Citation: European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 9

M. Peeters¹, T. Price², Y. Hotko³, A. Cervantes⁴, M. Ducreux⁵, T. André⁶, E. Chan⁷, F. Lordick⁸, A. Rong⁹, J. Gansert<sup>9

1</sup>University Hospital Ghent, Ghent, Belgium
²Queen Elizabeth Hospital, Woodville, Australia
³Uzhgorod National University, Uzhgorod Regional Oncology Dispensary, Uzhgorod, Ukraine
⁴Hospital Clínico, University of Valencia, Spain
⁵Institut Gustave Roussy, Villejuif, France
⁶Hôpital Pitié-Salpêtrière, Paris, France
⁷Vanderbilt University Medical Center, Nashville, Tennessee, USA
⁸Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany
⁹Amgen Inc., Thousand Oaks, California, USA

Background: Panitumumab (pmab) is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) approved as monotherapy for pts with mCRC. The 181 study was designed to evaluate the efficacy and safety of pmab with FOLFIRI vs FOLFIRI alone as 2nd-line tx for mCRC (clinicaltrials.gov identifier: NCT00339183; sponsor: Amgen Inc).
Methods: This was a randomized, multicenter, phase 3 study. Pts were randomized 1:1 to receive pmab 6.0 mg/kg Q2W+FOLFIRI (Arm 1) vs FOLFIRI alone (Arm 2). Pts had metastatic adenocarcinoma of the colon or rectum; only 1 prior chemotherapy regimen for mCRC; ECOG 0–2; and available tumor tissue for biomarker testing. Randomization was stratified by ECOG 0–1 vs 2, prior oxaliplatin, and prior bevacizumab exposure. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS) and were independently tested. Originally designed to compare the tx effect in the all randomized population, the study was amended to focus on hypothesis testing in the wild-type (WT) KRAS subset. KRAS status was determined by a blinded central laboratory using allele-specific PCR prior to the first efficacy analysis.
Results: From June 2006 to March 2008, a total of 1186 pts were randomized, signed informed consent, and received tx. 591 Arm 1, 595 Arm 2. Overall demographics included 61% men, median (range) age 61 (28–86) years, ECOG 0 or 1 94%. 1083/1186 pts (91%) had KRAS results: 597 (55%) WT, 486 (45%) mutant (MT). For pts with WT KRAS, median PFS was 5.9 months for Arm 1, and 3.9 months for Arm 2; HR (95% CI) = 0.73 (0.593, 0.903), p = 0.004; median OS was 14.5 months for Arm 1, and 12.5 months for Arm 2; HR (95% CI) = 0.85 (0.702, 1.039); p = 0.115, and response rate (by blinded central review) was 35% (Arm 1) and 10% (Arm 2). There was no difference in PFS, OS, or response rate among patients with MT KRAS who received pmab. In general, adverse event rates were comparable across arms with the exception of known toxicities associated with anti-EGFR therapy such as rash, diarrhea, and hypomagnesemia. Pmab-related grade 3/4 infusion reactions were reported for 2 patients in Arm 1 (<1%).
Conclusions: Pmab significantly improves PFS and is well tolerated when added to FOLFIRI for 2nd-line tx in pts with WT KRAS mCRC. This study confirms the importance of KRAS as a predictive biomarker in the setting of 2nd-line mCRC tx with a mAb against EGFR in combination with standard chemotherapy.