Bevacizumab plus m folfox6 versus mfolfox6 alone as first line

1. Bevacizumab Plus mFOLFOX6
Versus mFOLFOX6 Alone as First-
Line Treatment for RAS Mutant
Unresectable Colorectal Liver-
Limited Metastases: The BECOME
Randomized Controlled Trial

2. Introduction
• Globally, nearly 1,200,000 new CRC cases are
believed to occur, which accounts for
approximately 10% of all incident of cancers, and
mortality from CRC is estimated at nearly 609,000
• Prevalence estimates reveal that in unscreened
individuals aged 50 years or older, there is a 0.5%
to 2.0% chance of harboring an invasive CRC, a
1.0% to 1.6% chance of an in situ carcinoma, a 7%
to 10% chance of a large (≥1 cm) adenoma,

3. • Sporadic CRC increases dramatically above
the ages of 45 to 50 years for all groups.
• In almost all countries, age-standardized
incidence rates are less for women than for
men

11. Hepatic resection for colorectal
cancer liver metastasis
• Over one-half of these patients will develop liver
metastases at some point.
• Of those, only 20 percent will be candidates for potentially
curative liver resection.
• Long-term survival after surgery for colorectal liver
metastases (CRLMs) has improved dramatically, with five-
year overall survival (OS) rates doubling from approximately
30 percent in the 1980s to 1990s to almost 60 percent in
the last two decades

12. • A risk score was developed based upon known risk factors for mortality.
Mortality for those with scores ≤3 were <2 percent, whereas for a score
>3, mortality was between 7 and 15 percent. The components of the score
●No points: Benign disease
Less than lobectomy
●1 point: Age (>65 years)
Lobectomy or more
●2 points: Ischemic heart disease
Heart failure
Cerebrovascular disease
Malignancy as indication for surgery
●3 points: Preexisting cirrhosis-related complications
●4 points: Preexisting renal disease

13. PATIENT SELECTION
Patient factors —
• Liver resection subjects patients to substantial
physiologic stress.
• In patients with significant medical comorbidities
(eg, significant underlying liver disease, extensive
cardiopulmonary disease, advanced age),
although a CRLM may be resectable, the
perioperative risks may be prohibitive

14. LIVER VOLUME AND FUNCTIONAL
ASSESSMENT
• The growth rate after PVE as well as the degree of
hypertrophy (DH), which is the difference
between the FLR percentage before and after
PVE, have been shown to be important predictors
of post-hepatectomy liver failure
• The FLR percentage is the ratio of the FLR volume
measured with computed tomography (CT)
volumetry (numerator) and the functional liver
volume

15. • DH = [FLR/(TLV-tumor volume)]post-PVE -
[FLR/(TLV-tumor volume)]pre-PVE
• Where: DH: degree of hypertrophy
TLV: total liver volume
FLR: future liver remnant
PVE: portal vein embolization

16. Functional liver remnant thresholds
• In an otherwise normal liver (this is a rare situation):
•A standardized FLR of <20 percent, or
•FLR to body weight ratio of <0.5 percent (Truant criterion)
• In the presence of significant steatosis/cholestasis/chemotherapy-
associated steatohepatitis/chronic hepatitis:
•A standardized FLR of <30 percent , or
•FLR to body weight ratio of <0.8 percent
• In the presence of cirrhosis (Child A):
•A standardized FLR of <40 percent , or
•FLR to body weight ratio <1.4 percent ,

17. Tumor factors

18. • CRLMs from midgut origin (ie, right colon tumors)
were associated with worse pathologic response to
chemotherapy and worse survival after resection
compared with CRLMs from hindgut origin (ie,
left/sigmoid colon tumors).
• The adverse impact of right- versus left-sided primary
tumor location has been noted in colorectal cancer
(CRC) populations including those with unresectable
metastatic disease and localized nonmetastatic disease

19. Anatomic factors
• In patients undergoing liver resection for hepatic
colorectal metastases, a positive surgical margin
is associated with a higher local recurrence and
worse OS and should be avoided whenever
possible.
• While a wide (>1 cm) resection margin should
remain the goal when performing a liver
resection, an anticipated margin of <1 cm should
not be used as an exclusion criterion for
resection.

20. • Assessment of resectability of hepatic colorectal
metastases should focus on the ability to obtain a
complete resection
• The presence of extrahepatic disease should no
longer be considered an absolute
contraindication to hepatic resection provided
the patient is carefully selected and a complete
(margin-negative) resection of both intra- and
extrahepatic disease is feasible.

21. Anatomic factors

23. Preoperative portal vein embolization
• Preoperative PVE is the elective obliteration of
portal blood flow to a selected portion of the
liver a few weeks prior to planned major liver
resection.
• PVE initiates hypertrophy of the anticipated FLR
• Preoperative PVE is a valuable adjunct to major
liver resection, particularly for right-sided tumors,
and it may allow a more extensive resection or
staged bilateral resections

24. • RAS mutational status — Signaling through
the RAS oncogene is an important regulator of cellular
signal transduction, and mutations in RAS represent an
early step in colorectal tumorigenesis.
• RAS mutations are associated with a more aggressive
tumor biology of CRLMs and have been associated with
more positive margins and worse survival after resection.
• Consequently, anatomic resection and/or a wider surgical
margin (eg, >10 mm) may be indicated for patients
with RAS-mutated CRLMs.

25. • In a retrospective study of 633 patients who underwent curative-
intent resection for CRLM at the MD Anderson Cancer Center, 36.2
percent had a RAS mutation .
• Patients with a RAS mutated tumor were twice as likely to have a
positive resection margin (<1 mm) compared with those without
a RAS mutation (11 versus 5 percent).
• RAS mutation (hazard ratio 1.6) and positive margin (hazard ratio
3.4) were independent predictors of poor overall survival by
multivariate analysis.
• It was proposed to aim for a 1 cm resection margin for RAS-
mutated CRLMs

26. • In study of 411 patients who underwent
resection for CRLMs at Johns Hopkins, a 1 to 4
mm margin was associated with improved
survival compared with a positive margin (<1 mm
or R1) for wild-type KRAS tumors
• In KRAS-mutated tumors, however, negative
margin status, which included a 1 cm margin, did
not improve survival

27. • In one study, 389 patients underwent either an anatomic or
non anatomic CRLM resection.
• Patients with wild-type RAS tumors had no difference in
disease-free survival (DFS) based on the type of resection.
• By contrast, patients with RAS mutations had worse DFS
with non anatomic compared with anatomic resection
(10.5 versus 33.8 months).
• The authors of the study suggested that the more
aggressive anatomic resections may be warranted in
patients with RAS mutated tumors.

28. INTRODUCTION
• Over the past decade, oxaliplatin- or irinotecan-based
combination chemotherapy plus molecule-targeted
drugs have been reported to downsize liver metastases
(LMs) and facilitate secondary resection for patients
with colorectal LMs (CLMs).
• Bevacizumab, a recombinant humanized monoclonal
antibody directed against vascular endothelial growth
factor, has been proven to improve survival in first-line
treatment of metastatic colorectal cancer (mCRC) when
added to bolus fluorouracil plus irinotecan

29. • However, randomized studies could not demonstrate a
significantly higher objective response rate when
bevacizumab was added to an infusional doublet in a
mixed cohort of patients with RAS wild-type and
mutant disease
• Randomized studies especially designed for patients
with RAS mutant disease have not been designed so far
as preoperative treatment to achieve liver resection in
patients with liver-limited disease.

30. • Several nonrandomized phase II studies on
bevacizumab plus doublet or triplet chemotherapy
have been reported to yield a high response and
resection rate of LMs for initially unresectable CLMs
• However, all these studies recruited a small number of
patients, and with the lack of a randomized
comparison, the value of bevacizumab added to
chemotherapy for patients with liver-limited RAS
mutant CLMs remains unknown.

31. • Therefore, a single-center randomized trial
was designed to investigate whether
bevacizumab added to modified fluorouracil,
leucovorin, and oxaliplatin (mFOLFOX6) will
result in more liver resections in patients with
initially unresectable liver-limited RAS mutant
synchronous mCRC

32. METHODS
Patient Eligibility
• Patients with mCRC routinely underwent
detection of RAS (codons 12, 13, 59, 61, 117, and
146 of KRAS and NRAS) and BRAF (V600E) status
• Patients with histologically confirmed RAS
mutations and BRAF wild-type colorectal
adenocarcinoma with unresectable liver-limited
metastases were eligible for inclusion

33. • The evaluation was conducted by a local
multidisciplinary team, which included at least 3
liver surgeons and 1 radiologist.
• Other criteria for eligibility were
– age ≥18 and ≤75 years;
– evidence of at least 1 measurable tumor;
– Eastern Cooperative Oncology Group performance
status of 0-1; life expectancy ≥3 months; and
– adequate hepatic, renal, and hematologic function

34. • Patients were also excluded if they had
extrahepatic metastases or other cancers (with
the exception of cervical cancer in situ and
squamous cell carcinoma of the skin) within the
previous 5 years.
• In this controlled trial, patients who met the
eligibility criteria were randomly assigned to
mFOLFOX6 plus bevacizumab (arm A) or
mFOLFOX6 alone (arm B)

35. Treatment
• For arm A, patients received bevacizumab once every 2
weeks (5 mg/kg on day 1) followed by mFOLFOX6 (day 1:
oxaliplatin 85 mg/m2 , folinic acid 400 mg/m2 , and
fluorouracil 400 mg/m2 intravenous bolus and then 2,400
mg/m2 over 46 hours continuous infusion).
• In arm B, patients received the same regimen of
mFOLFOX6.
• Treatments were continued until tumor response indicated
suitability for surgery for LM or until disease progression or
unacceptable toxicity

36. • In the event of predefined toxicity related to
chemotherapy or bevacizumab, protocol-
specified treatment modifications were
permitted
• Patients with progressive disease were treated
at the discretion of the investigators.

37. Trial Design
• The primary end point was the actual conversion rate
to radical resection for LM, which was assessed by the
multidisciplinary team every 4 cycles of treatment up
to 12 cycles
• A cycle was 2 weeks for both arms.
• Patients continued to second-line treatment if they
had disease progression or to maintenance treatment
if they had stable disease after 12 cycles of treatment
without successful conversion.

38. • The maintenance therapy was fluorouracil plus
bevacizumab in arm A and fluorouracil alone in arm B
• LM resectability was determined using 4 criteria:
– ability to obtain a negative margin,
– preservation of 2 contiguous hepatic segments,
– preservation of adequate vascular inflow and outflow as well as
biliary drainage, and
– ability to preserve adequate future liver remnant ( ≥30% in
healthy liver)
• Non resectability was defined as not meeting any of these
criteria

39. • To provide an objective assessment of resectability,
radiologic images were presented by a radiologist to 3 liver
surgeons
• Both the radiologist and the liver surgeons were blinded to
the study treatment.
• LM was considered to be resectable if at least 2 surgeons
voted for radical resection
• For patients whose LMs were assessed as resectable,
resection was scheduled to be performed 6 weeks later in
arm A (2 cycles of chemotherapy without bevacizumab) or
2 weeks after the last treatment cycle in arm B

40. • Once completely recovered from resection, patients
were advised to continue the same therapeutic
regimen (first cycle of chemotherapy without
bevacizumab in arm A) until treatment reached a total
of 12 cycles
• Disease-free survival (DFS) was calculated from the
date of liver surgery to the date of disease recurrence
or last tumor assessment
• Secondary outcomes included tumor response, overall
survival (OS), progression-free survival (PFS), and
toxicity

41. • Adverse events (AEs) were categorized
according to the National Cancer Institute
Common Terminology Criteria for Adverse
Events (version 3.0).
• Postoperative complications were graded
using the Clavien-Dindo grading system

42. • In this trial, tumor response was assessed by a
multidisciplinary team with the use of contrast-
enhanced computed tomography or magnetic
resonance imaging according to RECIST version
1.1.
• The total number of complete responses (CRs)
and partial responses (PRs) was reported as the
overall response rate (ORR), whereas the disease
control rate included CRs, PRs, and stable disease.

43. • PFS was defined as the first day of bevacizumab or
chemotherapy to the date of disease progression or
death.
• Patients without disease progression who discontinued
the study for any reason were censored at the last on-
study tumor assessment date.
• OS was defined as the time from random assignment
to death as a result of any cause or the date of last
follow-up, at which point the data were censored

44. Statistical Methods and Considerations
• Patient baseline characteristics and disease factors
were summarized using descriptive statistics.
• The categorical parameters were compared using 2-
sided Pearson’s x2 test or Fisher’s exact test as
appropriate
• All summary statistics on time-to-event variables were
calculated according to the Kaplan-Meier method and
were compared by means of the log-rank test. SPSS
version 16.0 software was used for statistical analyses

45. • This study is a superior trial design. Sample size is estimated using the Z-
test (pooled).
• It was estimated that 15% of patients would convert to resection for LMs
in the bevacizumab plus mFOLFOX6 group and 5% in the mFOLFOX6-alone
group.
• The number of patients in each group was at a 1:1 ratio.
• The statistical analysis used the Z-test (pooled), 1-sided a α = 0.05, and β =
0.2 (power = 80%).
• The overall dropout rate was considered to be approximately 10%.
• The sample size was estimated as 120 patients in each group using PASS
2011 software

46. RESULTS
Baseline Patient Characteristics
• From October 2013 to December 2017, 445 patients
with CLMs were enrolled at Zhongshan Hospital.
• After screening, 241 patients were randomly assigned
(121 in arm A, 120 in arm B) and accordingly formed
the intention-to-treat (ITT) population.
• Of the ITT population, 11 patients were considered
early dropouts because they discontinued study
treatment within the first 4 treatment cycles, and they
were observed every 2 months in the study

51. • Thus, the evaluable population consisted of 230
patients (115 in both arms A and B)
• There were no major imbalances between the 2
groups in terms of baseline characteristics
• The cutoff date for survival data was June 2019,
with a median potential follow-up time for the
entire cohort of 37.0 months

52. Efficacy
• For the total ITT population, the median PFS, median
OS, and 3-year OS rate were 7.2 months, 22.5 months,
and 23.5%, respectively.
• After evaluation of resectability by the multidisciplinary
team, 28 patients in arm A and 8 in arm B were
determined to be eligible for radical surgery for LM
• However, 2 patients (1 each in arm A and B) refused
further surgical intervention

53. • The remaining 27 patients in arm A and 7 in arm B
achieved R0 resection
• None of the patients who were early dropouts underwent
liver surgery.
• The actual resection rate of LMs in arm A was significantly
higher than that in arm B (22.3% v 5.8%; P < .001).
• The median number of treatment cycles administered
before liver surgery was 4 cycles of bevacizumab (range, 3-
10 cycles) and another 2 cycles of mFOLFOX6 (range, 2-3
cycles).

55. • Of the 27 patients who underwent R0 hepatic resection
in arm A, 12 (44.4%) had multiple wedge resections, 10
(37.0%) had hepatic segmentectomy, and 5 (18.5%)
had right-side hemihepatectomy
• Among these 27 patients, 17 had not undergone
primary tumor resection before random assignment
• When the LMs of the 17 patients were assessed as
resectable, 10 had simultaneous resection of both
primary tumors and LMs, and 7 had staged resection

56. • All 7 patients in arm B underwent hepatic
segmentectomy for LMs.
• Four patients had their primary tumors
resected before random assignment.
• Two patients had simultaneous resection of
primary tumors and LMs, and 1 had a staged
resection.

57. • There were no serious complications after liver
surgery .
• Three grade 3 postoperative AEs were observed
in arm A, including 2 patients with pleural
effusion and 1 with diaphragm effusion.
• There was 1 patient with grade 3 diaphragm
effusion and 1 with diaphragm effusion plus high
fever in arm B.

59. • At a median follow-up of 26.0 months for the 27
patients who underwent R0 resection of LMs in arm A,
the median DFS was 7.8 months (95% CI, 5.4 to 10.2
months), and the median OS was 37.8 months (95% CI,
28.9 to 46.7 months).
• A total of 21 patients (77.8%) experienced relapse, and
15 (55.6%) experienced recurrence in the hepatic
remnant, 4 (14.8%) in the lung, 1 (3.7%) in both the
hepatic remnant and the lung, and 1 (3.7%) in the
retroperitoneal lymph node.

60. • Among the 21 patients experiencing relapse, 5 underwent another
metastasis resection, and 4 received radiofrequency ablation plus
systemic treatment.
• At the cutoff date, 11 of these 27 patients in arm A had died, and
the median OS was 28.0 months (95% CI, 15.8 to 40.2 months).
• OS for patients in arm A improved compared with arm B (3-year
survival, 25.5% v 20.5%; median, 25.7 v 20.5 months; HR, 0.71; P <
.031), and PFS was significantly longer (median, 9.5 v 5.6 months;
HR, 0.49; P< .001).
• Post hoc subgroup analyses showed that the benefit of the LM
resection rate was consistent across subgroups of sidedness and
primary tumor status

61. Safety Analyses
• Overall, the observed toxicity was mostly mild.
• The overall incidence of predefined grade 3/4 events was
39.7% in arm A and 26.7% in arm B, with a significant
difference (P < .032).
• The most common AEs were leukopenia/neutropenia.
• Patients in arm A had a significantly higher incidence of
proteinuria (9.9% v 3.3%; P 5 .040) and hypertension (8.3%
v 2.5%; P 5 .048) than those in arm B.

62. • The occurrence of hemorrhage and thrombosis was 3.3%
and 3.3%, respectively, in arm A, with no significant
difference compared with arm B.
• In arm A, 10.7% of patients discontinued bevacizumab as a
result of grade 3/4 AEs.
• AEs resulted in discontinuation of chemotherapy in 12.4%
and 10.8% of patients in arm A and arm B, respectively.
• There were no grade 5 events in either arm

63. DISCUSSION
• Radical resection of liver-limited metastases was
reported to lead to a 5-year OS rate of . 55% for
patients with CLMs.
• However, , 20% of patients with CLMs have LMs that
are initially resectable.
• This is the first randomized controlled trial to test
whether the introduction of bevacizumab added to
chemotherapy (doublet or triplet) will increase the
resection rate of LMs for patients with RAS mutant
CLMs.

64. • This study confirms that bevacizumab improves R0
resection rate of LMs, PFS, and OS when combined
with mFOLFOX6 for patients with RAS mutant, initially
unresectable CLMs
• The significant benefit of LM resection rates in the
bevacizumab-containing arm was consistent among
subgroups of sidedness and primary tumor status.
• There is phase II or uncontrolled evidence of
bevacizumab combined with intense chemotherapy for
patients with CLMs regardless of RAS status

65. • For example, the TRICC0808 (mFOLFOX6 plus
bevacizumab for unresectable liver-only metastases of
CRC) trial reported a conversional hepatectomy rate of
23.1%
• Similarly, the R0 resection rate was 23% in the
bevacizumab plus mFOLFOX6 cohort in the OLIVIA trial
• In this trial, the bevacizumab combination yielded a
higher resection rate of LMs (22.3%) compared with
the mFOLFOX6-alone group (5.8%) in patients with RAS
mutant CRC with unresectable LMs

66. • The result is highly in agreement with the reported
resection rate in the TRICC0808 and OLIVIA trials
• Data in this study from the mFOLFOX6-alone group
demonstrate a low rate of metastasectomy
• The AVF2107 trial first compared bolus fluorouracil,
leucovorin, and irinotecan with or without
bevacizumab in the first-line treatment of mCRC and
was the only one to demonstrate a significant
improvement in ORR, PFS, and OS in the bevacizumab
group

67. • 2 randomized phase III trials, NO16966 and ITACa,
investigated the role of bevacizumab in the first-line
setting in combination with doublet chemotherapy but
failed to demonstrate a higher ORR and longer OS with
the introduction of bevacizumab, except for a small,
albeit statistically significant PFS benefit (9.4 v 8.0
months; P 5 .002) in the N016966 trial
• The BECOME trial is the first to result in significant
ORR, PFS, and OS benefits when bevacizumab was
added to mFOLFOX6

68. • No benefit of OS in N016966 and ITACa, which is
different from this trial could be due to
– the distribution of RAS status was unknown in N016966
and was missing in approximately 12% of patients with
ITACa
– a higher proportion of patients discontinued study
treatment largely because of oxaliplatin-induced toxicities
in the bevacizumab containing arms compared with the
placebo-containing arms (30% v 21%) in N016966
– no significant trend of OS benefit by bevacizumab added
to doublets (21.3 v 19.9 months; P 5 .077) in N016966
could also be ascribed to the trial design and sample size
because OS was not the primary end point of the trial.

73. • Twelve (44.4%) of 27 patients had
nonanatomical resection in arm A, while no
patients in arm B had nonanatomical
resection.
• The median DFS was 4.9 months for
nonanatomical resection and 13.7 months for
anatomic resection in arm A and 14.8 months
in arm B

74. • The median OS of the 27 patients in arm A
who underwent R0 resection of LMs was 37.8
months.
• The median OS of patients with R0 resection
of LMs in arm A in BECOME trial was longer
than that of patients who underwent R0
resection in CELIM

75. • Although RAS mutation is associated with worse DFS and
OS in patients who undergo liver resection for CLMs, liver
resection still results in a median OS of > 40 months
• However, the longest median OS for unresectable RAS
mutant mCRC reported so far is 27.3 months by
fluorouracil, leucovorin, oxaliplatin, and irnotecan plus
bevacizumab in the TRIBE trial
• The median OS was 37.8 months for patients with R0
resection of LMs and 22.5 months for patients without liver
resection in arm A in this trial, which further indicates a
benefit in OS by liver resection in RAS mutant disease.

76. • No unexpected AEs were observed in the
BECOME trial.
• The incidence of grade ≥ 3 hypertension and
proteinuria was slightly higher than that observed
in other clinical trials of these regimens.
• However, there was no increased bleeding or
thrombosis risk in patients receiving bevacizumab
during conversion therapy

77. • In the BECOME trial, all liver surgeries in arm A
were carried out 6 weeks after the last treatment
with bevacizumab.
• For 27 patients in arm A who underwent radical
metastasectomy, there was no grade ≥3 bleeding,
anastomotic leakage, or wound infection, except
for 2 patients with pleural effusion and 1 patient
with diaphragm effusion

78. • A sensitivity analysis of PFS was done to explore the
potential effect by censoring patients who underwent
LM resection in both arms at 2 weeks before LM
resection, which showed similar results (HR, 0.45; 95%
CI, 0.34 to 0.60; P <.001)
• However, sensitivity analysis of OS showed that the OS
benefit was attenuated to a nonsignificant HR of 0.76
(95% CI, 0.55 to 1.05; P < .092), which indicates that R0
resection of LMs contributed to the observed OS
benefit in arm A.

79. Limitations
• The single center study produced a limited level
of evidence.
• the primary study end point was conversional
resection rate, which is a surrogate for long-term
outcomes.
• There was no strict regulation of subsequent
treatment after progression, which may have
affected OS.
• The lack of placebo control in the chemotherapy-
alone arm may have biased the study results.

80. • In summary, this study confirmed that for
Chinese patients with RAS mutant, initially
unresectable colorectal liver-limited
metastases, the addition of bevacizumab to
mFOLFOX6 increased radical resections of LMs
with minimal perioperative complication and
prolonged long-term survival