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Introduction

Association of skin toxicity (ST) severity with clinical outcomes and health-related quality of life (HRQoL) with panitumumab (Pmab).

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Introduction

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  1. Association of skin toxicity (ST) severity with clinical outcomes and health-related quality of life (HRQoL) with panitumumab (Pmab) Yves Humblet,1 Marc Peeters,2 Salvatore Artale,3 Alain Hendlisz,4 Bart Neyns,5 A. Sobrero,6 Michael Wolf,7 Michael Woolley,7Rafael Amado,7 Eric Van Cutsem8 Abstract #4038 1St-Luc University Hospital, Brussels, Belgium; 2Ghent University Hospital, Ghent, Belgium; 3Ospedale Niguarda Ca’ Granda, Milan, Italy; 4Jules Bordet Institute, Brussels, Belgium; 5AZ Vrije Universiteit Brussel, Brussels, Belgium; 6Ospedale San Martino, Genoa, Italy; 7Amgen Inc., Thousand Oaks, CA; 8University Hospital Gasthuisberg, Leuven, Belgium

  2. Introduction • Skin toxicity severity has been shown to be associated with efficacy in patients with metastatic colorectal cancer (mCRC) receiving anti- epidermal growth factor receptor (EGFr) therapy • Panitumumab is a fully human monoclonal antibody directed against the EGFr and is indicated for use in patients with mCRC who progressed on or following standard chemotherapy1,2 • This phase 3, randomized controlled trial demonstrated that panitumumab plus best supportive care (BSC) improved progression-free survival (PFS) compared with BSC alone in chemorefractory mCRC patients3 • We conducted an exploratory analysis to evaluate the association of skin toxicity severity with PFS, overall survival (OS), disease-related symptoms and HRQOL with panitumumab treatment

  3. R A N D O M I Z E Study Design Panitumumab PD* Follow-up 6.0 mg/kg Q2W + BSC BSC PD* Follow-up Optional Panitumumab Crossover Study 1:1 *PD= progressive disease • Stratification: • ECOG score: 0-1 vs. 2 • Geographic region (Western Europe vs. Central and Eastern Europe vs. the rest of world)

  4. Key Eligibility Criteria

  5. Assessments • Skin toxicity was measured by: • CTCAE grading criteria version 3.0 (modified for dermatology toxicities) and • Modified Dermatology Life Quality Index (mDLQI) (See Table 1) • CRC symptoms were measured by the NCCN/FACT CRC symptom index (FCSI) (See Table 1) • HRQoL was measured by the EQ-5D and EORTC QLQ-C30 Global QoL subscale (See Table 1)

  6. Table 1. Patient Reported Outcomes

  7. Statistical Analyses Overall Treatment Effect • PRO Analysis set included all patients who had at least 1 post-baseline PRO assessment Association of skin toxicity with efficacy and PROs • Analyses of skin toxicity by CTCAE grading criteria and mDLQI were restricted to patients in the panitumumab arm who were progression-free for at least 28 days to allow for onset of skin toxicity and • had  grade 1 skin toxicity (for CTCAE) or • had at least 1 post-baseline PRO assessment (mDLQI) • Dichotomization of PFS for degree of being bothered was explored using all possible cut points of mDLQI (based on Cox model) • Hazard ratios (HR) adjusted for randomization factors and correlation analyses were used to determine relationships between PFS and OS to skin toxicity, and skin toxicity to colorectal cancer symptoms and overall HRQoL

  8. Statistical Analyses (cont.) Association of skin toxicity with efficacy and PROs (cont.) • Missing PRO data were imputed using 2 imputation methods: • The last value carried forward (LVCF) method, in which missing observations were replaced with the LVCF, or zero value carried forward at death; and • The slope method, in which a forward linear interpolation of observed data was utilized to impute missing data

  9. ResultsDisposition and Patient Analysis Sets

  10. Demographics and Disease CharacteristicsPRO All Enrolled Analysis Set aOne patient had ECOG score of 3

  11. Overall Treatment Effect The mDLQI-Bother Score Indicated That Panitumumab Patients Were More Bothered By Their Skin Condition Mean (+/- SE)

  12. Difference (95% CI) in HRQOL Scores (EQ-5D) at Prespecified Timepoints for Panitumumab minus BSC Patients (Primary PRO Analysis) Difference in EQ-5D Scores (panitumumab- BSC) Panitumumab N=207 BSC N=184 • LVCF imputation method used for missing PRO data • The yellow line at -0.08 represents a minimum clinical important difference (MCID) anchored to a ½ point change in ECOG score • Although panitumumab patients were more bothered by their skin conditions, HRQOL scores were numerically in favor of panitumumab

  13. Difference (95% CI) in CRC Symptom Scores (FCSI) at Prespecified Timepoints for Panitumumab minus BSC Patients (Primary PRO Analysis) Difference in FCSI scores (panitumumab- BSC) Panitumumab N=207 BSC N=184 MCID MCID • LVCF imputation method used for missing PRO data • The yellow line at -3.94 represents a minimum clinical important difference (MCID) anchored to a ½ point change in ECOG score • Although panitumumab patients were more bothered by their skin condition, disease-relatedsymptom scores were numerically in favor of panitumumab

  14. Time to Onset of Worst Severity Skin Toxicity • Among all patients: • The median time (95% CI) to most severe skin toxicity was 15 (14,16) days (Kaplan-Meier method) • The worst severity of skin toxicity may occur beyond 28 days, thus lead-time bias cannot be completely eliminated

  15. Association of Skin Toxicity with Outcomes Progression-Free Survival by Worst Severity of Skin Toxicity in Panitumumab Patients (Landmark Analysis) hazard ratio (grade 2-4:1)=0.66 p=0.01 Landmark Analysis set included patients who were progression free for ≥ 28 days • Panitumumab patients with worst grade of 2-4 had better progression free survival vs those with a worst grade of 1

  16. Overall Survival by Worst Severity of Skin Toxicity in the Panitumumab Patients (Landmark Analysis) hazard ratio (grade 2-4:1)=0.68 p=0.03 Landmark Analysis set included patients who were progression free for ≥ 28 days • Panitumumab patients with worst grade of 2-4 had better overall survival vs those with a worst grade of 1

  17. Progression-Free Survival by Minimum Post-Baseline mDLQI Score in the Panitumumab Patients (Landmark Analysis) hazard ratio (≤66.667:>66.667)=0.41 p<0.0001 Landmark Analysis set included patients who were progression free for ≥ 28 days; at least 1 post-baseline PRO assessment was also required. mDLQI nadir timing: mean – 30 days, median – 14 days, 75th Percentile – 28 days • Panitumumab patients with a minimum post-baseline mDLQI score ≤ 66.667(more bothered by their skin toxicity)had longer progression free survival

  18. Overall Survival by Minimum Post-Baseline mDLQI Score in the Panitumumab Patients (Landmark Analysis) hazard ratio (≤66.667:>66.667)=0.35 p<0.0001 Landmark Analysis set included patients who were progression free for ≥ 28 days; at least 1 post-baseline PRO assessment was also required. mDLQI nadir timing: mean – 30 days, median – 14 days, 75th Percentile – 28 days • Panitumumab patients with a minimum post-baseline mDLQI score ≤ 66.667(more bothered by their skin toxicity)had longer overall survival

  19. Minimum Post-Baseline mDLQI Bother Score Association with Median Post-Baseline Patient-Reported Outcomes PRO All Enrolled Analysis set, panitumumab patients only. Pearson correlation coefficients are shown with p-values in parentheses. NOTES: Bother = the mDLQI “bother” item; EQ-5D Index = EQ-5D Index; EQ-5D VAS = EQ-5D Visual Analog Store; EORTC Global = EORTC QLQ-C30 Global Quality of Life Scale; FCSI = FACT/NCCN Colorectal Cancer Symptom Index • In the panitumumab patients, lower mDLQI scores (more skin bother) were associated with higher HRQOL scores (improved HRQoL)

  20. Conclusions • As expected, panitumumab patients reported being more bothered by their skin conditions than BSC patients; however, CRC symptoms and HRQOL scores trended in favor of panitumumab vs BSC • Based on the minimal clinical important difference, a negative effect with panitumumab treatment could be excluded • From this exploratory analysis of data from a phase 3 trial, improved PFS, overall survival, CRC symptomalogy, and HRQOL were associated with worse skin toxicity as measured by the CTCAE grading scale and mDLQI. • These findings support the role of skin toxicity severity as a pharmacodynamic marker of on-target activity that appears to be associated with clinical benefit. Further analyses are being conducted to explore the predictive value of early onset of skin toxicity severity (see abstract #4134, poster #P5 by Berlin et al.)

  21. References • Foon KA, Yang X-D, Weiner LM, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004:58:984-990. • VectibixTM Prescribing Information, Amgen Inc. Thousand Oaks CA; 2006. • Van Cutsem E, Peeters M, Siena S, et al. An open-label, randomized, phase 3 clinical trial of panitumumab plus best supportive care versus best supportive care in patients with chemotherapy-refractorymetastatic colorectal cancer. J Clin Oncol 2007;25:1658-1664.

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