1 / 20

Introduction

Predictive value of skin-toxicity severity for response to panitumumab in patients with metastatic colorectal cancer (mCRC): a pooled analysis of 5 clinical trials.

dalton-woods
Download Presentation

Introduction

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Predictive value of skin-toxicity severity for response to panitumumab in patients with metastatic colorectal cancer (mCRC): a pooled analysis of 5 clinical trials Jordan Berlin,1Eric Van Cutsem,2 Marc Peeters,3 J. Randolph Hecht,4 Rolando Ruiz,5 Mike Wolf,5 Rafael G. Amado,5 Neal J. Meropol6 1Vanderbilt University Medical Center, Nashville, TN; 2University Hospital Gasthuisberg, Leuven, Belgium; 3Ghent University Hospital, Ghent, Belgium; 4UCLA School of Medicine, Los Angeles, CA; 5Amgen Inc., Thousand Oaks, CA; 6Fox Chase Cancer Center, Philadelphia, PA

  2. Introduction • Panitumumab is a high-affinity (Kd = 5  10−11 M), fully humanmonoclonal antibody directed against the epidermal growth factor receptor (EGFr).1 • Panitumumab is approved for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression during or following fluoropyrimidine-, irinotecan-, and oxaliplatin-containing chemotherapy regimens.2 • A recent analysis of safety data from 789 patients enrolled in 10 clinical studies indicated that panitumumab is well tolerated in patients with mCRC.3 • The most common adverse events associated with panitumumab monotherapy were skin-related toxicities.3 • Here we present the results of an exploratory analysis examining the association between skin-related toxicities and panitumumab efficacy as well as the predictive value of skin toxicity severity for response to panitumumab in pooled data for 727 patients from 5 clinical studies of panitumumab monotherapy.

  3. Objectives • An exploratory analysis on pooled data from 5 clinical studies of panitumumab monotherapy to: • assess the association between severity of skin toxicity throughout treatment and panitumumab efficacy • evaluate predictive value of skin toxicity severity in the first 4 weeks for response to panitumumab • Key endpoints of panitumumab monotherapy studies: • Objective response rate • Progression-free survival • Duration of response • Time to response • Safety (including skin toxicities, infusion reactions, and anti-panitumumab antibody formation)

  4. Design and Methods PD: progression of disease; RECIST: Response Evaluation Criteria in Solid Tumors; WHO: World Health Organization. Van Cutsem & Peeters and Hecht (2007a and b) studies are complete; Berlin study is interim. aES: extension study. Patients who developed progressive disease while receiving best supportive care in the phase 3 study were allowed to cross over to this extension study to receive panitumumab until disease progression or drug intolerability. bBy immunohistochemistry at central laboratory using DakoCytomation EGFr pharmDxTM staining kit (DakoCytomation, Carpinteria, CA). cHigh: ≥ 10% of tumor cells with 2+ and 3+ staining intensity score. dLow: ≥ 10% of tumor cells with 1+, 2+, and 3+ staining intensity score, but < 10% with 2+ and 3+ staining intensity score.

  5. Key Eligibility Criteria • Pathologic diagnosis of CRC • Age  18 years • ECOG score of 0 – 2 (4 studies) 0 – 1 (1 study) • Radiographic documentation of disease progression during or within 6 months after the most recent chemotherapy of fluoropyrimidine with • Irinotecan  65 mg/m2/week for 8 weeks and • Oxaliplatin  30 mg/m2/week for 6 weeks • For the Hecht 2007b study, documentation of disease progression was not required and patients could have received prior fluoropyrimidine and irinotecan or oxaliplatin, or both. • Pre-specified levels of EGFr tumor membrane staining according to each study (by immunohistochemistry at central laboratory).

  6. Statistical Analysis

  7. Patient Disposition Results aPatients in boththe safety and efficacy sets who received at least 2 infusions (exposure over 2 weeks for QW dosing or over 4 weeks for Q2W dosing) and had known grade of skin toxicity. bPercentages based on patients in both the safety and efficacy sets. cFollow-up time was calculated from the day of enrollment to the date of last contact.

  8. Demographics aECOG status 3 was reported in 1 patient in the phase 3 study.

  9. Disease Characteristics aHecht 2007b study had incomplete data. bValue unknown for 6 patients.

  10. Incidence and Severity of Skin-Related Toxicities Graded using the NCI CTCAE v 2.0, except for selected dermatology/skin adverse events that were graded using the CTCAE v 3.0 with modifications.

  11. Skin-Related Toxicities Occurring in at Least 5% of Patients MedDRA v.8 preferred terms; graded using the NCI CTCAE v 2.0, except for selected dermatology/skin adverse events that were graded using the CTCAE v 3.0 with modifications.

  12. Probability of Time to Skin Toxicity Onset for Patients With a Skin Toxicitya 1.0 0.9 0.8 0.7 0.6 0.5 Median weeks Event probability All grades 1.4 0.4 Grade 2-4 2.6 0.3 0.2 0.1 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Subjects at risk: Grade 1-4 727 294 70 42 29 18 8 3 2 2 2 2 1 1 0 0 0 0 0 0 0 0 0 0 Grade 2-4 727 479 341 282 236 175 117 88 79 63 56 44 36 29 24 15 15 12 9 5 3 2 1 1

  13. Severity of Skin Toxicity Throughout Treatment is Weakly Associated With Objective Response Association Between Severity of Skin Toxicity and Panitumumab Efficacy Excluded patients common to the efficacy and safety analysis sets with < 2 infusions or with unknown grade of skin toxicity. aPredictive value of grade 2-4 for response. bPredictive value of grade 0-1 for non-response. cPercentage of non-responders with grade 0-1 skin toxicity throughout treatment . dPercentage of responders with grade 2-4 skin toxicity throughout treatment. eStatistical measure of agreement between objective response and grade 2-4 skin toxicity, a value of 1.0 indicates positive agreement, and -1.0 negative agreement.

  14. Severity of Skin Toxicity Throughout Treatment is Associated With Progression-Free Survival 100 Median Months Grade 2-4 2.6 90 Grade 0-1 1.8 80 70 Hazard ratio = 0.66 (95% Cl: 0.56, 0.78) P < 0.0001 60 Event-free probability (%) 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Months Patients at risk: Grade 2-4 488 466 255 212 132 123 73 63 38 28 18 14 8 8 5 3 2 2 1 1 1 1 1 1 Grade 0-1 239 224 87 67 44 34 19 16 10 7 5 3 2 0 0 0 0 0 0 0 0 0 0 0

  15. Severity of Skin Toxicity Throughout Treatment is Associated With Overall Survival 100 Median Months Grade 2-4 8.4 90 Grade 0-1 5.4 80 70 Hazard ratio = 0.62 (95% Cl: 0.52, 0.74) P < 0.0001 60 Survival probability (%) 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Months Patients at risk: Grade 2-4 488 456 393 310 233 159 110 73 42 27 19 9 3 Grade 0-1 239 204 138 99 72 48 32 21 17 9 5 1 1

  16. Severity of Skin Toxicity in the First 4 Weeks is Not a Predictive Factor for Objective Response Predictive Value of Skin Toxicity Severity in the First 4 Weeks for Response to Panitumumab Excluded patients common to the efficacy and safety analysis set with < 2 infusions or with unknown grade of skin toxicity. aPredictive value of grade 2-4 for response. bPredictive value of grade 0-1 for non-response.

  17. Severity of Skin Toxicity in the First 4 Weeks is Not a Predictive Factor for Progression-Free Survival 100 Median Months Grade 2-4 2.5 90 Grade 0-1 1.9 80 70 Hazard ratio = 0.85 (95% Cl: 0.73, 0.99) P = 0.0332 60 Event-free probability (%) 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Months Patients at risk: Grade 2-4 400 383 196 162 97 90 57 50 29 21 14 11 6 6 4 3 2 2 1 1 1 1 1 1 Grade 0-1 327 307 146 117 79 67 35 29 19 14 9 6 4 2 1 0 0 0 0 0 0 0 0 0

  18. Severity of Skin Toxicity in the First 4 Weeks isa Predictive Factor for Overall Survival 100 Median Months Grade 2-4 8.1 90 Grade 0-1 6.3 80 70 Hazard ratio = 0.79 (95% Cl: 0.67, 0.93) P = 0.0052 60 50 Survival probability (%) 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Months Patients at risk: Grade 2-4 400 372 323 250 183 124 86 56 31 21 15 8 2 Grade 0-1 327 288 208 159 122 83 56 38 28 15 9 2 2

  19. Conclusions • In this large combined analysis, severity of skin toxicity throughout treatment was associated withanumerically higher ORR and disease control rate and better PFS and OS. • The association between efficacy outcomes and severity of skin toxicity reported throughout the treatment may have been confounded by the lead-time bias. • Substantial number of patients developed severe skin toxicity after the first 4 weeks of treatment. • Severity of skin toxicity in the first 4 weeks of treatment was a predictive factor for OS but not for ORR, disease control rate, and PFS. • Overall, patients with a higher skin toxicity severity appear to have a better prognosis. • The findings of this exploratory analysis suggest that lack of grade 2-4 skin toxicity at week 4 should not guide the treatment. • Careful monitoring and early treatment of skin toxicities should be performed while continuing to treatment with panitumumab.

  20. References • Foon K, et al. Int J Radiat Oncol Biol Phys. 2004;58:984-990. • VectibixTM Prescribing Information, Amgen Inc. Thousand Oaks CA; 2006. • Berlin J, et al. Annals Oncol. 2006;17 (supp 9): Abstract #3260. • Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664. • Berlin J, et al. J Clin Oncol 2006;24 (suppl 16): Abstract #3548. • Hecht JR, et al. Proc Gasterointestinal Cancer Symp. 2007a: Abstract. • Hecht JR, et al. Cancer. 2007b; In press.

More Related