PEAK: A Randomized, Multicenter Phase II Study of Panitumumab Plus Modified Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) or Bevacizumab Plus mFOLFOX6 in Patients With Previously Untreated, Unresectable, Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer

Purpose To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and 13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS. Patients and Methods Patients with WT KRAS exon 2 tumors were randomly assigned at a one-to-one ratio to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and safety. Results Of 285 randomly assigned patients, 278 received treatment. In the WT KRAS exon 2 intent-to-treat group, PFS was similar between arms (hazard ratio [HR], 0.87; 95% CI, 0.65 to 1.17; P = .353). Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms, respectively (HR, 0.62; 95% CI, 0.44 to 0.89; P = .009). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS), PFS favored the panitumumab arm (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). Median OS was 41.3 and 28.9 months (HR, 0.63; 95% CI, 0.39 to 1.02; P = .058) in the panitumumab and bevacizumab arms, respectively. Treatment discontinuation rates because of adverse events were similar between arms. Conclusion PFS was similar and OS was improved with panitumumab relative to bevacizumab when combined with mFOLFOX6 in patients with WT KRAS exon 2 tumors. Patients with WT RAS tumors seemed to experience more clinical benefit with anti–epidermal growth factor receptor therapy.

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Panitumumab versus cetuximab in patients with wild-type KRAS exon 2 metastatic colorectal cancer who received prior bevacizumab therapy: A combined analysis of individual patient data from ASPECCT and WJOG6510G.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.745 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 745-745 ◽

Cited By ~ 2

Author(s):

Hiroya Taniguchi ◽

Takeharu Yamanaka ◽

Daisuke Sakai ◽

Kentaro Yamazaki ◽

Kei Muro ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Individual Patient Data ◽

Progression Free Survival ◽

Patient Data ◽

Rank Test ◽

Wild Type ◽

Exon 2 ◽

Combined Analysis ◽

Kras Exon

745 Background: The ASPECCT (Price T, et al. Eur J Cancer 2016) and WJOG6510G (Sugimoto N, et al. ASCO-GI 2017) trials demonstrated noninferiority of panitumumab (Pmab), compared with cetuximab (Cmab), regarding the overall survival (OS) for chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). However, the subgroup analyses of both trials revealed a longer survival with Pmab than Cmab in patients who previously received bevacizumab (Bev). We performed a combined analysis of both trials using individual patient data. Methods: In both trials, patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to CPT-11- or L-OHP-based chemotherapy were randomized to receive Pmab or Cmab monotherapy (ASPECCT) or in combination with CPT-11 (WJOG). The patient subgroup with prior Bev was eligible for enrollment in this analysis. Results: In the combined data of 374 patients, 185 patients were enrolled in the Pmab arm (ASPECCT, 126; WJOG, 59) and 189 patients in the Cmab arm (ASPECCT, 132; WJOG, 57). The patient characteristics were well-balanced in both arms. Of the 374 patients, 341 (91%) and 369 (99%) had the OS and progression-free survival (PFS) events, respectively. The median OS was 12.8 months in the Pmab arm and 10.1 months in the Cmab arm ( P = 0.0031; the log-rank test stratified by trial). The hazard ratio (HR) for OS was 0.72 (95% confidence interval [CI], 0.58–0.90). The median PFS in the Pmab and Cmab arms were 4.7 and 4.1 months, respectively (P = 0.0207). HR for PFS was 0.79 (95% CI: 0.64–0.97). Response rates in the Pmab and Cmab arms were 23% and 16%, respectively (P = 0.114). Although the incidence of skin toxicities was similar, the infusion reaction was observed more in the Cmab arm (any grade, 1.1% vs 8.6%), whereas hypomagnesemia was noted more in the Pmab arm (48% vs 33%). Conclusions: This combined analysis demonstrated that Pmab significantly prolonged OS and PFS compared with Cmab, raising the potential that Pmab is the more reliable anti-EGFR option for patients with wild-type KRAS exon 2 metastatic colorectal cancer who previously received Bev.

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Clinical Impact of Circulating Tumor RAS and BRAF Mutation Dynamics in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy Plus Anti–Epidermal Growth Factor Receptor Therapy

JCO Precision Oncology ◽

10.1200/po.18.00289 ◽

2019 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Joan Maurel ◽

Vicente Alonso ◽

Pilar Escudero ◽

Carlos Fernández-Martos ◽

Antonieta Salud ◽

...

Keyword(s):

Colorectal Cancer ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Metastatic Colorectal Cancer ◽

Growth Factor Receptor ◽

Wild Type ◽

Braf Mutations ◽

Exon 2 ◽

Epidermal Growth

PURPOSE RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti–epidermal growth factor receptor therapy. METHODS RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease ( P < .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD ( P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations ( P = .016). CONCLUSION Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti–epidermal growth factor receptor therapy.

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