67 Prior adjuvant treatment (%) 22 27 16 Liver metastases (%) 72 75 77 Lymph node metastases (%) 44 50 44 Lung metastases (%) 39 40 39 Peritoneal metastases (%) 21 13 19

Chemotherapy toxicity (%) C CB CBM Grade* Grade Grade Type of toxicity All (3–5) All (3–5) All (3–5) Diarrhoea 62 (11 65 (17) 71 (16) Hand-foot syndrome † 65 (16) 77 (26) 78 (28) Stomatitis 26 (3) 48 (1) 53 (4) Vomiting 31 (5) 38 (5) 40 (4) Nausea 54 (6) 67 (5) 70 (6) Fatigue 74 (10) 78 (10) 85 (13) Febrile neutropenia 2 (2) 3 (3) 2 (2) Infection, no neutropenia 26 (6) 35 (10) 35 (11) Neutropenia, no infection 10 (1) 12 (0) 21 (2) Thrombocytopenia 10 (0) 15 (0) 44 (4) High bilirubin 8 (3) 6 (1) 7 (1) † The only toxicity occurring more often in CB and CBM than C was HFS. When the rate was adjusted for duration of treatment (average cycles: C, 8.4; CB, 10.9; CBM, 10.7), the rate of HFS was no higher in CB or CBM than C (unadjusted OR for HFS: CB vs C was 1.85, for CBM v C was 2.02 (P=0.03), and after adjustment, these were 1.30 and 1.39, respectively (P=0.40)). * NCI CTCAE version 3.0 Grades -- NCI CTCAE version 3.0

Bevacizumab toxicity (%) C CB CBM Grade* Grade Grade Type of toxicity All (3–5) All (3–5) All (3–5) Proteinuria 12 (1) 31 (3) 47 (6) Hypertension 12 (1) 29 (4) 25 (6) Thrombosis or embolism 10 (7) 10 (9) 11 (10) Bowel perforation 1 (1) 3 (3) 1 (1) Haemorrhage 13 (3) 15 (1) 27 (6) Grades -- NCI CTCAE version 3.0 * NCI CTCAE version 3.0

Tumour response (%)* C CB CBM Complete response 1 2 2 Partial response 30 36 44 Overall response 31 38 46 Stable disease 49 54 48 Progressive disease 18 3 3 * C vs CB, P=0.2; C vs CBM, P=0.006

Progression-free survival P values adjusted for level of significance 0.025

Multivariate analysis: progression-free survival Variable % HR (95% CI) P Treatment group C 33 1.00 CB 33 0.63 (0.50–0.79) <0.001 CBM 34 0.56 (0.44–0.71) <0.001 Performance status 0 56 1.00 ≥1 44 1.52 (1.25–1.85) <0.001 Primary tumour resected No 21 1.00 Yes 79 0.72 (0.57–0.92) 0.007 Number of metastatic sites <2 58 1.00 ≥2 42 1.28 (1.05–1.55) 0.01 Alkaline phosphatase U/L <140 64 1.00 ≥140 36 1.37 (1.12–1.67) 0.002 Serum bilirubin µmol/L <14 81 1.00 ≥14 19 1.32 (1.03–1.68) 0.03

Quality of life at 3 and 6 weeks CB vs C CBM vs C First 3 are UBQ summary scales. favours C favours CB favours C favours CBM

Overall survival

Multivariate analysis: overall survival Variable % HR (95% CI) P Treatment group C 33 1.00 CB 33 0.88 (0.68–1.13) 0.3 CBM 34 0.94 (0.73–1.21) 0.6 Performance status 0 56 1 or 2 44 1.91 (1.54–2.35) <0.001 Neutrophils  109/L <8 85 ≥8 15 1.50 (1.12–2.01) 0.007 Alkaline phosphatase U/L <140 64 ≥140 36 1.68 (1.35–2.10) <0.001 Prior radiotherapy No 87 Yes 13 1.43 (1.05–1.95) 0.02 Primary tumour resected No 21 Yes 79 0.73 (0.57–0.93) 0.01

Subsequent treatment after progression(%) C CB CBM Any systemic therapy 68 62 61 Oxaliplatin 50 40 44 Irinotecan 45 44 35 Anti-EGFR 9 10 13 Bevacizumab 4 1 1 Oxaliplatin + irinotecan 31 27 25 Oxaliplatin + irinotecan + EGFR 9 6 11 * Rates are not exclusive: that is, patients treated with multiple regimens are also listed under individual regimens. Each row refers to any regimen containing this drug with or without a fluoropyrimidine.

Conclusions All treatment regimens were well tolerated. Adding bevacizumab, with or without mitomycin C, to capecitabine significantly improves progression-free survival without causing major additional toxicity or impairment of quality of life. Overall survival results were not significantly different between arms, but are promising for a relatively older patient cohort. Capecitabine and bevacizumab, with or without mitomycin C, is an active, low-toxicity regimen that may be considered as a treatment option for patients with metastatic colorectal cancer.

Contact Dr Niall Tebbutt Consultant Medical Oncologist Austin Hospital Heidelberg VIC 3084 Australia Tel: +61 3 9496 5763 Fax: +61 3 9457 6698 niall.tebbutt@ludwig.edu.au