1 / 20

ASCO Annual Meeting 2012

ASCO Annual Meeting 2012. PHASE II STUDY OF PANITUMUMAB (P) IN COMBINATION WITH FOLFOXIRI AS FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER (MCRC): HIGH ACTIVITY IN MOLECULARLY SELECTED PATIENTS (PTS).

osborn
Download Presentation

ASCO Annual Meeting 2012

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. ASCO Annual Meeting 2012 PHASE II STUDY OF PANITUMUMAB (P) IN COMBINATION WITH FOLFOXIRI AS FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER (MCRC): HIGH ACTIVITY IN MOLECULARLY 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

  2. Rationale • 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

  3. Study Design • 35 mCRC pts • wild-type for: • KRAS codon 12-13-61 • BRAF codon 600 • HRAS-NRAS codon 12-13-61 FOLFOXIRI + P-mab P-mab +/- 5FU • INDUCTION TX • up to 12 cycles • or PD • or unacceptable toxicity • or patient’s refusal • MAINTENANCE TX • until PD • or intolerable toxicity • or patient’s refusal *≈70 ptsneeded to be screened  incidence of RAS and BRAF mutations ≈50%

  4. Induction Treatment Schedule (after amendment) Day 1 Day 2 & Day 3 P-mab 6 mg/Kg 5FU DOSE AMENDED AFTER 2 SAEs OCCURRED AMONG THE FIRST 3 PTS ENROLLED Irinotecan 150 mg/sqm Oxaliplatin 85 mg/sqm L-LV 200 mg/sqm 5FU flat continuous infusion 2400 mg/sqm 1 hour 1 hour 2 hours 48 hours Repeated every 2 weeks

  5. Main Enrollment Criteria • 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

  6. Study Objective and End-points The objective of the trial is to investigate the activity of FOLFOXIRI + panitumumabas first-line treatment in KRAS, NRAS, HRAS and BRAF wild-typemCRCpatients. • PRIMARY END-POINT: • Response Rate • SECONDARY END-POINTS: • Progression Free Survival • Secondary R0 surgery of metastases • Overall survival • Safety profile • Analyses of potentialpredictivefactors of treatment activity or efficacy

  7. Statistics • 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

  8. Main Enrollment Criteria • 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

  9. Screening and Enrollment

  10. Patient characteristics

  11. Safety: 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

  12. Maximum per patient toxicities after amendment

  13. Maximum per cycle toxicities after amendment

  14. Serious Adverse Events (SAEs) after amendment

  15. Treatment administration during INDUCTION THERAPY Reported after amendment *Data are expressed as No. (%) of cycles

  16. Response 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

  17. Conversion 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

  18. Activity: Maximum tumour shrinkage

  19. Efficacy: Progression-free survival (PFS) Median follow up: 12.2 months No. of pts: 37 No. of events: 24 Median PFS: 10.8 months

  20. CONCLUSIONS - 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.

More Related