Bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX)

David Cunningham, 1 Lorusso, 4 Janja Ocvirk, Istvan Lang, 5 2 Eugenio Marcuello, Dong Bok Shin, 6 Derek Jonker, 7 3 Vito Stuart Osborne, 8 Niko Andre, 9 Daniel Waterkamp, 8 Mark P. Saunders 10

1 Royal Marsden Hospital, London and Surrey, United Kingdom; 2 National Institute of Oncology, Budapest, Hungary; 3 Hospital de Sant Pau de Barcelona, Barcelona, Spain; 4 National Cancer Institute "Giovanni Paolo II" Bari, Italy; 5 Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia; 6 Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea; 7 Department of Medical Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada; 8 F. Hoffmann-La Roche Ltd, Basel, Switzerland; 9 Roche Pharma AG, Grenzach-Wyhlen, Germany; 10 Christie Hospital, Withington, Manchester, United Kingdom

Disclosures

•

David Cunningham

–

Research funding from F. Hoffmann-La Roche Ltd., Merck KGaA, Novartis, Celgene, Amgen, and AstraZeneca

Background and rationale

•

Although the median age of patients diagnosed with mCRC is 69 years, older patients are in general undertreated and the optimal treatment approach still needs to be evaluated 1,2

•

Bevacizumab (BEV) is a standard of care in mCRC 3-5 and prior analyses have suggested that elderly patients benefit from the addition of BEV to chemotherapy 6-8

•

AVEX is the first phase III trial to prospectively evaluate the use of a biologic in an elderly patient population with mCRC

1 Howlader N, et al. http://seer.cancer.gov/csr/1975_2009_pops09; 2 Golfinopoulos V, et al. Cancer Treat Rev. 2006;32:1 –8; 3 Hurwitz H, et al. N Engl J Med. 2004;350:2335 –42; 4 Giantonio BJ, et al. J Clin Oncol. 2007;25:1539 –44; 5 Bennouna J, et al. Lancet Oncol. 2013;14:29 – 37; 6 Cassidy J, et al. J Cancer Res Clin Oncol. 2010;136:737 –43; 7 Kozloff MF, et al. Oncology. 2010;78:329 –39; 8 Price TJ, et al. Ann Oncol. 2012;23:1531 –6.

Study design

•

Capecitabine 1000 mg/m 2 days 1 –14, q21d b.i.d. + Bevacizumab 7.5 mg/kg day 1, q21d Previously untreated mCRC, age



70 years N=280 Randomize 1:1 Stratification factors:

– –

ECOG PS (0 –1 vs 2) Geographic region Capecitabine 1000 mg/m 2 days 1 –14, q21d b.i.d. Key inclusion criteria

–

ECOG PS 0 –2

– –

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

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

Select baseline patient characteristics

Sex, % Median age, years (range) Female ECOG performance status, % Prior adjuvant therapy, % Site of metastatic disease, % Surgical resection, % Location of primary disease, % <75 years, % ≥75 years, % 0 1 2 Yes Liver Lung Other Liver only Yes Colon only Rectum Colon and rectum Cape + BEV (n=140) 40.0

76 (70 –87) 39.3

60.7

50.0

41.4

7.1

32.1

62.9

35.7

35.0

37.1

73.6

57.9

31.4

10.7

Cape (n=140) 40.0

77 (70 –87) 32.9

67.1

42.9

47.9

7.9

18.6

67.9

40.7

22.9

38.6

63.6

54.3

25.0

19.3

ITT population. Cape = capecitabine; ECOG PS = Eastern Cooperative Group performance status.

Progression-free survival

1.0

0.8

0.6

0.4

Cape + BEV (n=140) Cape (n=140) HR=0.53 (95% CI: 0.41

–0.69) P<0.001

0.2

0.0

5.1 mo 9.1 mo 0 2 4 6 8 10 12 14 16 18 20 22 Time (months) 24 26 28 30 32 34 36 38 40 Number at risk Cape + BEV 140 121 99 80 68 55 41 28 23 16 13 9 8 3 2 2 2 2 1 0 0 Cape 140 109 82 56 38 25 13 9 6 4 4 2 1 1 1 1 1 1 1 1 0

ITT population. 113 PFS events in the Cape + BEV arm; 127 PFS events in the Cape arm. CI = confidence interval; PFS = progression-free survival

Subgroup analysis of PFS

Category All Sex Age Subgroup All Female Male <75 years ≥75 years 0 Baseline ECOG performance status Prior adjuvant therapy Liver metastases only Surgical resection Location of primary disease >0 No Yes No Yes No Yes Colon only Rectum and colon Rectum only N 280 112 168 101 179 130 147 206 71 162 106 86 192 157 42 79 Cape + BEV better Cape alone better 0.51

0.59

0.53

0.54

0.27

0.62

0.67

0.22

0.41

HR 0.53

0.47

0.57

0.52

0.52

0.61

0.50

(95% CI) (0.41

–0.69) (0.30

–0.72) (0.41

–0.80) (0.32

–0.83) (0.37

–0.72) (0.41

–0.89) (0.34

–0.72) (0.37

–0.69) (0.33

–1.04) (0.38

–0.75) (0.35

–0.83) (0.16

–0.48) (0.45

–0.85) (0.47

–0.94) (0.08

–0.56) (0.24

–0.69) HR 0 0.6

1 2

ITT population.

Overall survival

1.0

0.8

0.6

0.4

Cape + BEV (n=140) Cape (n=140) HR=0.79 (95% CI: 0.57

–1.09) P=0.182

0.2

0.0

16.8 mo 20.7 mo 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (months) 28 30 32 34 36 38 40 42 44 46 Number at risk Cape + BEV 140 126 120 106 95 89 81 67 60 51 44 40 34 24 16 15 12 10 8 6 5 4 2 0 Cape 140 120 108 94 85 73 62 57 49 37 33 23 19 13 11 10 9 7 6 5 5 3 1 0

ITT population. 75 OS events in each treatment arm.

Subsequent therapies

Subsequent therapy (selected), % Any additional treatment for malignancy 5-Fluorouracil Capecitabine Oxaliplatin-doublet Irinotecan-doublet Bevacizumab Cetuximab Panitumumab Cape + BEV (n=140) 37.1

10.7

5.0

2.1

5.7

5.7

2.9

0.7

ITT population.

Cape (n=140) 37.1

9.3

7.9

0.7

2.9

7.9

1.4

4.3

Overall response rate

Outcome, % ORR (CR + PR) SD PD CR PR Disease control rate (CR + PR + SD) Missing Cape + BEV (n=140) 19.3

P=0.042

Cape (n=140) 10.0

2.1

1.4

17.1

55.0

8.6

47.9

10.0

74.3

21.4

57.9

P=0.005

15.7

ITT population. CR = complete response; PD = disease progression; PR = partial response; SD = stable disease.

20.7

Study drug exposure

Safety population.

Overview of adverse events

AE, % Any AE SAE Grade ≥3 AE Grade 5 AE Any AE leading to dose modification AE leading to discontinuation Cape + BEV (n=134) 95.5

30.6

59.0

8.2

54.5

25.4

Cape (n=136) 95.6

32.4

44.1

11.8

43.4

14.0

Safety population. AE = adverse event; SAE = severe adverse event.

AEs of special interest to BEV

AE% Bleeding/hemorrhage Hypertension Cape + BEV (n=134) All grades 25.4

Grade ≥3 – 19.4

2.2

Venous thromboembolic events Proteinuria 11.9

7.5

8.2

1.5

Arterial thromboembolic events Wound healing complications Pulmonary hemorrhage/hemoptysis Fistulae Congestive heart failure GI perforation RPLS 4.5

1.5

0.7

0.7

– – – 3.7

– – – – – –

Safety population. GI = gastrointestinal; RPLS = reverse posterior leukoencephalopathy syndrome.

All grades 6.6

5.1

Cape (n=136) Grade ≥3 0.7

1.5

5.1

0.7

2.9

– 0.7

– 0.7

– – 4.4

– 1.5

– 0.7

– 0.7

– –

AEs related to chemotherapy occurring in ≥5% of patients in the Cape + BEV arm (selected)

AE,% Hand-foot syndrome Diarrhea Asthenia Fatigue Nausea Vomiting Stomatitis Neutropenia Cape + BEV (n=134) Cape (n=136) All grades Grade ≥3 48.5

14.9

All grades 39.7

Grade ≥3 6.6

40.3

22.4

23.9

23.9

20.1

14.9

5.2

6.7

5.2

3.7

0.7

1.5

– 0.7

35.3

15.4

27.2

26.5

11.0

8.1

1.5

6.6

4.4

0.7

– 1.5

0.7

0.7

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.

Conclusion

• • • • •

AVEX is the first phase III trial to prospectively evaluate the use of a biologic in mCRC patients ≥70 years, a population that is in general undertreated The addition of BEV to cape significantly improved PFS and ORR

–

PFS 9.1 vs 5.1 months (HR 0.53; p<0.001)

–

ORR 19.3% vs 10.0% (p=0.042) A numerically longer OS was observed in the BEV-containing arm, but this did not reach statistical significance The safety profile was consistent with previously reported data of BEV in mCRC Results from AVEX suggest that the combination of BEV and cape is an effective and well tolerated regimen for patients ≥70 years with mCRC

Acknowledgments

•

The authors would like to thank the patients and their families, the study investigators, study coordinators and nurses

AVEX Study Investigators

Austria Greil R Ludwig H Nitsche D Canada Berry S Brezden-Masley C Dowden S Jeyakumar A Jonker D Lohrisch C Welch S Hungary Dank M Lang I Pintér T Ruzsa A Italy Boni C Di Costanzo F Lorusso V Zeuli M Mexico Leon Rodríguez E Magallanes-Maciel M Poland Deptala A Koralewski P Slovenia Ocvirk J South Korea Park J-H Park Y-S Shin D-B Shin S-J Spain Alonso JD Anton Torres A Duenas Garcia R Marcuello E United Kingdom Cleator S Cunningham D Gollins S Hopkins K Potter V Saunders M Sizer B Steward W Waterston A