The impact of panitumumab treatment on survival and quality of life in patients with RAS wild-type metastatic colorectal cancer.
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ABSTRACT:
SUBMITTER: Battaglin F
PROVIDER: S-EPMC6607986 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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The impact of panitumumab treatment on survival and quality of life in patients with <i>RAS</i> wild-type metastatic colorectal cancer.
Battaglin Francesca F Puccini Alberto A Ahcene Djaballah Selma S Lenz Heinz-Josef HJ
Cancer management and research 20190628
Panitumumab is a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR). It is currently approved for the treatment of <i>RAS</i> wild-type (WT) metastatic colorectal cancer (mCRC) in combination with chemotherapy in first- and second-line and as monotherapy in chemorefractory patients. This review will provide an overview of main efficacy data on panitumumab from its early development up to latest evidences, including novel perspectives on predictive biomarkers of ...[more]
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Project description:Lessons learnedAntitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted.BackgroundThe epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, and may delay or reverse anti-EGFR resistance.MethodsIn this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab.ResultsTwenty-five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3-7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5-14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib.ConclusionThe combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.
| S-EPMC8176979 | biostudies-literature
Project description:INTRODUCTION:Metastatic colorectal cancer is rarely curable. Improving quality of life is therefore a key treatment goal. We report quality of life for patients with RAS wild-type metastatic colorectal cancer in the PRIME study. METHODS:A randomised phase 3 open-label study of first-line panitumumab+FOLFOX4 vs FOLFOX4 enrolled adults with untreated metastatic colorectal cancer and an Eastern Cooperative Oncology Group performance status of 0-2. This analysis includes patients with wild-type RAS tumours (n=505). Quality of life (prespecified end point) was assessed using the EuroQoL 5-domain health state index and overall health rating in all patients and by early tumour shrinkage status (?30% reduction in size by week 8; exploratory end point). Differences in quality of life were assessed using analysis of covariance and a mixed-effect piecewise linear model, and were also analysed by skin toxicity severity. RESULTS:There were no statistically significant differences between treatment arms from baseline to progression or to discontinuation. Grade 3+ skin toxicity was reported by 38% of patients receiving panitumumab+FOLFOX4 and 2% receiving FOLFOX4 alone. There were no significant differences in quality of life between patients with grade 0-2 skin toxicity and those with grade 3+ skin toxicity. More patients receiving panitumumab+FOLFOX4 vs FOLFOX4 had early tumour shrinkage (p<.001). In patients with tumour symptoms at baseline, there were statistically significant improvements in quality of life in those with early tumour shrinkage versus those without early tumour shrinkage. CONCLUSIONS:Addition of panitumumab to FOLFOX4 in first-line therapy for metastatic colorectal cancer prolongs survival and has no negative effect on overall quality of life compared with FOLFOX4 alone. Specific quality of life assessments for skin toxicity should be included in study designs to better define the direct effect of these adverse events. TRIAL REGISTRATION NUMBER:NCT00364013.
| S-EPMC5070244 | biostudies-literature
Project description:PurposeEpidermal growth factor receptor inhibitors such as panitumumab are associated with characteristic skin toxicities. We summarise data from three panitumumab clinical trials to investigate the potential impact of skin toxicity on quality of life (QoL) in patients with metastatic colorectal cancer (mCRC).MethodsThe studies were randomised, open-label trials comparing standard treatment (first-line FOLFOX4 [n = 456], second-line FOLFIRI [n = 381], or best supportive care [n = 114]) with or without panitumumab in adults with KRAS/NRAS (RAS) wild-type mCRC. QoL was assessed using the EuroQoL 5-domain health state index (HSI) and overall health rating (OHR) measures. Impact of skin toxicity on changes in QoL scores was estimated using a linear mixed-effects model. Worst skin toxicity was defined in separate models as a subgroup variable or as a measure over time.ResultsRegardless of analysis method, there were no statistically significant differences between the panitumumab and comparator arms in any of the studies in terms of change in HSI or OHR scores. There were no statistically significant differences in QoL outcomes between patients with worst skin toxicity grade <3 and those with grade ≥3. In addition, there were no statistically significant differences between the panitumumab and comparator arms in subgroups of patients with worst skin toxicity of grade <3 and ≥3.ConclusionsAddition of panitumumab to chemotherapy in RAS wild-type mCRC has no statistically significant negative effect on overall QoL, despite skin toxicity. Skin toxicity of worst grade ≥3 appeared to have similar impact on QoL as skin toxicity of grade <3.
| S-EPMC5010834 | biostudies-literature
Project description:PurposePanitumumab is a human monoclonal antibody targeting the epidermal growth factor receptor for the treatment of wild-type RAS metastatic colorectal cancer (mCRC). Currently, no dedicated clinical studies have evaluated the effect of organ impairment on the pharmacokinetics of panitumumab. Here, we present data from late phase studies of panitumumab in patients with mCRC and analyses of the effect of hepatic or renal impairment on the exposure of panitumumab.MethodsFrom three multicenter, open-label, phase 2 and phase 3 studies, 349 and 351 patients were included in hepatic and renal function subgroup analyses, respectively. Patients who received IV panitumumab and serum exposures were compared to patients with varying degrees of hepatic and renal organ dysfunction.ResultsThe Cmax and Ctrough values for patients with mild (n = 119) and moderate (n = 4) hepatic impairment were within the range of serum concentrations of panitumumab for the normal hepatic function subgroup. The distributions of serum concentration of panitumumab in patients with mild (n = 85) or moderate (n = 19) renal impairment were similar to the serum concentrations of panitumumab in the normal renal function subgroup. Population pharmacokinetic modeling and covariate analysis results were also consistent with lack of any significant effect of renal or hepatic impairment on the pharmacokinetics of panitumumab. Additionally, real-world evidence from case studies of patients with mCRC and severe hepatic or renal impairment, which is a rare patient population to study, indicated lack of clinically relevant differences in exposure of panitumumab compared with patients with mCRC and normal hepatic or renal function.ConclusionsMild-to-moderate hepatic or renal dysfunction had no clinically meaningful impact on the pharmacokinetics of panitumumab in patients with mCRC. No dose adjustments for panitumumab are warranted in patients with mCRC with mild-to-moderate hepatic or renal dysfunction.Trial registrationClinicalTrials.gov; NCT00083616, NCT00089635, NCT00113763.
| S-EPMC8367910 | biostudies-literature
Project description:ImportanceFew studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined.ObjectiveTo determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen.Design, setting, and participantsThis open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018.InterventionsPatients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites.Main outcomes and measuresThe prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A.ResultsOverall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07; P = .01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B.Conclusions and relevanceIn patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects.Trial registrationClinicalTrials.gov identifier: NCT02476045.
| S-EPMC6613306 | biostudies-literature
Project description:INTRODUCTION:The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS:We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as >70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS:We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95%CI: 0.11-0.52; P=.0004) and with shorter OS in POSIBA (adjusted HR: 1.67; 95%CI: 0.96-2.90; P=.07). CONCLUSION:A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP.
| S-EPMC6030389 | biostudies-literature
Project description:ObjectiveData from a trial of first-line panitumumab plus FOLFIRI (folinic acid, infusional 5-fluorouracil and irinotecan) in metastatic colorectal cancer were retrospectively analysed to investigate the effects of primary tumour location and early tumour shrinkage on outcomes.MethodsPatients with RAS wild-type metastatic colorectal cancer from a single-arm, open-label phase II study (NCT00508404) were included. Tumours located from the splenic flexure to rectum and in the caecum to transverse colon were defined as left- and right-sided, respectively. Baseline characteristics were summarised by primary tumour location and the effects of primary tumour location on outcomes-including objective response rate, resection rate, depth of response, duration of response and progression-free survival-were analysed. Progression-free survival and objective response rate were analysed by early tumour shrinkage status.ResultsPrimary tumour location was determined in 52/69 (75%) patients with RAS wild-type metastatic colorectal cancer; 45 (87%) had left-sided disease. Median progression-free survival was longer in patients with left-sided tumours (11.2 vs. 7.2 months for right-sided disease) and more of these patients experienced early tumour shrinkage ≥ 30% (53% vs. 29%). Early tumour shrinkage ≥ 30% was associated with improved progression-free survival irrespective of tumour location. More patients with early tumour shrinkage ≥ 30% achieved a partial or complete response. Objective response rate, duration of response, depth of response and resection rates were similar in patients with left- and right-sided tumours.ConclusionsThis analysis has confirmed a prognostic effect of primary tumour location in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab plus FOLFIRI. Early tumour shrinkage was associated with improved progression-free survival irrespective of tumour location. In right-sided disease, early tumour shrinkage may identify a subgroup of patients who might respond to panitumumab. CLINICALTRIALS.Gov identifierNCT00508404.
| S-EPMC6738356 | biostudies-literature
Project description:To report exploratory analyses of early tumour shrinkage (ETS) and depth of response (DpR) in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), receiving the first-line treatment in three randomised panitumumab trials.Data from the PRIME (NCT00364013), PEAK (NCT00819780) and PLANET (NCT00885885) studies were included. Median DpR, the proportion of patients achieving ETS ? 20% or ? 30% at week 8, and the impact of ETS and DpR (including by category) on outcome were analysed. Factors associated with ETS and DpR and the optimal ETS/DpR cut-off values for predicting improved overall survival (OS) were assessed.Overall, 505, 170 and 53 patients had RAS WT mCRC in PRIME, PEAK and PLANET, respectively. Patients receiving panitumumab had higher ETS rates (? 30%: PRIME 59% vs. 38%; PEAK 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those receiving treatment without panitumumab. In multiple regression analyses, panitumumab treatment, liver-only metastases and WT BRAF status were consistently associated with improved ETS and DpR outcomes. Irrespective of treatment, ETS and DpR were associated with improved progression-free survival, overall survival and resection rates; most resections occurred in patients in the two highest DpR categories. In PRIME and PEAK, respectively, the optimal cut-offs for predicting improved OS were 32 and 34% for ETS, and 59 and 70% for DpR.These exploratory analyses suggest that panitumumab is associated ETS and DpR benefits in patients with RAS WT mCRC and that achieving these endpoints during first-line treatment is linked with favourable outcomes.
| S-EPMC5794806 | biostudies-other
Project description:BackgroundDoublets plus anti-epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI-bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI-bevacizumab versus doublets plus anti-EGFRs is available in left-sided RAS/BRAF wild-type mCRC.Materials and methodsWe selected patients with left-sided RAS and BRAF wild-type mCRC treated with first-line FOLFOX-panitumumab or FOLFOXIRI-bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score-based analysis was performed to compare FOLFOXIRI-bevacizumab with FOLFOX-panitumumab.ResultsA total of 185 patients received FOLFOX-panitumumab and 132 received FOLFOXIRI-bevacizumab. Median progression-free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI-bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX-panitumumab group (propensity score-adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64-1.04; p = .11; propensity score-adjusted HR for OS, 0.80; 95% CI, 0.59-1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI-bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy-related adverse events were more frequent in the FOLFOXIRI-bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI-bevacizumab and FOLFOX-panitumumab are valuable treatment options in left-sided RAS/BRAF wild-type mCRC.Implications for practiceA propensity score-based analysis of five trials was performed to compare FOLFOX-panitumumab versus FOLFOXIRI-bevacizumab in left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI-bevacizumab achieved numerically superior survival outcomes versus FOLFOX-panitumumab. Chemotherapy-related adverse events were more frequent in the FOLFOXIRI-bevacizumab group. These observations suggest that although doublet chemotherapy plus anti-EGFRs remains the preferred treatment in patients with left-sided RAS/BRAF wild-type mCRC, FOLFOXIRI-bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients' preference and potential impact on quality of life.
| S-EPMC8018298 | biostudies-literature
Project description:Tumour biomarker status is being used more and more frequently to guide treatment decisions in patients with metastatic colorectal cancer (mCRC). Continued cycles of hypothesis generation and biomarker testing in retrospective, prospective-retrospective and prospective analyses from studies of the epidermal growth factor (EGFR)-targeted monoclonal antibodies (mAbs), panitumumab and cetuximab, have resulted in improved patient selection in mCRC. Initial data suggested EGFR-targeted mAb treatment should be limited to patients with KRAS exon 2 wild-type (WT) tumours, but the availability of tumour samples from large phase III studies permitted evaluation of additional potential biomarkers of activity for these agents. Subsequent analyses further refined the target population to those patients whose tumours were WT for KRAS and NRAS exons 2, 3 and 4 (i.e., those with RAS WT status). Here, we review key clinical data for panitumumab in mCRC across the lines of treatment, assessing in detail the impact of more comprehensive RAS selection on patient outcomes. Panitumumab data across first- to third-line therapy consistently demonstrate that by testing tumour RAS status, it is possible to select patients more likely to benefit from treatment.
| S-EPMC4419154 | biostudies-literature