colon cancer: highlights - aiommedia.aiom.it/userfiles/files/doc/aiom-servizi/20160206... ·...

COLON CANCER: Highlights

AIOM POST ASCO-GI Review

Updates and news from the Gastrointestinal Cancer Symposium in San Francisco, CA,

USA

Roma, 5-6 Febbraio 2016

Alfredo Falcone Dipartimento di Ricerca Traslazionale e Nuove Tecnologie in Med. e Chir., Università di Pisa

Polo Oncologico – Azienda Ospedaliero Universitaria Pisana

Istituto Toscano Tumori

Italy

OUTLINE

Studio STEAM (abst. 492)

Studio MAVERICC (abst. 493)

CDX2 (Keynote Lecture)

Overall response rate in STEAM, a randomized,

open-label, phase 2 trial of sequential and

concurrent FOLFOXIRI-bevacizumab vs

FOLFOX-bevacizumab for the first-line treatment of

patients with metastatic colorectal cancer

Bendell J,1 Tan BR,2 Reeves JA,3 Xiong H,4 Somer B,5 Lenz H-J,6

Hochster HS,7 Scappaticci F,8 Sommer N,8 Day B-M,8 Hurwitz HI9

1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 2Washington University School of

Medicine, Saint Louis, MO, USA; 3Florida Cancer Specialists – South Region, Ft. Meyers, FL, USA; 4The Center for

Cancer and Blood Disorders, Fort Worth, TX, USA; 5West Clinic, Memphis, TN, USA; 6USC Norris Comprehensive

Cancer Center, Los Angeles, CA, USA; 7Yale University, New Haven, CT, USA; 8Genentech, Inc., South San Francisco,

CA, USA; 9Duke University Medical Center, Durham, NC, USA

Presented by: Dr. J. Bendell, Sarah Cannon Research Institute/Tennessee

Oncology, Nashville, TN, USA

Overview of the STEAM Study (NCT01765582)

Treatment-

naive mCRC

(N=280)

Stratified by

extent of

metastatic

disease,

primary tumor

location,

and study

center

4-month induction phase (plus optional 2 months)

• Primary endpoints:

– Investigator-assessed ORR during first-line therapy (ORR1) for cFOLFOXIRI-BEV vs FOLFOX-BEV

– PFS during first-line therapy (PFS1) for FOLFOXIRI-BEV regimens (concurrent and sequential) vs

FOLFOX-BEV

Leucovorin/

5-FU/BEV

or

Capecitabine

/

BEV

Maintenance

phase

PD1 PD2

Fluoropyrimidin

e-based

chemotherapy

(investigator’s

choice)

plus

BEV

Second-line

phase

Concurrent

FOLFOXIRI-BEV

(cFOLFOXIRI-BEV)

Sequential

FOLFOXIRI-BEV

(FOLFOXIRI-BEV)

FOLFOX-BEV

PD1, progression on first-line therapy; PD2, progression on second-line

therapy.

Patient Eligibility

• Key inclusion criteria:

– Histologically confirmed mCRC with ≥1 measurable and unresectable lesion

– 18–75 years of age

– Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (<71 years) or

0 (71–75 years)

– Adequate hematologic, liver, and renal function

• Key exclusion criteria:

– Prior systemic treatment for mCRC (except palliative radiosensitizers)

– Adjuvant chemotherapy completed <12 months prior to study enrollment

– Sensory peripheral neuropathy (grade ≥2)

– Surgery within 28 days prior to randomization

– Current/recent (≤10 days prior to first bevacizumab dose) use of aspirin >325 mg/day

– Inadequately controlled hypertension, clinically significant cardiovascular disease, serious non-

healing wound, active peptic ulcer, or untreated bone fracture

Statistical Considerations

• Efficacy analyses were conducted in all randomized patients (intent-to-treat population). Safety analyses

were conducted in all patients who received ≥1 dose of study medication; treatment group based on

treatment received

• Sample size (280 patients), based on the following assumptions, and 5% type I error (1-sided) will

provide 80% power:

– cFOLFOXIRI-BEV and FOLFOX-BEV exhibit ORRs of 70% and 50%, respectively

– An improvement of 43% from median PFS1 14.3 months in (concurrent and sequential)

FOLFOXIRI-BEV to median PFS1 of 10 months in FOLFOX-BEV

• Fixed-sequence hypothesis testing adjusted for co-primary endpoints (ORR1 and PFS1)

– ORR1: 1-sided alpha of 5% to compare cFOLFOXIRI-BEV with FOLFOX-BEV

– If the test of ORR1 is significant, then PFS1 will be tested for cFOLFOXIRI-BEV and

sFOLFOXIRI-BEV vs FOLFOX-BEV with a 1-sided alpha of 5%

• Here we present preliminary efficacy data from STEAM (final ORR1 and interim PFS1)

Patient Disposition (N=280, ITT Population)

cFOLFOXIRI-

BEV

sFOLFOXIRI-

BEV

FOLFOX-BEV

Randomized (ITT population), n 93 92 95

Treated (safety population),a n 91 90 90

Median duration of follow-up,

months (range)

13.7

(0.4, 28.9)

13.1

(0.1, 27.0)

12.4

(0.1, 25.7)

Remaining on study at data cut-off

for present analysis, n (%)

64 (69%) 62 (67%) 60 (63%)

First patient in: January 23, 2013

Last patient in: December 26, 2014

Data cutoff: July 1, 2015 (when the last patient completed the induction phase)

aSafety population is grouped according to treatment received.

Baseline Characteristics (ITT)

cFOLFOXIRI-BEV

(n=93)

sFOLFOXIRI-BEV

(n=92)

FOLFOX-BEV

(n=95)

Age, years (median, range) 58.0 (23–75) 56.0 (25–74) 58.0 (34–73)

Sex, n (%)

Male 51 (55) 52 (57) 59 (62)

Female 42 (45) 40 (43) 36 (38)

ECOG performance status, n (%)

0 62 (67) 52 (57) 51 (54)

1 31 (33) 40 (43) 44 (46)

Cancer type at initial diagnosis, n (%)

Colon 68 (73) 64 (70) 76 (80)

Rectal 25 (27) 28 (30) 19 (20)

Prior cancer surgery, n (%) 48 (52) 55 (60) 61 (64)

Baseline Characteristics (ITT, Continued)

cFOLFOXIRI-BEV

(n=93)

sFOLFOXIRI-BEV

(n=92)

FOLFOX-BEV

(n=95)

Extent of metastatic disease, n (%)

Liver-limited disease 28 (30) 28 (30) 27 (28)

Non-liver-limited disease 65 (70) 64 (70) 68 (72)

Tumor location, n (%)a

Right 43 (46.2) 38 (41) 40 (42)

Left 50 (54) 54 (59) 55 (58)

KRAS status, n (%)

Wild-type 25 (27) 23 (25) 25 (26)

Mutant 23 (25) 22 (24) 20 (21)

Unknown or not done 45 (48) 47 (51) 50 (53)

aRight included the right colon and transverse up to splenic flexure. Left included everything distal from the

splenic flexure, including rectal cancer.

ORR During First-Line Treatment (ORR1-Confirmed)a

cFOLFOXIRI-BEV

(n=93)

sFOLFOXIRI-BEV

(n=92)

Pooled

FOLFOXIRI-BEV

(n=185)

FOLFOX-BEV

(n=95)

ORR, % 60.2 62 61.1 47.4

Odds ratio vs

FOLFOX-BEV (90% CI)b

1.7 (1.05, 2.77)

p=0.077c

1.8 (1.12, 2.97)

p=0.040c

1.8 (1.16, 2.68)

p=0.025c

CR, % 4.3 0 2.2 1.1

PR, % 55.9 62.0 58.9 46.3

SD, % 31.2 32.6 31.9 40

PD, % 2.2 1.1 1.6 6.3

Unable to evaluate, % 6.5 4.3 5.4 6.3

aConfirmed response (sensitivity analysis, ITT population), defined as a CR or PR, as assessed by the investigator,

on two consecutive assessments at least 4 weeks apart. bStratified by extent of metastatic disease and tumor location after randomization. c1-sided Cochran-Mantel-Haenszel p-value (no multiplicity adjustments).

Interim PFS1 (ITT): cFOLFOXIRI-BEV and

sFOLFOXIRI-BEV vs FOLFOX-BEV cFOLFOXIRI-

BEV

(n=93)

sFOLFOXIRI-

BEV

(n=92)

FOLFOX-

BEV

(n=95)

Median PFS,

months (90% CI)a

11.7

(9.9, 16.6)

10.7

(8.7, 12.7)

9.3

(7.7, 10.4)

Stratified HR vs

FOLFOX-BEV (90%

CI)b

0.672

(0.489, 0.922)

0.738

(0.537, 1.012)

cFOLFOXIRI-BEV

sFOLFOXIRI-BEV

FOLFOX-BEV

100

80

60

40

20

0

Pro

gre

ss

ion

-fre

e S

urv

iva

l (%

)

0 3 6 9 12 15 18 21 24 27

Time (months)

aPFS1 is defined as the time from randomization to first occurrence of disease progression or death from any cause during first-line treatment,

whichever occurs first. Patients without an event are censored at their last tumor assessment. bStratified by extent of metastatic disease and tumor location after correction post randomization.

HR, hazard ratio.

cFOLFOXIRI-Bev

FOLFOX-Bev

Liver Resection Rates During First-Line Treatment (ITT)

cFOLFOXIRI

-BEV

(n=93)

sFOLFOXIRI

-BEV

(n=92)

Pooled

FOLFOXIRI-

BEV

(n=185)

FOLFOX-

BEV

(n=95)

Liver resection rates, % 15.1 9.8 12.4 7.4

R0 resection 15.1 8.7 11.9 6.3

Percent difference in

resection rates vs

FOLFOX-BEV (90%

CI)a

7.7

(0.2, 15.2)

2.4

(-4.3, 9.2)

5.1

(-0.9, 11.0)

p-valueb 0.094 0.555 0.195

aNormal approximation to the binomial distribution. bPreliminary and exploratory p-value (2-sided Pearson’s chi squared test, no multiplicity

adjustments).

Overview of Treatment-Emergent Adverse Eventsa

cFOLFOXIRI-

BEV

(n=91)

sFOLFOXIRI-

BEV

(n=90)

FOLFOX-

BEV

(n=90)

Any TEAE, % 100 99 100

Grade ≥3 TEAE, % 90 87 82

TEAEs of special

interest, % 82 77 69

TEAE leading to

withdrawal from study

treatment, %

41 33 38

TEAE leading to study

discontinuation, % 15 3 6

Fatal TEAE, % 3 4 3

aSafety population.

TEAE, treatment-emergent adverse event.

Serious Chemotherapy-Associated TEAEs

TEAE, % cFOLFOXIRI-

BEV

(n=91)

sFOLFOXIRI-

BEV

(n=90)

FOLFOX-BEV

(n=90)

Diarrhea 6 1 4

Nausea 3 0 0

Vomiting 3 0 3

Neutropenia 2 2 0

Febrile

neutropenia

2 2 2

Stomatitis 0 0 0

Peripheral

neuropathy

0 0 0

TEAEs of Special Interest for Bevacizumab

aGrade ≥3. bAny grade. cGrade ≥3 (any grade central nervous system bleeding, grade ≥2 hemoptysis). dGrade ≥2.

ePosterior Reversible Encephalopathy Syndrome (PRES; previously RPLS).

GI, gastrointestinal.

TEAE of special interest by

category, %

cFOLFOXIRI-

BEV

(n=91)

sFOLFOXIRI-

BEV

(n=90)

FOLFOX-BEV

(n=90)

Any TEAE of special interest 29 (32) 26 (29) 22 (24)

Hypertensiona 18 (20) 14 (16) 11 (12)

Venous thromboembolic eventsa 5 (5) 5 (6) 5 (6)

Arterial thromboembolic eventsb 2 (2) 4 (4) 0

Bleeding/Hemorrhagec 2 (2) 1 (1) 4 (4)

GI perforation, abscess, or fistulab 3 (3) 1 (1) 2 (2)

Non-GI fistula or abscessd 1 (1) 0 2 (2)

Proteinuriaa 0 2 (2) 0

Congestive heart failurea 0 0 0

PRESb,e 0 0 0

Wound healing complicationsa 0 0 0

Conclusions • STEAM is the first study to compare cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, and FOLFOX-

BEV head-to-head

• Limitations

– This phase 2 study was exploratory and outcomes were not corrected for multiplicity

– The present analysis of PFS is preliminary; updated PFS results will be presented in

the future

– OS results are immature and this study is not powered to compare treatment arms for

this outcome

• Compared with FOLFOX-BEV, the triplet regimen of cFOLFOXIRI-BEV demonstrated

trends for improved ORR, PFS, and metastatic resection rates

– Similar trends were seen for sFOLFOXIRI-BEV and the pooled FOLFOXIRI-BEV arms

(cFOLFOXIRI-BEV and sFOLFOXIRI-BEV)

• All three regimens were well tolerated. There was no increase in serious chemotherapy-

associated TEAEs and the safety profile was consistent with the known side effects of BEV

– cFOLFOXIRI-bev associated with higher incidence of grade ≥3 hypertension

• Biomarker and additional subgroup analyses are in progress

• The interim results of STEAM align with findings from TRIBE1 that support the role of

FOLFOXIRI-BEV as a treatment option in selected patients with first-line mCRC

1Loupakis, et al. NEJM 2014.

OUTLINE




MAVERICC, a Phase 2 Study of the Efficacy and

Safety of mFOLFOX6-bevacizumab (BV) vs

FOLFIRI-BV in the First-line (1L) Treatment of

Metastatic Colorectal Cancer

Lenz HJ,1 Lee F-C,2 Yau L,3 Koh H,4 Knost J,5 Mitchell E,6 Bosanac I,7

Mancao C,3 and Parikh A3

1University of Southern California, Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA; 2University of New Mexico Cancer Center, Albuquerque, NM, USA; 3Genentech, Inc., South San Francisco, CA, USA;

4Southern California Permanente Group, Bellflower, CA, USA; 5Illinois Cancer Center, Peoria, IL, USA; 6Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, USA;

7F. Hoffmann-La Roche, Ltd., Basel, Switzerland

Presented by: Dr HJ Lenz, University of Southern California, Norris

Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA,

USA

Study Design and Patient Eligibility

Key inclusion criteria

• Histologically confirmed mCRC with ≥1

measurable and unresectable lesion

• Age 18–75 years

• Eastern Cooperative Oncology Group (ECOG)

performance status of 0 or 1

• Adequate hematologic, liver, and renal function

Key exclusion criteria

• Prior systemic treatment for mCRC (except

palliative radiosensitizers)

• Adjuvant chemotherapy completed <12 months

prior to study enrollment

• Surgery within 28 days prior to randomization

Untreated mCRC

(N=376)

Stratification factors:

• ERCC-1 (high vs low)

• Geographic area (US vs ex-US)

R

A

N

D

O

M

I

Z

E

mFOLFOX6-BV

(n=188)

FOLFIRI-BV

(n=188)

1:1 Progressive

Disease (PD)

Objectives and Statistical Methods

Primary objectives:

• Assess whether tumor ERCC1 is associated with progression-free survival (PFS) in first-line therapy

with mFOLFOX6-BV vs FOLFIRI-BV

• Assess pVEGF-A as a potential biomarker for response to BV or, used in combination with tumor

ERCC1, as a potential biomarker for response to chemotherapy

Secondary objectives:

• Evaluate the effect of tumor ERCC1 and pVEGF-A on overall survival (OS), objective response rate

(ORR), liver resection rate, or risk of specific toxicities

• Assess other potential biomarkers (including KRAS), as well as biomarker subgroups and their

association with clinical outcomes

Statistics:

• Efficacy analyses were based on the ITT population

• Median time to PFS and OS were estimated by the Kaplan–Meier method

• Hazard ratios (HR) were estimated by Cox regression (stratified by tumor ERCC1 level and region)

• The study was powered at 80% to detect a HR of 0.7 on PFS for FOLFIRI-BV vs mFOLFOX6-BV at the

2-sided 0.05 significance level

ITT: Baseline Characteristics

mFOLFOX6-BV

(n=188)

FOLFIRI-BV

(n=188)

Median age, years (range) 61.0 (31–87) 61 (34–81)

Sex, n (%)

Male 122 (64.9) 117 (62.2)

Female 66 (35.1) 71 (37.8)

ECOG performance status, n

(%)

0 93 (49.5) 110 (58.5)

1 94 (50.0) 77 (41.0)

Cancer type, n (%)

Colon 131 (69.7) 135 (71.8)

Rectal 50 (26.6) 48 (25.5)

Colon and rectal 7 (3.7) 5 (2.7)

Prior cancer surgery, n (%) 118 (62.8) 112 (59.6)

Prior adjuvant therapy, n (%) 22 (11.7) 20 (10.6)

Liver-limited disease, n (%) 44 (23.4) 36 (19.1)

ITT: Baseline Characteristics (continued)

mFOLFOX6-BV

(n=188)

FOLFIRI-BV

(n=188)

Tumor location, n (%)

Right 75 (39.9) 79 (42.0)

Left 113 (60.1) 109 (58.0)

Tumor ERCC-1 (x 10-3 ERCC1/-actin

mRNA), mean (SD)

1.6 (1.34) 1.8 (1.32)

High (>1.7), n (%) 64 (34.0) 67 (35.6)

Low (≤1.7), n (%) 124 (66.0) 120 (63.8)

pVEGF-A,(pg/mL), mean (SD) 9.4 (12.79) 9.1 (12.31)

High (>5.1), n (%) 94 (50.0) 91 (48.4)

Low (≤5.1), n (%) 90 (47.9) 95 (50.5)

KRAS status, n (%)

Wild-type 107 (56.9) 101 (53.7)

KRAS exon 2 mutation 65 (34.6) 63 (33.5)

Unknown 16 (8.5) 24 (12.8)

Patient Disposition

mFOLFOX6-BV FOLFIRI-BV

Randomized (ITT

population), n (%) 188 (100) 188 (100)

Treated (safety population),

n (%) 185 (98.4) 183 (97.3)

Median duration of follow-up,

months (interquartile range) 18.4 (12.0–25.4) 18.6 (11.8–24.9)

Number of BV cycles

received, mean (SD) 14.8 (11.3) 17.6 (13.8)

Number of chemotherapy

cycles received, mean (SD) Oxaliplatin: 11.1 (6.3)

5-fluorouracil: 15.3 (10.9)

Irinotecan: 17.5 (13.4)

5-fluorouracil: 18.4 (13.8)



USA

ITT: PFS and OS by Treatment Group

PFS



USA

mFOLFOX6-BV (n=188)

FOLFIRI-BV (n=188)

100

80

60

40

20

0

Pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

0 4 8 12 16 20 24 28 32 36

Months since randomization

OS

mFOLFOX

6-BV

FOLFIRI-

BV

Median survival,

months 23.9 27.5

Stratified HR

(95% CI)

0.76 (0.56–1.04)

P=0.086

mFOLFOX6-BV (n=188)

FOLFIRI-BV (n=188)

100

80

60

40

20

0

Su

rviv

al

(%)

0 4 8 12 16 20 24 28 32 36


40 44

mFOLFOX

6-BV

FOLFIRI-

BV

Median PFS,

months 10.1 12.6

Stratified HR

(95% CI)

0.79 (0.61–1.01)

P=0.056

ITT: PFS by Treatment Group and ERCC1 Level

mFOLFOX6

-BV FOLFIRI-BV

Median PFS,

months 11.0 12.7

Stratified HR

(95% CI)

0.76 (0.55–1.03)

P=0.079

mFOLFOX6-

BV FOLFIRI-BV

Median PFS,

months 9.9 11.2

Stratified HR

(95% CI)

0.84 (0.56–1.26)

P=0.394

High (>1.7) Baseline Tumor ERCC1 (N=131)

mFOLFOX6-BV (n=64)

FOLFIRI-BV (n=67)

100

80

60

40

20

0

Pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

0 4 8 12 16 20 24 28 32 36


Low (≤1.7) Baseline Tumor ERCC1 (N=244)

mFOLFOX6-BV

(n=124)

FOLFIRI-BV (n=120)

100

80

60

40

20

0

Pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)


0 4 8 12 16 20 24 28 32 36

ITT: OS by Treatment Group and ERCC1 Level

mFOLFOX6

-BV

FOLFIRI-

BV

Median OS,

months 25.5 27.9

Stratified HR

(95% CI)

0.74 (0.49–1.12)

P=0.152

mFOLFOX6-

BV FOLFIRI-BV

Median OS,

months 22.5 26.5

Stratified HR

(95% CI)

0.80 (0.51–1.26)

P=0.330

mFOLFOX6-BV (n=124)

FOLFIRI-BV (n=120)

100

80

60

40

20

0

Su

rviv

al

(%)

0 4 8 12 16 20 24 28 32 36


40 44

mFOLFOX6-BV (n=64)

FOLFIRI-BV (n=67)

100

80

60

40

20

0

Su

rviv

al

(%)

0 4 8 12 16 20 24 28 32 36


40 44

High (>1.7) Baseline Tumor ERCC1 (N=131) Low (≤1.7) Baseline Tumor ERCC1 (N=244)

ITT: PFS by Treatment Group and Location of

Primary Tumor (Right vs Left)

Right Left

mFOLFOX6-BV

(n=75)

FOLFIRI-BV

(n=79)

mFOLFOX6-BV

(n=113)

FOLFIRI-BV

(n=109)

Median PFS,

months 10.0 11.2 10.2 13.8

Stratified HR for

FOLFIRI-BV vs

mFOLFOX6-BV

(95% CI)

0.88 (0.60–1.28)

P=0.494

0.71 (0.51–0.98)

P=0.040

Conclusions

• Among patients with high tumor ERCC1 levels (predefined cutoff of 1.7), there

was no statistically significant difference between treatment arms for PFS or OS

– Results should be interpreted with caution due to the lower prevalence of

tumor ERCC1

• In the first-line treatment of mCRC, FOLFIRI-BV and FOLFOX-BV appeared

comparable in this exploratory study with respect to PFS and OS

– A trend toward benefit with FOLFIRI-BV over FOLFOX-BV was observed,

but the difference was not statistically significant

– Results could be due, in part, to more treatment cycles administered in

FOLFIRI-BV (on average 6 more cycles of irinotecan than oxaliplatin)

• Analyses of results for pVEGF-A and other biomarkers are ongoing

OUTLINE




Discovery data-set Validation data-set

Dalerba P et al. NEJM 2016

STAGE III

Dalerba P et al. NEJM 2016

STAGE II

Grazie per l’attenzione!

[email protected]

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