Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study
Publication: Journal of Clinical Oncology
Abstract
Purpose
Panitumumab, a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC.
Patients and Methods
In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status.
Results
KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy.
Conclusion
This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
Introduction
Colorectal cancer (CRC) is the third most common cancer among men and women in the United States, resulting in approximately 175,000 new cancers yearly.1 Worldwide, there are more than one million new cases of CRC each year.2 On the basis of its role in the pathogenesis of CRC, the epidermal growth factor receptor (EGFR) has proven to be a clinically meaningful target for monoclonal antibodies (mAbs) with efficacy established in all lines of treatment of metastatic CRC (mCRC).3–9 Panitumumab is a fully human mAb targeting the EGFR.
Retrospectively analyzed studies identified KRAS mutation in tumors as a negative predictive factor for panitumumab and cetuximab for improved response rate (RR), progression-free survival (PFS), and overall survival (OS).10–16 In September 2007, a prospectively defined, retrospective analysis of the pivotal phase III study of panitumumab as monotherapy in the mCRC setting provided evidence that clinical benefit was specific to patients with wild-type (WT) KRAS tumors.17
The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) is an open-label, randomized, multicenter, phase III trial prospectively investigating panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment for mCRC in patients with WT KRAS tumors. Originally designed to compare the treatment effect in all randomly assigned patients, the trial was amended to focus on prospective hypothesis testing in the WT KRAS stratum.
Patients and Methods
Patients
Eligible patients were ≥ 18 years old, had previously untreated metastatic adenocarcinoma of the colon or rectum, and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2. Fluorouracil-based adjuvant chemotherapy was allowed if disease recurrence occurred 6 months after completion; however, prior oxaliplatin was not allowed. At least one measurable lesion (≥ 20 mm) was required. Paraffin-embedded tumor tissue from the primary tumor or metastasis had to be available for central biomarker analyses. EGFR expression and KRAS status were not required at entry. The protocol was approved by the ethics committees at participating sites. All patients signed informed consent before any study-related procedures were performed.
Study Design and Treatment Schedule
This is an open-label, multicenter, phase III trial that compared the efficacy of panitumumab-FOLFOX4 with FOLFOX4 alone in patients with previously untreated mCRC according to tumor KRAS status. Patients were randomly assigned 1:1 to receive either panitumumab-FOLFOX4 or FOLFOX4. Random assignment was stratified by geographic region (Western Europe, Canada, and Australia v rest of the world) and ECOG PS (0 or 1 v 2).
Panitumumab was administered intravenously (IV) over 1 hour at 6 mg/kg every 2 weeks on day 1 before FOLFOX4 chemotherapy. If tolerated, subsequent infusions could be administered over 30 minutes. FOLFOX4 was administered every 2 weeks as oxaliplatin 85 mg/m2 IV infusion on day 1 and leucovorin 200 mg/m2 (or equivalent) IV infusion followed by fluorouracil 400 mg/m2 IV bolus and 600 mg/m2 22-hour continuous infusion on days 1 and 2. Treatment was administered until progression or unacceptable toxicity (Fig 1A).
Objective tumor response was evaluated by blinded central radiology review using modified Response Evaluation Criteria in Solid Tumors (RECIST)18 in all patients with baseline measurable disease per central review. Patients were evaluated every 8 weeks until progression. Responses were confirmed at least 4 weeks later. Resections of metastases were reported as being either complete or partial; the status of the surgical margins was not specifically captured. Patients were observed for safety 30 days after the last study drug administration and for survival every 3 months. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events (version 3.0) with modifications for specific skin- and nail-related toxicities. Safety results were summarized for patients who received at least one dose of protocol therapy. Patient-reported outcomes were measured and will be reported separately. An independent data monitoring committee reviewed interim analyses of safety and one descriptive interim analysis of PFS.
KRAS and Antibody Testing
KRAS testing was performed in a blinded central laboratory using allele-specific polymerase chain reaction (DxS, Manchester, United Kingdom), as previously described.17 Testing was initiated after the study population was enrolled and was completed 3 months before the primary analysis (Appendix Fig A1, online only). Serum antipanitumumab antibodies were analyzed as previously described.19
Statistical Analysis
The primary objective of this study was to assess the treatment effect of the addition of panitumumab to FOLFOX4 on PFS (blinded central radiology review) as initial therapy for mCRC in patients with WT KRAS tumors and also in patients with mutant (MT) KRAS tumors. Originally designed to test the treatment effect in all randomly assigned patients (N = 900), the study was amended to compare PFS (primary end point) and OS (secondary end point) according to KRAS status before any efficacy analyses. The sample size was increased to 1,150 to ensure adequate power to test PFS in the WT KRAS population. No multiplicity adjustments were made for end points other than PFS and OS. There was no planned interim analysis by KRAS status after the amendment, because KRAS status was not expected to be available until approximately the time of the primary analysis. A treatment comparison of OS in the WT KRAS stratum and of PFS in the MT KRAS stratum was conditional on first demonstrating a significant difference in PFS (P < .05) in the WT KRAS stratum. A treatment comparison of OS in the MT KRAS stratum was conditional on a significant difference in PFS in the same stratum. The primary OS analysis was planned when at least 50% of patients in both treatment arms had died in the WT KRAS stratum, and a significance level of P = .0499 was used to account for a planned interim OS analysis.
A log-rank test stratified by random assignment factors was used to compare PFS and OS. In the WT KRAS stratum, a hazard ratio (HR) of 0.714 was hypothesized (panitumumab-FOLFOX4 to FOLFOX4). To achieve 90% power for a two-sided, P = .05 significance level in the WT KRAS stratum, a total of 380 PFS events (radiologic progression per modified RECIST by blinded central review or death) and a sample size of 1,150 patients independent of KRAS status were required. Treatment effects on PFS and OS were estimated using stratified Cox proportional hazards models and the Kaplan-Meier method. An exact 95% CI was estimated for a stratified odds ratio for objective RR. The random assignment factors were used for analysis stratification. Descriptive analyses of treatment effects were planned in prospectively identified subsets. After protocol amendment, an interim PFS analysis after 258 events in all randomly assigned patients (because tumor KRAS results were not yet available) was retained to stop for inferior results given an estimated HR ≥ 1.28. At the time of the primary PFS analysis, a P = .001 nominal significance level was used to compare OS in an interim analysis in the WT and MT KRAS strata. The interim OS results were reported along with the primary PFS results (after the cutoff date for the primary OS analysis).20 A prespecified final analysis, which will include OS, is planned after a 2.5-year minimum follow-up period.
Results
Patients
Between August 2006 and February 2008, 1,183 patients were randomly assigned from among 133 institutions in 19 countries; 593 patients (50%) were randomly assigned to receive panitumumab-FOLFOX4, and 590 patients (50%) were randomly assigned to receive FOLFOX4 (Fig 1B). Of these patients, 1,096 patients (93%) had available tumor KRAS status results; 656 patients (60%) had WT KRAS tumors, and 440 patients (40%) had MT KRAS tumors.
Baseline demographics and disease characteristics were generally balanced within each treatment arm and KRAS stratum (Table 1), with the exception that there were more patients with three or more disease sites, elevated baseline carcinoembryonic antigen, and elevated lactate dehydrogenase in the panitumumab-FOLFOX4 arm than in the FOLFOX4 arm in the MT KRAS stratum. For the primary PFS analysis, median follow-up time from random assignment to data cutoff in the WT KRAS stratum was 13.2 months (range, 0 to 25.2 months) for patients who received panitumumab-FOLFOX4 and 12.5 months (range, 0 to 24.7 months) for patients who received FOLFOX4. Median follow-up time was 10.8 months (range, 0.7 to 22.4 months) for patients with MT KRAS status who received panitumumab-FOLFOX4 and 12 months (range, 0.2 to 23.1 months) for patients who received FOLFOX4.
| Demographic or Clinical Characteristic | WT KRAS | MT KRAS | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Panitumumab- FOLFOX4(n = 325) | FOLFOX4 (n = 331) | Panitumumab- FOLFOX4(n = 221) | FOLFOX4 (n = 219) | ||||||
| No. of Patients | % | No. of Patients | % | No. of Patients | % | No. of Patients | % | ||
| Male | 217 | 67 | 204 | 62 | 145 | 66 | 128 | 58 | |
| Age, years | |||||||||
| Median | 62 | 61 | 63 | 61 | |||||
| Range | 27-85 | 24-82 | 33-83 | 27-82 | |||||
| White race | 296 | 91 | 307 | 93 | 196 | 89 | 196 | 89 | |
| ECOG performance status* | |||||||||
| 0-1 | 305 | 94 | 312 | 94 | 213 | 96 | 209 | 95 | |
| ≥ 2 | 20 | 6 | 18 | 5 | 8 | 4 | 10 | 5 | |
| Region: Western Europe, Canada, Australia | 194 | 60 | 187 | 56 | 119 | 54 | 122 | 56 | |
| Primary tumor type | |||||||||
| Colon | 214 | 66 | 216 | 65 | 151 | 68 | 160 | 73 | |
| Rectal | 111 | 34 | 115 | 35 | 70 | 32 | 59 | 27 | |
| Site of metastatic disease | |||||||||
| Liver only | 60 | 18 | 56 | 17 | 32 | 14 | 36 | 16 | |
| Liver + other | 223 | 69 | 227 | 69 | 156 | 71 | 159 | 73 | |
| Other only | 40 | 12 | 47 | 14 | 31 | 14 | 23 | 11 | |
| Missing or unknown | 2 | 1 | 1 | < 1 | 2 | 1 | 1 | < 1 | |
| No. of sites of disease | |||||||||
| 1 | 68 | 21 | 67 | 20 | 39 | 18 | 43 | 20 | |
| 2 | 112 | 34 | 116 | 35 | 70 | 32 | 80 | 37 | |
| ≥ 3 | 143 | 44 | 147 | 44 | 110 | 50 | 95 | 43 | |
| CEA > ULN | 255 | 78 | 255 | 77 | 188 | 85 | 170 | 78 | |
| LDH ≥ 1.5× ULN | 92 | 28 | 96 | 29 | 73 | 33 | 59 | 27 | |
| Prior adjuvant chemotherapy | 53 | 16 | 55 | 17 | 35 | 16 | 26 | 12 | |
Abbreviations: WT, wild type; MT, mutant; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin; ECOG, Eastern Cooperative Oncology Group; CEA, carcinoembryonic antigen; ULN, upper limit of normal; LDH, lactate dehydrogenase.
*
One patient had an unknown ECOG performance status at baseline.
Efficacy
PFS.
In the WT KRAS stratum, there were 414 progression or death events—199 (61%) in the panitumumab-FOLFOX4 arm and 215 (65%) in the FOLFOX4 arm. A statistically significant improvement in PFS was observed with panitumumab-FOLFOX4 compared with FOLFOX4 (HR = 0.80; 95% CI, 0.66 to 0.97; P = .02, stratified log-rank test; Fig 2A). Median PFS was 9.6 months (95% CI, 9.2 to 11.1 months) for panitumumab-FOLFOX4 and 8.0 months (95% CI, 7.5 to 9.3 months) for FOLFOX4. From the planned subgroup analyses for PFS in the WT KRAS stratum, the HR for all subsets was less than 1 (panitumumab-FOLFOX4 v FOLFOX4), with the exception of patients ≥ 65 years old, women, and patients with ECOG PS of 2 (Fig 3A).
In the MT KRAS stratum, there were 324 progression or death events—167 (76%) in the panitumumab-FOLFOX4 arm and 157 (72%) in the FOLFOX4 arm. PFS was inferior in patients receiving panitumumab-FOLFOX4 versus FOLFOX4 (HR = 1.29; 95% CI, 1.04 to 1.62; P = .02, stratified log-rank test; Fig 2B). Median PFS was 7.3 months (95% CI, 6.3 to 8.0 months) for panitumumab-FOLFOX4 and 8.8 months (95% CI, 7.7 to 9.4 months) for FOLFOX4.
OS.
In the WT KRAS stratum, at the time of the analysis, 355 deaths had occurred—165 (51%) in the panitumumab-FOLFOX4 arm and 190 (57%) in the FOLFOX4 arm. Median OS was 23.9 months (95% CI, 20.3 to 28.3 months) for panitumumab-FOLFOX4 and 19.7 months (95% CI, 17.6 to 22.6 months) for FOLFOX4 arm, resulting in an absolute difference of 4.2 months. The HR was 0.83 (95% CI, 0.67 to 1.02; P = .072) favoring the panitumumab-FOLFOX4 arm (Fig 2C). From planned subgroup analyses for OS, the HR for all subsets was less than 1, with the exception of the small subsets with no liver metastases and ECOG PS ≥ 2 (Fig 3B).
Subsequent to study treatment, 8% of patients in the panitumumab-FOLFOX4 arm and 18% of patients in the FOLFOX4 arm received anti-EGFR mAb therapy. Median time to anti-EGFR therapy from random assignment was 18 months in the panitumumab-FOLFOX4 arm and 11 months in the FOLFOX4 arm. Subsequent chemotherapy (including oxaliplatin, irinotecan, and/or fluoropyrimidine) was received by 62% of patients in the FOLFOX4 arm and 53% of patients in the panitumumab-FOLFOX4 arm and included bevacizumab in 12% and 15% of patients, respectively.
In the MT KRAS stratum, 294 deaths occurred—152 (69%) in the panitumumab-FOLFOX4 arm and 142 (65%) in the FOLFOX4 arm. Median OS was 15.5 months (95% CI, 13.1 to 17.6 months) for panitumumab-FOLFOX4 and 19.3 months (95% CI, 16.5 to 21.8 months) for FOLFOX4 (HR = 1.24; 95% CI, 0.98 to 1.57; P = .068, stratified log-rank test; Fig 2D).
Within the panitumumab-FOLFOX4 arm, the HR for OS for the WT stratum versus MT stratum was 0.57 (95% CI, 0.46 to 0.71; P < .001). In the FOLFOX4 arm, the HR for OS for the WT stratum versus MT stratum was 0.87 (95% CI, 0.70 to 1.08; P = .21).
Objective response.
In the WT KRAS stratum, the RR was 55% for panitumumab-FOLFOX4 and 48% for FOLFOX4 (stratified odds ratio, 1.35; P = .068). In the MT KRAS stratum, the RR was 40% in each arm.
Resection rate.
Metastasectomy of any site was attempted in 10.5% of patients treated with panitumumab-FOLFOX4 and 9.4% of patients treated with FOLFOX4 with WT KRAS status; complete resections were achieved in 8.3% and 7.0% of patients, respectively.
Safety
Grade 3 and 4 AEs of interest are listed in Table 2. The incidence of skin toxicity was 96% for patients receiving panitumumab-FOLFOX4 and 31% for patients receiving FOLFOX4. In the WT KRAS stratum, the rates of AEs in the panitumumab-FOLFOX4 and FOLFOX4 arms were 82% and 63%, respectively, for worst grade 3 or 4 treatment-related AEs (considered by the investigator to be related to chemotherapy and/or panitumumab treatment) and 40% and 36%, respectively, for serious AEs. Fatal AEs were reported in 16 patients (5%) in the panitumumab-FOLFOX4 arm and in 20 patients (6%) in the FOLFOX4 arm and included cases where the primary cause of death was disease progression. In each arm, there were four fatal treatment-related AEs including two that were panitumumab related, pneumonitis (no infectious etiology identified) and pneumonia.
| Adverse Event by MedDRA Term | WT KRAS (n = 649) | MT KRAS (n = 435) | ||||||
|---|---|---|---|---|---|---|---|---|
| Panitumumab- FOLFOX4 (n = 322) | FOLFOX4(n = 327) | Panitumumab- FOLFOX4 (n = 217) | FOLFOX4 (n = 218) | |||||
| No. of Patients | % | No. of Patients | % | No. of Patients | % | No. of Patients | % | |
| Patients with any event | 270 | 84 | 227 | 69 | 173 | 80 | 159 | 73 |
| Neutropenia | 136 | 42 | 134 | 41 | 81 | 37 | 103 | 47 |
| Skin toxicity | 116 | 36 | 7 | 2 | 66 | 30 | 3 | 1 |
| Diarrhea | 59 | 18 | 29 | 9 | 43 | 20 | 21 | 10 |
| Neurologic toxicities | 52 | 16 | 51 | 16 | 36 | 17 | 37 | 17 |
| Hypokalemia | 32 | 10 | 15 | 5 | 19 | 9 | 8 | 4 |
| Fatigue | 30 | 9 | 10 | 3 | 16 | 7 | 11 | 5 |
| Mucositis*† | 28 | 9 | 2 | < 1 | 12 | 6 | 6 | 3 |
| Hypomagnesemia | 20 | 6 | 1 | < 1 | 13 | 6 | 1 | < 1 |
| Paronychia† | 11 | 3 | 0 | 0 | 4 | 2 | 0 | 0 |
| Pulmonary embolism | 9 | 3 | 5 | 2 | 7 | 3 | 8 | 4 |
| Febrile neutropenia | 8 | 2 | 7 | 2 | 7 | 3 | 7 | 3 |
| Infusion-related reaction (panitumumab)† | 2 | < 1 | — | — | 0 | 0 | — | — |
NOTE. All events are included, regardless of relatedness to therapy.
Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; WT, wild type; MT, mutant; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin.
*
Results are based on the following prespecified list of preferred terms: stomatitis, mucosal inflammation, aphthous stomatitis, mouth ulceration, mucosal dryness, and mucosal ulceration.
†
No grade 4 events.
In the MT KRAS stratum, the AE rates in the panitumumab-FOLFOX4 and FOLFOX4 arms were 79% and 69%, respectively, for worst grade 3 or 4 treatment-related AEs and 47% and 29%, respectively, for serious AEs. Fatal AEs were reported in 17 patients (8%) in the panitumumab-FOLFOX4 arm and in seven patients (3%) in the FOLFOX4 arm; fatal events included cases where the primary cause of death was disease progression. There were three treatment-related fatal AEs, none of which were reported as related to panitumumab (one septic shock in each arm and one febrile neutropenia in the panitumumab-FOLFOX4 arm). Grade 3 panitumumab-related infusion reactions occurred in two patients (0.3%); both patients received additional panitumumab treatment after premedication.
Treatment Exposure
The median number of cycles of panitumumab and chemotherapy and the relative dose-intensity were similar between treatment arms in both the WT and MT KRAS strata (Table 3). The most common reason for chemotherapy discontinuation was disease progression, which occurred in 51% of patients with WT KRAS tumor status and 61% of patients with MT KRAS tumor status. Other reasons for discontinuation included patient request and AEs and were balanced between treatment arms and KRAS strata.
| Treatment Measure | WT KRAS | MT KRAS | ||
|---|---|---|---|---|
| Panitumumab-FOLFOX4 (n = 322) | FOLFOX4 (n = 327) | Panitumumab-FOLFOX4 (n = 217) | FOLFOX4 (n = 218) | |
| Median No. of cycles received | ||||
| Panitumumab | 11 | — | 10 | — |
| Oxaliplatin | 11 | 11 | 11 | 11 |
| FU (bolus) | 12 | 12 | 12 | 12 |
| FU (continuous infusion) | 12 | 12 | 12 | 12 |
| Median relative dose-intensity, % | ||||
| Panitumumab | 81 | — | 83 | — |
| Oxaliplatin | 77 | 79 | 80 | 80 |
| FU (bolus) | 77 | 81 | 80 | 81 |
| FU (continuous infusion) | 78 | 81 | 81 | 81 |
| Median cumulative total dose | ||||
| Panitumumab, mg/kg | 62 | — | 57 | — |
| Oxaliplatin, mg/m2 | 859 | 865 | 824 | 856 |
| FU (bolus), mg/m2 | 8,627 | 8,618 | 8,294 | 8,711 |
| FU (continuous infusion), mg/m2 | 13,483 | 13,229 | 12,878 | 13,109 |
Abbreviations: WT, wild type; MT, mutant; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin; FU, fluorouracil.
Antibody
Treatment-emergent binding antipanitumumab antibodies were detected in 14 (3.0%) of 470 patients who received panitumumab. Neutralizing antibodies were detected in postdose samples from two (0.4%) of 470 patients.
Discussion
PRIME is the first study, to our knowledge, to evaluate the impact of the addition of panitumumab to FOLFOX4 for the initial treatment of patients with WT KRAS mCRC. Importantly, the results were prospectively analyzed by KRAS status, and the study achieved the primary objective by demonstrating a significant improvement in the probability of being alive without disease progression when panitumumab is added to chemotherapy for patients with WT KRAS tumors. The difference in median OS for patients with WT KRAS status, although not statistically significant, was also favorable, with a 4.2-month improvement in the panitumumab-FOLFOX4 arm compared with the FOLFOX4 arm. There was a statistically significant interaction between the treatment effect and KRAS tumor status for PFS (Appendix Table A1, online only). The goal of the primary OS analysis was to obtain median estimates, and only 51% of patients had an event in the panitumumab-treated WT KRAS population at the time of this analysis. Responses were more frequent in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (Appendix Table A2, online only); however, resection rates were similar.
A total of 87 patients were excluded from analysis who were unevaluable for KRAS, which may have introduced ascertainment bias; however, various prospective and post hoc intent-to-diagnosis sensitivity analyses provided results consistent with the primary analysis for each KRAS stratum. Details are included in Appendix Table A3, online only.
All planned subsets consistently demonstrated favorable effects of panitumumab on PFS, with the exception of patients ≥ 65 years old, women, and the small subset of patients with ECOG PS of 2 (Fig 3A). Importantly, however, a favorable OS effect was observed in women and older patients receiving panitumumab (Fig 3B). In addition, absolute differences in RR were similar between men and women (data not shown).
Safety was as expected when an anti-EGFR mAb is added to chemotherapy and included increased skin toxicity in panitumumab-treated patients. There is evidence that skin toxicity associated with EGFR inhibition can be effectively managed.21 As reported in other studies,3,5,8 an association between skin toxicity and efficacy was observed in PRIME (data not shown). Additional analyses are underway to determine the importance of skin toxicity as a predictive factor after adjusting for other prognostic characteristics. Although diarrhea and hypomagnesemia were increased, these toxicities were clinically manageable based on the infrequency with which they lead to treatment discontinuation (Amgen, data on file). Infusion reactions were rare. Two patients (0.3%) experienced a grade 3 panitumumab-related infusion reaction; both received additional panitumumab treatment.
The positive results in the WT KRAS population in PRIME are consistent with the findings of a recently reported trial in which panitumumab was added to fluorouracil, leucovorin, and irinotecan chemotherapy in previously treated patients with mCRC.22 The effect observed in PRIME is also generally consistent with that seen in two other first-line mCRC studies with cetuximab and chemotherapy, although KRAS status was analyzed retrospectively in those studies.8,9 The 4.2-month benefit in median OS observed in PRIME, although not statistically significant, is comparable to the median OS improvement of 3.5 months reported for the WT KRAS population in the phase III CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study with cetuximab and fluorouracil, leucovorin, and irinotecan based on an updated retrospective efficacy analysis.23 In contrast, there was no improvement in either OS or PFS when cetuximab was added to oxaliplatin-based chemotherapy in the recently reported Medical Research Council COIN (Continuous Chemotherapy Versus Intermittent Chemotherapy) trial, which, similar to PRIME, was prospectively analyzed according to tumor KRAS status.24 Efficacy results in the WT KRAS population in PRIME also compared favorably with those reported for the subset of all patients who received FOLFOX4 chemotherapy when bevacizumab was added to treatment.25
Although data from the PRIME trial demonstrate that KRAS is not a prognostic biomarker in this treatment setting (the outcomes of patients with MT KRAS receiving FOLFOX4 were generally similar to those of patients with WT KRAS with respect to RR, PFS, and OS), this trial does confirm the importance of KRAS as a predictive biomarker of efficacy for anti-EGFR mAb therapy. As opposed to the positive effects seen in the WT KRAS strata, in the MT KRAS strata, the addition of panitumumab resulted in a significant detrimental effect on PFS. A similar detrimental effect was also observed in patients with MT KRAS tumors when cetuximab was used in combination with oxaliplatin.9 There were no appreciable differences in chemotherapy exposure or AEs to explain this finding, and the mechanism is still unknown. These results emphasize the importance of incorporating early KRAS testing into treatment algorithms for patients with mCRC.
Consistent with findings from studies of panitumumab in patients with previously treated mCRC,3,22 panitumumab, when added to FOLFOX4, significantly improved PFS for patients with previously untreated WT KRAS mCRC. Other clinically meaningful attributes of panitumumab include that severe panitumumab-related infusion reactions are rare and a standard 2-week dosing regimen allows for synchronization with chemotherapy dosing and minimizes the number of required clinic visits. In conclusion, panitumumab is well tolerated and effective when added to FOLFOX4. This combination represents a relevant and new therapeutic option for the treatment of patients with WT KRAS mCRC. Efforts are underway to identify additional predictive biomarkers for anti-EGFR therapy within the WT KRAS population.
Acknowledgment
We thank the patients, their families, and the site staff. We thank the Amgen country staff and study team: Pamela Ward, Byron Espina, Sarah Edgington, Nora Burr, Feng Xu, and Judith Dionisio. Finally, we thank Barbara Schreader of Amgen for medical writing assistance.
Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; the 2008 Gastrointestinal Cancers Symposium, January 25-27, 2008, Orlando, FL; the joint 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology, September 20-24, 2009, Berlin, Germany; the 6th Annual Meeting of the International Society of Gastrointestinal Oncology, October 1-3, 2009, Philadelphia, PA; the 2009 National Cancer Research Institute Cancer Conference, October 4-7, 2009, Birmingham, United Kingdom; and the 2010 Gastrointestinal Cancers Symposium, January 22-24, 2010, Orlando, FL.
Clinical trial information can be found for the following: NCT00364013.
J Clin Oncol Douillard et al 28: 10.1200/JCO.2009.27.4860
Publisher's Note
The article by Douillard et al, entitled "Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study" (J Clin Oncol 10.1200/JCO.2009.27.4860), was published online October 4, 2010, with errors.
In Figure 2B, erroneous data were given for the number of patients at risk receiving both panitumumab + FOLFOX4 and FOLFOX4 alone. This has been corrected as of October 25, 2010. Journal of Clinical Oncology apologizes to the authors and readers for the mistakes.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Kelly S. Oliner, Amgen (C); Michael Wolf, Amgen (C); Jennifer Gansert, Amgen (C) Consultant or Advisory Role: Jean-Yves Douillard, Amgen (C), sanofi-aventis (C), Merck Serono (C); Salvatore Siena, Amgen (C), AstraZeneca (C), Merck Serono (C), Roche (C), Celgene (C); James Cassidy, Roche (C), sanofi-aventis (C), Amgen (C), Merck Serono (C); Josep Tabernero, Amgen (C), Merck Serono (C), ImClone Systems (C); Ronald Burkes, Amgen (C) Roche (C), sanofi-aventis (C), Eli Lilly (C); Mario Barugel, Amgen (C), Roche (C); Yves Humblet, Amgen (C), Merck Serono (C), Roche (C); György Bodoky, Amgen (C), Merck Serono (C); David Cunningham, Amgen (C); Paul Ruff, Amgen (C), Novartis (C); Fernando Rivera, Amgen (C); Jean-Luc Canon, Amgen (C); Mark Rother, Amgen (C) Stock Ownership: Kelly S. Oliner, Amgen; Michael Wolf, Amgen; Jennifer Gansert, Amgen Honoraria: Jean-Yves Douillard, Amgen, sanofi-aventis; James Cassidy, Amgen, Roche, sanofi-aventis; Ronald Burkes, Amgen, Roche, sanofi-aventis, Eli Lilly; Mario Barugel, Roche; Yves Humblet, Amgen, Merck Serono; György Bodoky, Amgen, Roche; Fernando Rivera, Amgen; Paul Ruff, Amgen, Merck Serono, Pfizer; Jean-Luc Canon, Amgen; Mark Rother, Amgen Research Funding: James Cassidy, Roche, Amgen; Yves Humblet, Amgen, Merck Serono, Bayer Pharmaceuticals; David Cunningham, Amgen, Roche, Merck Serono; Fernando Rivera, Amgen; Paul Ruff, Amgen, Novartis, Roche, Merck Serono, Pfizer; Jean-Luc Canon, Amgen Expert Testimony: None Other Remuneration: None
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Appendix
Investigators of the Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) are listed in Table A4.
| End Point | Value |
|---|---|
| PFS | |
| WT ITD KRAS patients | |
| No. of patients | 738 |
| No. of events | 474 |
| HR (panitumumab-FOLFOX4 v FOLFOX4) | 0.853 |
| 95% CI | 0.710 to 1.023 |
| MT KRAS patients | |
| No. of patients | 436 |
| No. of events | 321 |
| HR (panitumumab-FOLFOX4 v FOLFOX4) | 1.261 |
| 95% CI | 1.006 to 1.581 |
| P for quantitative interaction test | .0083 |
| OS | |
| WT ITD KRAS patients | |
| No. of patients | 738 |
| No. of events | 268 |
| HR (panitumumab-FOLFOX4 v FOLFOX4) | 0.801 |
| 95% CI | 0.628 to 1.022 |
| MT KRAS patients | |
| No. of patients | 436 |
| No. of events | 193 |
| HR (panitumumab-FOLFOX4 v FOLFOX4) | 1.609 |
| 95% CI | 1.199 to 2.161 |
| P for quantitative interaction test | < .001 |
NOTE. For PFS, an analysis was planned to test for a treatment by KRAS interaction at a two-sided 5% significance level. OS was analyzed descriptively. A quantitative interaction test (Gail M, Simon R: Biometrics 41:361-372, 1985) was used to compare the relative treatment effects between the WT ITD and MT KRAS analysis sets with KRAS unevaluable patients included in the WT ITD set. For both PFS and OS, the relative treatment effect was estimated by the log HR (panitumumab-FOLFOX4 v FOLFOX4 alone) from a Cox model adjusted by the random assignment factors (Eastern Cooperative Oncology Group performance status and geographic region) and stratified by quintiles of propensity scores estimated from a logistic regression model with prespecified covariates for the probability of being in the panitumumab treatment group. The analysis excluded patients with covariate missing values. The analyses of PFS were based on data from the blinded central radiology review.
Abbreviations: PFS, progression-free survival; OS, overall survival; WT, wild type; ITD, intent to diagnose; HR, hazard ratio; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin; MT, mutant.
| Efficacy | WT KRAS | MT KRAS | ||||
|---|---|---|---|---|---|---|
| Panitumumab-FOLFOX4 | FOLFOX4 | P | Panitumumab-FOLFOX4 | FOLFOX4 | P | |
| Survival | ||||||
| No. of patients | 325 | 331 | 221 | 219 | ||
| Progression-free survival* | .02 | .02 | ||||
| Progression event | ||||||
| No. of patients | 199 | 215 | 167 | 157 | ||
| % | 61 | 65 | 76 | 72 | ||
| Median progression-free survival, months | 9.6 | 8.0 | 7.3 | 8.8 | ||
| 95% CI | 9.2 to 11.1 | 7.5 to 9.3 | 6.3 to 8.0 | 7.7 to 9.4 | ||
| Overall survival | .07 | .07 | ||||
| Deaths | ||||||
| No. of patients | 165 | 190 | 152 | 142 | ||
| % | 51 | 57 | 69 | 65 | ||
| Median overall survival, months | 23.9 | 19.7 | 15.5 | 19.3 | ||
| 95% CI | 20.3 to 28.3 | 17.6 to 22.6 | 13.1 to 17.6 | 16.5 to 21.8 | ||
| Response*† | ||||||
| No. of patients | 317 | 323 | 215 | 211 | ||
| Objective response rate | .07 | .98 | ||||
| No. of patients | 175 | 154 | 85 | 85 | ||
| % | 55 | 48 | 40 | 40 | ||
| 95% CI | 50 to 61 | 42 to 53 | 33 to 46 | 34 to 47 | ||
| Complete response | ||||||
| No. of patients | 0 | 1 | 0 | 0 | ||
| % | 0 | < 1 | 0 | 0 | ||
| Partial response | ||||||
| No. of patients | 175 | 153 | 85 | 85 | ||
| % | 55 | 47 | 40 | 40 | ||
| Stable disease | ||||||
| No. of patients | 95 | 117 | 81 | 91 | ||
| % | 30 | 36 | 38 | 43 | ||
Abbreviations: WT, wild type; MT, mutant; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin.
*
By central radiology review.
†
Included only patients With baseline measurable disease per central review.
| End Point* | WT KRAS Evaluable† (n = 656) | WT KRAS Evaluable + Imputed (n = 708) | MT KRAS Evaluable† (n = 440) | MT KRAS Evaluable + Imputed (n = 475) |
|---|---|---|---|---|
| PFS | ||||
| HR | 0.80 | 0.81 | 1.29 | 1.26 |
| 95% CI | 0.66 to 0.97 | 0.79 to 0.83 | 1.04 to 1.62 | 1.21 to 1.32 |
| P | .024 | .027 | .023 | .036 |
| 95% CI | NA | .012 to .049 | NA | .011 to .081 |
| OS | ||||
| HR | 0.83 | 0.84 | 1.24 | 1.22 |
| 95% CI | 0.67 to 1.02 | 0.81 to 0.87 | 0.98 to 1.57 | 1.16 to 1.27 |
| P | .073 | .090 | .069 | .093 |
| 95% CI | NA | .042 to .157 | NA | .035 to .183 |
Abbreviations: PFS, progression-free survival; OS, overall survival; WT, wild type; MT, mutant; HR, hazard ratio; NA, not available.
*
HR is from proportional hazards model stratified by random assignment factors; P value is for the same HR; columns for evaluable + imputed display the mean and 95% CI of parameter estimates from 5,000 simulated trials.
†
Prospective primary analysis limited to patients evaluable for KRAS status.
| Country | Investigators |
|---|---|
| Argentina | Pedro Eugenia Alvarez, Mario Barugel, Cesar Blajman, María Andrea Cuevas, Mauricio Kotliar, Marcelo Tatángelo, María Viniegra, Raul Cesar Wainstein |
| Australia | Poh See Choo, Stephen Clarke, Andrew Haydon |
| Belgium | Jean-Luc Canon, Frédéric Forget, Geert D Haens, Yves Humblet, Bart Neyns, Marc Peeters, Eric Van Cutsem, Jean-Luc Van Laethem |
| Brazil | Carlos Barrios, Carlos Beato, Adilson Faccio, Rochelle Farias, Paulo Hoff, Yeni Nascimento, Francisco Paulo Rodolfo Radke, Ronaldo Ribeiro, Christian Sutmöller, Brigitte Van Eyll |
| Canada | Natalie Aucoin, Ronald Burkes, Haji Chalchal, Felix Couture, Richard Dalfen, Catherine Doyle, John Gapski, Rakesh Goel, Kamal-Uddin Haider, Cynthia Luk, Barbara Melosky, Karen Mulder, Jonathan Noble, Bryn Pressnail, Stephen Reingold, Mark Rother, Richard Shao, Silvana Spadafora, David Walde, Rafal Wierzbicki, Jonathon Wilson, Ralph Wong, Labib Zibdawi |
| Chile | Monica Campos, Hans Harbst, Waldo Ortuzar, Marcelo Adan Garrido Salvo, Eduardo Yañez |
| Costa Rica | Raul Fernando Falla, Rene Valladares |
| Czech Republic | Ilona Kocakova, Milan Kohoutek, Jana Prausová, Martin Šmakal |
| Estonia | Krista Leppik |
| France | Jean-Yves Douillard, Faress Husseini |
| Hungary | Gyorgy Bodoky, Jozsef Cseh, Zsuzsanna Papai, Béla Piko, Agnes Ruzsa |
| Italy | Oscar Alabiso, Carlo Barone, Stefano Cascinu, Luigi Cavanna, Silvana Chiara, Libero Ciuffreda, Pier Franco Conte, Francesco Di Costanzo, Luigi Dogliotti, Giampietro Gasparini, Vittorio Gebbia, Andrea Martoni, Rodolfo Mattioli, Salvatore Siena, Alberto Sobrero, Claudio Verusio, Eugenio Villa, Alberto Zaniboni |
| Latvia | Iveta Kudaba, Gunta Purkalne |
| Mexico | Germán Calderillo, Daniel Capdeville, Jesus Cardenas, Hector Gonzalez, Jesus Lopez, Jhony Alberto De la Cruz Vargas |
| Poland | Maria Basiska-Morawiec, Andrzej Deptata, Jacek Jassem, Andrzej Kaiser, Piotr Koralewski, Andrzej Mruk, Marek Nowacki, Joanna Pikiel, Wojciech Rogowski, Piotr Tomczak, Marek Wojtukiewicz, Iwona Zander |
| South Africa | Graham Cohen, Louis Goedhals, Diana Pillay, Johannes Raats, Bernado Rapoport, Barbara Robertson, Paul Ruff |
| Spain | José Enrique Alés, Andrés Cervantes, Mauel Constenla, Pilar García Alfonso, Cristina Grávalos, Monica Guillot, Joan Maurel, Fernando Rivera, Javier Sastre, Josep Tabernero |
| Switzerland | Markus Borner, Daniel Rauch, Arnaud Roth |
| United Kingdom | James Cassidy, David Cunningham, Mark Harrison, Paul Ross, Anne Thomas |
Abbreviation: PRIME, Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy.
Information & Authors
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© 2010 by American Society of Clinical Oncology.
History
Published online: October 04, 2010
Published in print: November 01, 2010
Authors
Author Contributions
Conception and design: Jean-Yves Douillard, Salvatore Siena, Josep Tabernero, Martin Šmakal, Michael Wolf, Jennifer Gansert
Administrative support: Martin Šmakal
Provision of study materials or patients: Jean-Yves Douillard, Salvatore Siena, James Cassidy, Josep Tabernero, Ronald Burkes, Mario Barugel, Yves Humblet, David Cunningham, Jacek Jassem, Fernando Rivera, Ilona Kocákova, Maria Błasińska-Morawiec, Martin Šmakal, Mark Rother
Collection and assembly of data: Salvatore Siena, Josep Tabernero, Ronald Burkes, Ilona Kocákova, Paul Ruff, Martin Šmakal, Mark Rother, Kelly S. Oliner, Michael Wolf, Jennifer Gansert
Data analysis and interpretation: Jean-Yves Douillard, Salvatore Siena, Josep Tabernero, Yves Humblet, György Bodoky, David Cunningham, Martin Šmakal, Michael Wolf, Jennifer Gansert
Manuscript writing: Jean-Yves Douillard, Salvatore Siena, Josep Tabernero, Ronald Burkes, Jacek Jassem, Paul Ruff, Michael Wolf, Jennifer Gansert
Final approval of manuscript: Jean-Yves Douillard, Salvatore Siena, James Cassidy, Josep Tabernero, Ronald Burkes, Mario Barugel, Yves Humblet, György Bodoky, David Cunningham, Jacek Jassem, Fernando Rivera, Ilona Kocákova, Paul Ruff, Maria Błasińska-Morawiec, Martin Šmakal, Jean-Luc Canon, Mark Rother, Kelly S. Oliner, Michael Wolf, Jennifer Gansert
Disclosures
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Funding Information
Supported by Amgen, Thousand Oaks, CA.
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Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study. JCO 28, 4697-4705(2010).
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Journal of Clinical Oncology 2010 28:31, 4697-4705
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