Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma

Abstract

PurposeTo report planned final overall (OS) and progression-free survival (PFS) analyses from the phase II PEAK trial (NCT00819780).MethodsPatients with previously untreated, KRAS exon 2 wild-type (WT) metastatic colorectal cancer (mCRC) were randomised to mFOLFOX6 plus panitumumab or bevacizumab. The primary endpoint was PFS; secondary endpoints included OS, objective response rate, duration of response (DoR), time to response, resection and safety. Treatment effect by tumour RAS status was a prespecified objective. Exploratory analyses included early tumour shrinkage (ETS) and depth of response (DpR).ResultsOne hundred seventy patients had RAS WT and 156 had RAS WT/BRAF WT mCRC. Median PFS was longer for panitumumab versus bevacizumab in the RAS WT (12.8 vs 10.1 months; hazard ratio (HR) = 0.68 [95% confidence intervals (CI) = 0.48–0.96]; p = 0.029) and RAS WT/BRAF WT (13.1 vs 10.1 months; HR = 0.61 [95% CI = 0.42–0.88]; p = 0.0075) populations. Median OS (68% OS events) for panitumumab versus bevacizumab was 36.9 versus 28.9 months (HR = 0.76 [95% CI = 0.53–1.11]; p = 0.15) and 41.3 versus 28.9 months (HR = 0.70 [95% CI = 0.48–1.04]; p = 0.08), in the RAS WT and RAS WT/BRAF WT populations, respectively. Median DoR (11.4 vs 9.0 months; HR = 0.59 [95% CI = 0.39–0.88]; p = 0.011) and DpR (65.0 vs 46.3%; p = 0.0018) were improved in the panitumumab group. More panitumumab patients experienced ≥30% ETS at week 8 (64 vs 45%; p = 0.052); ETS was associated with improved PFS/OS. No new safety signals occurred.ConclusionsFirst-line panitumumab + mFOLFOX6 increases PFS versus bevacizumab + mFOLFOX6 in patients with RAS WT mCRC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00384-017-2800-1) contains supplementary material, which is available to authorized users.

Relationship Between Tumor Response and Tumor-Related Symptoms in RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses From 3 Panitumumab Trials

“…5,6 PEAK (NCT00819780) was a randomized phase 2 study comparing mFOLFOX6 in combination with panitumumab (6 mg/ kg, every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks) (n ¼ 285). 9,10 Study 314 (NCT00508404) was a single-arm phase 2 study of patients treated with panitumumab (6 mg/kg, every 2 weeks) plus FOLFIRI (n ¼ 154). 7,8 All 3 studies recruited adult patients with previously untreated mCRC.…”

“…3,4 In Europe in the first-line setting, panitumumab is indicated for use in combination FOLFOX or FOLFIRI on the basis of the results of 2 randomized controlled trials (PRIME, phase 3; and PEAK, phase 2) and a single-arm phase 2 study (Study 314). [5][6][7][8][9][10] Importantly, systemic therapy can result in tumor shrinkage, which may enable patients with previously unresectable disease to undergo curative surgery (often referred to as conversion therapy). 11,12 Recent retrospective analyses of clinical trial data in mCRC have included investigation of newer measures of tumor response, including early tumor shrinkage (ETS) and depth of response (DpR).…”

Panitumumab‐based maintenance after oxaliplatin discontinuation in metastatic colorectal cancer: A retrospective analysis of two randomised trials

“…The PEAK study was a randomised, open-label, Phase II clinical trial in which modified fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) was administered in combination with either panitumumab (6 mg/kg every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks), as first-line treatment. 4,5 In both trials, it was foreseen that FOLFOX-based treatment would continue until progressive disease or unacceptable toxicity. Oxaliplatin discontinuation was recommended if Grade 3 neuropathy or other dose-limiting toxicity occurred.…”

“…First-line treatment outcomes are summarised in Table 2; pooled data are provided in Supporting Information Table S2. The median (range) number of oxaliplatin infusions that patients received during first-line treatment was 12 (2-31) and 11 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) for panitumumab plus 5-FU/LV in PRIME and PEAK, respectively, 13 (5-41) for 5-FU/LV maintenance in PRIME and 12 (3-9) for 5-FU/LV plus bevacizumab maintenance in PEAK. Patients who received panitumumab plus 5-FU/LV maintenance therapy were more likely to have received ≥9 months of first-line treatment, to have experienced ETS and to have had higher rates of complete response and partial response than patients who received maintenance therapy with 5-FU/LV AE bevacizumab.…”

“…Both studies assessed the use of panitumumab as part of oxaliplatin-containing first-line therapy. [3][4][5][6] Clinical trial data show that continuation of first-line therapy until disease progression occurs only in a subpopulation of patients with mCRC, suggesting that systemic therapy is deescalated in many patients before progression. 7,8 Considerations around maintenance therapy are of particular importance when drugs like oxaliplatinassociated with cumulative neurotoxicityform part of adopted regimens.…”