Impact of age and gender on safety and efficacy

of first-line FOLFOXIRI/bevacizumab in mCRC:

a pooled analysis of TRIBE and TRIBE2 studies.

G. Zucchelli, F. Marmorino, D. Rossini, G. Aprile, M. Casagrande, S. Lonardi, S. Murgioni, E. Dell’Aquila, G. Tomasello, R. Moretto, C. Antoniotti, B. Borelli, F. Urbano, M. Ronzoni, A. Zaniboni,

S. Manglaviti, A. Buonadonna, G. Ritorto, G. Masi, G. Allegrini, A. Falcone, C. Cremolini.

on behalf of the GONO Investigators

World Congress on Gastrointestinal CancerBarcelona, Spain 3 – 6 July 2019

ü In the phase III TRIBE and TRIBE2 studies by GONO, 1187 mCRC patients were randomized to receive FOLFOXIRI/bevacizumab or a doublet (FOLFIRI in TRIBE and FOLFOX in TRIBE2)/bevacizumab as first line treatment.

Loupakis et al., N Engl J Med 2014; Cremolini et al., ASCO 2019Cremolini et al., Lancet Oncol 2015

Background

ü Based on these results and other phase II randomized trials, FOLFOXIRI plus bevacizumab is recommended by major guidelines as an upfront therapeutic option in selected mCRC patients.

NCCN Clinical Practice Guidelines in Oncology—Colon Cancer v1.2019; Van Cutsem E. et al. ESMO Consensus Guidelines. Ann Oncol 2016;

Yoshino et al., Ann Oncol 2018

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Patients’ selection

ü Both male and female patients were eligible for TRIBE and TRIBE2 trials if 18-75 years old:

- ECOG PS≤2 if aged 18-70 years

- ECOG PS=0 if aged 71-75 years

Rationale

ü Based on retrospective literature data, age and gender seem to influence cancer risk and survival, safety profile and response to available oncological treatments.

Hurria et al., J Natl Compr Canc Netw 2012; Townsley et al., J Clin Oncol 2005Özdemir et al., J Clin Oncol 2018; Soldin et al., Clin Pharmacokinet. 2009

Objective

ü To investigate the effect of the intensification of the upfront chemotherapy backbone

in patients included in the TRIBE and TRIBE2 studies in terms of ORR, PFS and safety

profile according to:

- Age (<70 versus 70-75 years)

- Gender (males versus females)

(TRIBE2 results in terms of OS are still immature)

Patients’ characteristics

ITT population N=1187

Characteristic, % patients< 70 years

N=1005 (85%)70-75 years

N=182 (15%)Males

N=693 (58%)Females

N=494 (42%)

Primary Tumor Side (right / left) 36 / 64 32 / 68 33 / 67 38 / 62

RAS/BRAF (RAS mut / BRAF mut / wt / NE) 56 / 9 / 20 / 15 59 / 5 / 18 / 18 55 / 6* / 23 / 16 58 / 11* / 16 / 15

Resected Primary (Y / N) 57 / 43 61 / 39 55* / 45 62* / 38

Liver Only Disease (Y / N) 26 / 74 27 / 73 27 / 73 25 / 75

Prior Adjuvant CT (Y / N) 6 / 94 11 / 89 6 / 94 8 / 92

Synchronous Metastases (Y / N) 86 / 14* 78 / 22* 85 / 15 84 / 16

ECOG PS (0 / 1-2) 86* / 14 96* / 4 89 / 11 85 / 15

Gender (M / F) 57* / 43 68* / 32 - -

Age (< 70 / ≥ 70) - - 82* / 18 88* / 12

* p≤0.05

Results - Response Rate and Progression Free Survival

<70 years 70-75 yearsp for

interactionDoublet/bevN=511

FOLFOXIRI/bevN=494

Doublet/bevN=85

FOLFOXIRI/bevN=97

ORR, % 52.8 63.6 47.0 61.90.554

OR 95% CI 1.53 [1.19-1.97] 1.75 [0.97-3.15]

Median PFS, months 9.6 12.1 10.1 12.00.520

HR 95% CI 0.75 [0.66-0.86] 0.82 [0.60-1.11]

Doublet/bevFOLFOXIRI/bev

<70 years 70-75 years

Males Femalesp for

interactionDoublet/bevN=362

FOLFOXIRI/bevN=331

Doublet/bevN=234

FOLFOXIRI/bevN=260

ORR 52.2 61.9 51.7 65.00.527

OR 95% CI 1.49 [1.10-2.02] 1.73 [1.21-2.49]

Median PFS, months 9.7 12.0 10.0 12.70.870

HR 95% CI 0.77 [0.66-0.90] 0.78 [0.65-8.95]

Results - Response Rate and Progression Free Survival

Doublet/bevFOLFOXIRI/bev

Males Females

Results – Adverse Events, age subgroups

p<0.01

p<0.01

p<0.01

p<0.01

p=0.03

p=0.03

-p=0.27UNIVARIATE

MULTIVARIATE*

N=180SAFETY POPULATION N=1175 N=995

* covariates: gender (females vs males), treatment (triplet vs doublets), ECOG-PS (1-2 vs 0) and duration of the induction therapy (6 vs 4 months).

<70 years 70-75 yearsp for

interactionAdverse events, % patients

Doublet/bevN=505

FOLFOXIRI/bevN=490

Doublet/bevN=84

FOLFOXIRI/bevN=96

CT-related toxicity – Grade 3-4 37 66 51 820.468

OR 3.12 4.08

Diarrhoea – Grade 3-4 8 17 8 270.187

OR 2.17 4.20

Febrile neutropenia – Any grade 4 6 5 160.169

OR 1.47 3.49

Results – Adverse Events, age subgroups

Results – Adverse Events, gender subgroups

p<0.01

p<0.01

p=0.02

p=0.01

-p=0.70UNIVARIATE

MULTIVARIATE*

N=684

SAFETY POPULATION N=1175

N=491

p<0.01

p<0.01p<0.01

p<0.01

p<0.01

p<0.01

* covariates: age (≥ vs <70 years), treatment (triplet vs doublets), ECOG-PS (1-2 vs 0) and duration of the induction therapy (6 vs 4 months).

Males Femalesp for

interactionAdverse events, % patients

Doublet/bevN=358

FOLFOXIRI/bevN=326

Doublet/bevN=231

FOLFOXIRI/bevN=260

CT-related toxicity – Grade 3-4 33 64 51 740.317

OR 3.54 2.75

Nausea – Any grade / Grade 3-4 51 / 2 60 / 4 63 / 6 67 / 60.445 / 0.198

OR 1.47 / 2.08 1.22 / 0.95

Vomiting – Any grade / Grade 3-4 24 / 1 34 / 2 32 / 5 50 / 60.383 / 0.468

OR 1.71 / 2.22 2.13 / 1.22

Results – Adverse Events, gender subgroups

Summary

ü In terms of ORR and PFS, FOLFOXIRI/bevacizumab is confirmed as a more active and efficaciousoption than doublets/bevacizumab, irrespectively of age and gender.

ü In all subgroups this regimen was also associated with an increased risk of chemo-relatedtoxicities, but not beva-related ones.

ü Notably, in the FOLFOXIRI/bevacizumab population:- 27% and 16% of elderly patients had grade 3-4 diarrhoea and febrile neutropenia, respectively- 67% and 50% of females had any grade nausea and vomiting, respectively

Conclusions

ü Even if a recommended anti-emetic prophylaxis was not specified in the study protocols and data

about the administered anti-emetic regimens are lacking, nausea and vomiting should be carefully

managed in females treated with FOLFOXIRI/bevacizumab.

ü Due to the high registered rates of grade 3-4 diarrhoea and febrile neutropenia, it appears

reasonable to suggest dose reductions or primary G-CSF prophylaxis in elderly patients treated

with FOLFOXIRI/bevacizumab, though the absence of a prospective confirmation.

Thank you!