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.

BackgroundAdding 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

•Age, ≥65 vs <65

•PS, 0,1 vs 2

•Capecitabine dose

•Institution

RANDOMISE

capecitabine*

bevacizumab†

bevacizumab† + mitomycin C‡

d1 d8 d15 d22

* 1.25 or 1 g/m2 bd q3w; † 7.5 mg/kg q3w; ‡7 mg/m2 q 6w max 4 doses

capecitabine*

capecitabine*

C

CBM

CB

bevacizumab†

bevacizumab†

Dis

ease

pro

gres

sion

Metastatic CRC (suitable for capecitabine monotherapy)stratified by:

Interim safety analysis by IDSM after 60 and 150 patients completed 2 cycles.

EligibilityHistologically confirmed, unresectable metastatic colorectal cancer no prior chemotherapy, other than adjuvant therapy with no relapse for 6 months suitable for capecitabine monotherapy adequate organ functionlife expectancy at least 12 weeksECOG 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

toxicity

overall survival

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

No protocol treatment

IneligibleLost to follow-upDid not complete

QOLIncluded in analysis

C CB CBM

156 157 158

156 157 158

271

12

151

16

031

15

471 randomised

Baseline characteristicsC CB CBM

Median age (range, years) 69 (37–86) 67 (32–85) 67 (33–84)Male (%) 63 65 60Performance status 0–1 (%) 96 92 93Capecitabine 1000 mg/m2 bd (%) 66 67

67Prior adjuvant treatment (%) 22 27 16Liver metastases (%) 72 75 77Lymph node metastases (%) 44 50 44Lung 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(1165 (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

Bevacizumab toxicity (%)

C CB CBM Grade* Grade

GradeType 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)

* NCI CTCAE version 3.0

Tumour response (%)*

Complete response 12 2

Partial response 3036 44

Overall response 3138 46Stable disease 4954 48

Progressive disease 183 3

* C vs CB, P=0.2; C vs CBM, P=0.006

C CB CBM

Progression-free survival

Multivariate analysis: progression-free survival

Treatment group C 331.00CB 330.63 (0.50–0.79) <0.001CBM 340.56 (0.44–0.71) <0.001

Performance status 0 561.00≥1 441.52 (1.25–1.85) <0.001

Primary tumour resected No 211.00Yes 790.72 (0.57–0.92) 0.007

Number of metastatic sites <258 1.00≥2 421.28 (1.05–1.55) 0.01

Alkaline phosphatase U/L<140 641.00≥140 361.37 (1.12–1.67) 0.002

Serum bilirubin µmol/L <14 811.00≥14 191.32 (1.03–1.68) 0.03

Variable % HR (95% CI) P

Quality of life at 3 and 6 weeksCB vs C CBM vs C

favours C favours CB favours C favours CBM

Social

Physical function

Current health

EQ5D utility

0 0.2 0.4-0.2-0.4 0 0.2 0.4-0.2-0.4

Overall survival

Multivariate analysis: overall survivalVariable % HR (95% CI) PTreatment group C 331.00

CB 330.88 (0.68–1.13) 0.3CBM 340.94 (0.73–1.21) 0.6

Performance status 0 561 or 2 441.91 (1.54–2.35) <0.001

Neutrophils 109/L <8 85≥8 151.50 (1.12–2.01) 0.007

Alkaline phosphatase U/L <14064≥140 361.68 (1.35–2.10) <0.001

Prior radiotherapy No 87Yes 131.43 (1.05–1.95) 0.02

Primary tumour resected No 21Yes 790.73 (0.57–0.93) 0.01

Subsequent treatment after progression(%)

C CBCBMAny systemic therapy 6862 61Oxaliplatin 5040 44Irinotecan 4544 35Anti-EGFR 910 13Bevacizumab 41 1Oxaliplatin + irinotecan 3127 25Oxaliplatin + irinotecan + EGFR 96 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.

ConclusionsAll 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 TebbuttConsultant Medical

OncologistAustin HospitalHeidelberg VIC 3084AustraliaTel: +61 3 9496 5763Fax: +61 3 9457 6698niall.tebbutt@ludwig.edu.au