ASCO Annual Meeting 2012

PHASE II STUDY OF PANITUMUMAB (P) PHASE II STUDY OF PANITUMUMAB (P) IN COMBINATION WITH FOLFOXIRI AS IN COMBINATION WITH FOLFOXIRI AS

FIRST-LINE TREATMENT FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER OF METASTATIC COLORECTAL CANCER

(MCRC): HIGH ACTIVITY IN MOLECULARLY (MCRC): HIGH ACTIVITY IN MOLECULARLY SELECTED PATIENTS (PTS). SELECTED PATIENTS (PTS).

Sara Lonardi1, Lorenzo Fornaro2, Francesca Bergamo1, Marta Schirripa2, Giuseppe Aprile3, Manfredi Morvillo2, Gianluca Masi2, Fotios Loupakis2, Lorenzo Calvetti1, Chiara

Cremolini2, Lisa Salvatore2, Alberto Zaniboni4, Vittorina Zagonel1, Alfredo Falcone2;

1Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy; 2Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; 3Oncologia Medica, Azienda Ospedaliero-Universitaria, Udine, Italy; 4Oncologia Medica,

Casa di Cura Poliambulanza, Brescia, Italy

The combination of anti-EGFR monoclonal antibodies with doublet cemotherapy is an effective strategy in the first-line treatment of mCRC.

Van Cutsem E, N Eng J Med 2009

Douillard JY, J Clin Oncol 2010

The triple drug combination FOLFOXIRI demonstrated increased activity and efficacy over FOLFIRI.

Falcone A, J Clin Oncol 2007

Masi G, J Natl Cancer Inst 2011

KRAS codon 12-13 mutations predict resistance to Panitumumab.Amado RG, J Clin Oncol 2008

Mutations in other KRAS codons (such as codon 61) and other members of the RAS family (mainly HRAS and NRAS) may predict resistance to anti-EGFR agents.

De Roock W, Lancet Oncol 2010

BRAF V600E mutation may predict resistance to anti-EGFR agents.Di Nicolantonio F, J Clin Oncol 2008

Loupakis F, Br J Cancer 2009

RationaleRationale

Study DesignStudy Design

INDUCTION TXINDUCTION TX• up to 12 cycles

• or PD

• or unacceptable toxicity

• or patient’s refusal

MAINTENANCE TXMAINTENANCE TX• until PD

• or intolerable toxicity

• or patient’s refusal

*≈70 pts needed to be screened

incidence of RAS and BRAF mutations ≈50%

FOLFOXIRI + P-mabFOLFOXIRI + P-mab P-mab +/- 5FUP-mab +/- 5FU

35 mCRC pts35 mCRC ptswild-type for:wild-type for:

• KRAS codon 12-13-61 KRAS codon 12-13-61 • BRAF codon 600BRAF codon 600• HRAS-NRAS codon 12-13-61HRAS-NRAS codon 12-13-61

Induction Treatment Schedule (after amendment)Induction Treatment Schedule (after amendment)

5FU flat continuous infusion5FU flat continuous infusion2400 mg/sqm2400 mg/sqm

L-LV L-LV 200 mg/sqm200 mg/sqm

Oxaliplatin Oxaliplatin 85 mg/sqm85 mg/sqm

2 hours2 hoursRepeated every 2 weeks

IrinotecanIrinotecan150 mg/sqm150 mg/sqm

48 hours48 hours

Day 1 Day 2 & Day 3

1 hour1 hour

P-mabP-mab6 mg/Kg6 mg/Kg

1 hour1 hour

5FU DOSE AMENDED AFTER 2 SAEs OCCURRED AMONG THE FIRST 3 PTS ENROLLED

• Histologically confirmed colorectal adenocarcinoma

• Availability of formalin-fixed paraffin embedded tumor block from primary or metastasis

• RAS and BRAF wild-type status of primary colorectal cancer or related metastasis

• Unresectable and measurable metastatic disease (RECIST criteria)

• Adjuvant chemotherapy ended more than 12 months before relapse

• Age ≥ 18 years and ≤ 75 years

• ECOG PS ≤ 2 if aged < 71 years and ECOG PS = 0 if aged 71-75 years

• Adequate hematological, liver and kidney function

• Prior palliative chemotherapy

• Prior treatment with EGFR inhibitors

• Symptomatic peripheral neuropathy ≥ 2 grade according to NCIC-CTG criteria

Main Enrollment CriteriaMain Enrollment Criteria

Study Objective and End-pointsStudy Objective and End-points

The objective of the trial is to investigate the activity of FOLFOXIRI + panitumumab as first-line treatment in KRAS, NRAS, HRAS and BRAF wild-type mCRC patients.

The objective of the trial is to investigate the activity of FOLFOXIRI + panitumumab as first-line treatment in KRAS, NRAS, HRAS and BRAF wild-type mCRC patients.

PRIMARY END-POINT:PRIMARY END-POINT:

Response Rate

SECONDARYSECONDARY END-POINTS: Progression Free Survival Secondary R0 surgery of metastases Overall survival Safety profile Analyses of potential predictive factors of treatment activity or efficacy

The primary study end-point is Response rate (RECIST vers. 1.1)

Mini-max, two-stage design by Simon

• alpha and beta errors of 0.05 and 0.20, respectively

• p0 (RR in null hypothesis) of 0.60

• p1 (RR in alternative hypothesis) of 0.80

A total of 35 evaluable patients will be enrolled (considering an incidence of RAS and BRAF mutations around 50%, a total of around 70 patients should be screened)

If at least 26 response will be observed, the treatment will be considered promising

StatisticsStatistics

• Histologically confirmed colorectal adenocarcinoma

• Availability of formalin-fixed paraffin embedded tumor block from primary or metastasis

• RAS and BRAF wild-type status of primary colorectal cancer or related metastasis

• Unresectable and measurable metastatic disease (RECIST criteria)

• Adjuvant chemotherapy ended more than 12 months before relapse

• Age ≥ 18 years and ≤ 75 years

• ECOG PS ≤ 2 if aged < 71 years and ECOG PS = 0 if aged 71-75 years

• Adequate hematological, liver and kidney function

• Prior palliative chemotherapy

• Prior treatment with EGFR inhibitors

• Symptomatic peripheral neuropathy ≥ 2 grade according to NCIC-CTG criteria

Main Enrollment CriteriaMain Enrollment Criteria

No. (%)

Pts screened 87 (100%)Pts enrolled 37 (43%)Pts not enrolled 50 (57%) 1. RAS mutation 35 (40%) 2. BRAF mutation 4 (5%) 3. Patient refusal 2 (2%) 4. Mutational analysis failure 6 (7%) 5. Medical decision despite wild-type status 3 (3%)

Screening and EnrollmentScreening and Enrollment

No. = 37 pts

Age, median (range) 63 years (33-72)

Sex Male/Female 57% / 43%

ECOG PS 0/1-2 76% / 24%

Primary Colon/Rectum 70% / 30%

Primary on site 42%

Sites of mets 1/≥2 54% / 46%

Liver only mets 35%

Previous adjuvant CT Yes/No 16% / 84%

No. of treatment (ind+mant) cycles 492

Median No. of treatment (ind+mant) cycles (range) 13 (3-26)

Median No. of treatment (ind only) cycles (range) 11 (3-16)

Patient characteristicsPatient characteristics

Safety: results before amendmentSafety: results before amendment

Scheduled dose of 5FU before amendment was 3000 mg/sqm

2 out of the first 3 pts treated with the initially scheduled dose of 5FU experienced severe mucosal toxicity:

• 1 pt experienced grade 4 diarrhea and febrile neutropenia

• 1 pt experienced grade 3 diarrhea

Both pts were hospitalized due to toxicity, which resolved without sequelae

Because of the toxicities observed, study protocol was amended and 5FU dose reduced to 2400 mg/sqm

Maximum per patient toxicities after amendment Maximum per patient toxicities after amendment

34 pts assessed

Grade 1-2 Grade 3-4

Neutropenia 27% 53%

Febrile neutropenia 6%

Anemia 88% 0%

Thrombocytopenia 56% 0%

Nausea/Vomiting 70% / 44% 12% / 3%

Diarrhea 62% 35%

Stomatitis 53% 18%

Cutaneous rash 68% 24%

Asthenia 62% 29%

Neurotoxicity (grade 2-3) 35%

Maximum per cycle toxicities after amendment Maximum per cycle toxicities after amendment

34 pts assessed447 cycles administered

Grade 1-2 Grade 3-4

Neutropenia 17% 6%

Febrile neutropenia <1%

Anemia 58% 0%

Thrombocytopenia 17% 0%

Nausea/Vomiting 21% / 8% 1% / <1%

Diarrhea 34% 4%

Stomatitis 18% 1%

Cutaneous rash 59% 3%

Asthenia 31% 3%

Neurotoxicity (grade 2-3) 10%

Serious Adverse Events (SAEs) after amendmentSerious Adverse Events (SAEs) after amendment

34 pts assessedAll SAEs 17 events requiring hospitalization or resulting in death

Type of SAEs

Febrile neutropenia and sepsis (resulting in death)

Sudden cardiac death (after surgery on mts)

G4 Diarrhea + G3 Neutropenia Penumonitis (resulting in death)

G4 Neutropenia + G3 Stomatitis Bowel obstruction

Chest pain + G3 Diarrhea + G4 Stomatitis

Febrile neutropenia + G3 Diarrhea

Chest pain + G3 Diarrhea G3 Stomatitis + Hematemesis due to gastric ulcer

G4 Diarrhea + G3 Asthenia/Anorexia Bowel sub-obstruction

G4 Diarrhea + G3 Asthenia/Anorexia 2 Venous thromboembolic events

G4 Hypokalemia + G4 Neutropenia Necrotizing fascitis

Treatment administration during INDUCTION THERAPYTreatment administration during INDUCTION THERAPY

337 cycles administered 5FU LOHP CPT-11 P-mab

DOSE REDUCTIONS* 28 (8%) 34 (10%) 32 (9%) 27 (8%)

MEDIAN DOSE INTENSITY 79% 75% 74% 81%

DOSE DELAYS DUE TO TOXICITY* 32 (9%) - 15 (4%) due to SAEs

SECONDARY G-CSF SUPPORT* 46 (14%)

Reported after amendment

*Data are expressed as No. (%) of cycles

Response RateResponse Rate

All 37 pts have been evaluated for response

Best response is as follows:

• 34 pts achieved Objective Response (ORR: 92%)

• 2 pts (5%) achieved Disease Stabilization

• 1 pt (3%) progressed during treatment

Conversion to resectabilityConversion to resectability

Up today 15 pts (41%) underwent local procedures on metastases (R0 in 12 pts, 32% )

Among the 13 pts with liver-only disease, 10 pts (77%) underwent local procedures (surgery +/- RFA) on metastases (R0 in 9 pts, 69%)

3 pts achieved pathologic complete response

Activity: Maximum tumour shrinkageActivity: Maximum tumour shrinkage

Efficacy: Progression-free survival (PFS)Efficacy: Progression-free survival (PFS)

Median follow up: 12.2 monthsNo. of pts: 37No. of events: 24Median PFS: 10.8 months

- Combining a triple drug regimen such as FOLFOXIRI with Panitumumab seems feasible.

- However, treatment is associated with a relatively high incidence of severe mucosal toxicity (mainly diarrhea), therefore, a reduced dose of 5-FU and irinotecan compared with standard GONO-FOLFOXIRI is required.

- The primary end-point was met: in molecularly selected patients, FOLFOXIRI-Panitumumab achieved an ORR > 90%, leading to radical resection of metastases in 32% of the patients.

- Median PFS appears promising (mPFS: 10.8 months), while mOS has not been reached at a median follow-up of 12.2 months.

CONCLUSIONSCONCLUSIONS