Bevasizumab case presentation

1. Case presentation
Mr PR
58 year-old male

2. Initial Presentation
• Apr 2012
• attending Golf Masters in America
• change in bowel habit
• was once daily, then increased in
frequency and decreased in quantity
and caliber
• attributed this to diet change
• nil other symptoms e.g. tiredness, PR
bleeding

3. Initial Presentation
• routine blood donor, donates blood
every 3/12
• turned away on this occasion due to
anemia
• advised to attend GP for further
investigation of anemia
• developed weight loss of 4 kg (86 kg to
82 kg)
• latest health check-up in Feb 2012 with
GP NAD

4. Presented to GP
• investigated for iron deficiency anemia
• referred to Gastroenterologist (Michael
Merett) for OGD and colonoscopy
• Colono (9/8/12): sessile polyps- 3 in
ascending colon, 1 in distal rectum- all
removed; circumferential neoplasm with
distal margin 12 cm from anal verge
• Bx: moderately differentiated
adenocarcinoma

5. Staging
• CT TAP:
-multiple lung nodules up to 7mm in size;
-extensive liver metastases; largest measuring 8cm in segment
II/III and 7cm in segment VII/VIII; masses appeared confluent
and not confined to one lobe
• MRI rectum:
-widespread liver metastases and enlarged porta hepatis lymph
node
-mass at rectosigmoid junctionn 16cm from anal verge
-ill-defined posterior margin with infiltration into adjacent fat (T3
tumour)
• CT-PET Whole body:
-consistent with CT and MRI findings

6. Diagnosis
• AJCC Stage IV Rectal Cancer
• cT3N1M1
• Histo: moderately differentiated
adenocarcinoma
• Kras wildtype
• Braf wildtype

7. Referral
• presented at colorectal MDM
• referred to colorectal surgeon and
hepatic surgeon to assess for
resectability
• referred to radiation oncologist for
?radiation to primary
• referred to medical oncologist for
chemotherapy opinion

8. Medical History
• Nil significant; previous hernia repair
• No regular meds
• Nil supplements, complementary
therapies
• NKDA
• Nil significant FHx of cancer
• Both parents alive and well (Fa 87, Mo
83)

9. Social History
• CEO of golf club
• separated from wife; two daughters
• gym 5x/week; gold 1x/week
• balanced diet, nil excessive red meat
• social drinker
• non-smoker

10. Progress
• Lesions deemed unsuitable for
resection at this stage
• MDM decisioned for chemotherapy
• FOLFOX-6 with bevacizumab (Avastin)
• Port sited on 3/9/12

11. Chemotherapy
• responded well after first four cycles
• completed 20 cycles of FOLFOX-6 with
Avastin
• minimal side effects or disability except
mild mouth ulcers, minimal peripheral
neuropathy
• ECOG between 0 and 1 throughout
therapy
• dramatic fall in CEA
• good radiological response to chemo

12. CEA
• Index CEA (3/9/12) 458 ➔ 301 ➔ 163
➔ 108 ➔ 71 ➔ 44 ➔ 27 ➔ 16 ➔ 14 ➔
12 ➔ 13 ➔ 15 ➔ 19 ➔ 22 ➔ 18 ➔ 32
➔ 30 ➔ 37 ➔ 39 ➔ 50 ➔ 58 ➔ 95
• latest LDH 262 ➔ 265 ➔ 364
• 7/9/13 UECr, FBC, LFT NAD

13. Progress
• Currently switched to maintenance
chemo with capecitabine (Xeloda) and
Avastin
• presently on fourth cycle
• planned for re-staging CT after sixth
cycle
• KIV surgery if obstruction or further
response
• KIV radiation

14. Clinical question
• The role of bevacizumab in metastatic
colorectal cancer

15. Median OS
• on best supportive care: 5-6 mo
• systemic chemo with 5-FU and
oxaliplatin or irinotecan: ~2 years

16. Treatment aims
• Palliative:
-prolong survival
-maintain QOL
-aim to halt progression
• Curative:
-conversion therapy (conversion of
apparently unresectable disease to
resectable disease)
-aim for response rate

17. Chemo for mCRC
• 5-fluorouracil, capecitabine
• oxaliplatin
• irinotecan
• bevacizumab
• cetuximab, panitumumab
• aflibercept
• regorafinib

18. The “angiogenic
switch”
• inhibition of tumor growth in experimental animals by
selective inhibition of VEGF via anti-VEGF
monoclonal antibodies (MoAbs), VEGF receptor
small molecule kinase inhibitors or MoAbs, or
soluble VEGF receptors
• inhibition of one or more of the molecules that
stimulate VEGF expression (eg, EGF and its
receptor, platelet-derived growth factor [PDGF] and
its receptor, HIFs, cyclooxygenase-2 [COX-2]
inhibitors, and IL-1beta)
• efficacy of endogenous inhibitors of angiogenesis
(eg, endostatin, angiostatin) in xenografts

19. Bevacizumab
• humanized monoclonal antibody
directed against VEGF
• extremely long circulating half-life
~17 to 21 days
• taken up by platelets; virtually complete
neutralization of platelet VEGF
• first proven to have efficacy in
advanced colorectal cancer

20. Bevacizumab
• Benefit first shown in a trial of 813
patients who were randomly assigned
to IFL with or without bevacizumab
• improved objective response rate (45
versus 35 percent) and median survival
(20 versus 16 months)
• significantly improved time to tumor
progression (11 versus 6 months)
• N Engl J Med. 2004;350(23):2335

21. • limited data available on adding
bevacizumab to FOLFIRI
• trials on bevacizumab plus oxaliplatin-
based regimens generally showed
benefit
Bevacizumab

22. XELOX-1/NO16966
• randomized trial of XELOX and FOLFOX4
• later modified to allow for further
randomization to bevacizumab versus no
bevacizumab
• addition of bevacizumab to either regimen
significantly improved PFS
• however, there was no impact on response
rates

23. ECOG 3200
• 829 patients with previously treated
mCRC
• FOLFOX4 versus bevacizumab versus
FOLFOX4 plus bevacizumab
• bevacizumab/FOLFOX4 group had a
significantly better PFS (7.3 versus 4.7
months) and median overall survival
(12.9 versus 10.8 months) compared to
FOLFOX4 alone

24. CAIRO3 trial
• Dutch trial that randomly assigned 558
patients with stable disease or better
after six cycles of XELOX plus
bevacizumab who were not eligible for
potentially curative metastasectomy to
continued capecitable plus
bevacizumab versus observation alone
• Upon first progression (PFS1), patients
in both arms were supposed to be
treated with XELOX plus bevacizumab
until the second progression (PFS2) per
protocol

25. CAIRO3 trial
• maintenance therapy was associated
with a significantly longer PFS1
(median 8.5 versus 4.1 months, HR
0.44, p<0.0001) and PFS2 (11.5 versus
10.5 months, HR 0.81, p = 0.028)
• also longer time to second progression
• trend toward improved overall survival
(median 21.7 versus 18.2 months, HR
0.87, p = 0.16)

26. STOP and GO trial
• Turkish trial that randomly assigned 123
patients who received six cycles of
XELOX plus bevacizumab to to
continued therapy or discontinuation of
oxaliplatin
• median PFS was significantly better in
the group without oxaliplatin i.e.
maintenance therapy with bevacizumab
plus capecitabine (11 versus 8.3
months) (preliminary results)
• also less morbidity in group without
oxaliplatin

27. MACRO trial
• Spanish trial in which patients received six cycles of
first-line XELOX plus bevacizumab followed by
randomization to continued therapy or bevacizumab
maintenance therapy alone until progression or
treatment intolerance
• median PFS and OS in patients treated with
bevacizumab alone were not significantly worse
• but failed to achieve its primary endpoint of non-
inferiority
• similar result in Swiss SAKK 41/06 trial

28. anti-EGFR agents
• three trials (BOND-2, PACCE, CAIRO2)
showed worse survival with
simultaneous targeting of both VEGF
and EGFR
• reason for lack of synergy unknown
• suggestion that bevacizumab prevents
delivery of the drugs to the tumor cells;
reducing tumor targeting of anti-EGFR
antibodies

29. Adjuvant therapy
• NSABP C-08 trial; 2672 patients with
stage II (25 percent) or III colon cancer
• experimental arm received
bevacizumab concurrent with FOLFOX
for six months, and then as
monotherapy for an additional six
months; the control arm was six months
of FOLFOX alone
• no significant benefit with the addition of
bevacizumab in terms of DFS or OS

30. Adjuvant therapy
• AVANT trial; European multi-center trial
• 3451 patients with resected stage III or
high-risk stage II colon carcinoma
• FOLFOX4 alone versus FOLFOX plus
bevacizumab or XELOX plus
bevacizumab
• failed to show DFS or OS benefit
• suggestion of possible detrimental
impact of adding bevacizumab to
oxaliplatin-containing regimen

31. Summary
• For patients treated with a first-line
bevacizumab-containing chemotherapy
regimen, the use of bevacizumab
beyond progression in conjunction with
a second-line fluoropyrimidine-based
chemotherapy regimen can be
considered a standard approach.
• However, for patients with K-ras wild-
type tumors who are receiving
irinotecan-based second line regimens,
bevacizumab should not be used in
conjunction with an anti-EGFR