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2110 Efficacy outcomes by severity of skin toxicity from ASPECCT: Randomized phase 3 study of panitumumab (pmab) versus cetuximab (cmab) in chemorefractory wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC)
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Abstracts
2110 POSTER Efficacy outcomes by severity of skin toxicity from ASPECCT: Randomized phase 3 study of panitumumab (pmab) versus cetuximab (cmab) in chemorefractory wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) T. Price1 , T.W. Kim2 , J. Li3 , S. Cascinu4 , P. Ruff5 , A.S. Suresh6 , A. Thomas7 , S. Tjulandin8 , X. Guan9 , T. Hoang10 , Y.J. Hei10 , M. Peeters11 . 1 The Queen Elizabeth Hospital and University of Adelaide, Hematology/Oncology and Clinical Cancer Research, Woodville, Australia; 2 Asan Medical Center − University of Ulsan, Oncology, Seoul, Korea; 3 Fudan University Cancer Hospital, Medical Oncology, Shanghai, China; 4 Universita Politecnica delle Marche, Medical Oncology, Ancona, Italy; 5 University of Witwatersrand Faculty of Health Sciences, Medical Oncology, Johannesburg, South Africa; 6 Apollo Hospital, Medical Oncology, Hyderabad, India; 7 Leicester Royal Infirmary, Cancer Studies and Molecular Medicine, Leicester, United Kingdom; 8 N. N. Blokhin Cancer Research Center of RAMS, Department of Clinical Pharmacology and Chemotherapy, Moscow, Russian Federation; 9 Amgen Inc., Global Biostatistical Science, Thousand Oaks, USA; 10 Amgen Inc., Global Development − Hematology/Oncology, Thousand Oaks, USA; 11 Antwerp University Hospital, Oncology, Edegem, Belgium Background: The primary analysis of ASPECCT (NCT01001377; Sponsor: Amgen Inc.) demonstrated that pmab was non-inferior to cmab for overall survival (OS) in chemorefractory WT KRAS mCRC. Skin toxicity is the most common adverse event associated with EGFR inhibitors and prior studies with pmab or cmab suggested skin toxicity was associated with better outcome. Here we report skin toxicity and the relationship between severity and survival in patients treated with pmab versus cmab in ASPECCT. Materials and Methods: Patients were randomized 1:1 to receive pmab 6 mg/kg Q2W or cmab 400 mg/m2 followed by 250 mg/m2 QW. The primary endpoint was OS assessed for non-inferiority. Secondary endpoints included progression free survival (PFS) and safety. A retrospective analysis was conducted to evaluate the effect of skin toxicity severity (worst grade 1 versus worst grade 2−4) on efficacy (OS and PFS) from the primary analysis data of ASPECCT. Hazard ratios (HR) were estimated using a stratified Cox proportional hazards model. Skin toxicity was defined as any treatment emergent skin-related adverse event. Results: 496 patients were treated with pmab versus 503 with cmab. The incidence of worst grade skin toxicity by any grade (1−4), grade 1, and grade 2−4 was similar between arms: 87%, 47%, and 53%, respectively. Worst grade 3−4 skin toxicity was 12.5% in the pmab arm and 9.5% in the cmab arm. Median time to first event (any grade) was 10 days (range, 1 to 236) in the pmab arm and 11 days (range, 1 to 367) in the cmab arm. Median time to resolution after the last dose was 37 days in the pmab arm and 35 days in the cmab arm. Demographics and baseline characteristics were generally balanced between patients with worst grade 2−4 and worst grade 1 skin toxicity with the following exceptions: a higher percentage of patients with worst grade 2−4 skin toxicity were white, male, or Western (9% to 11% higher in either arm) and had ECOG performance status of 0 (11%, pmab arm only). Patients with worst grade 2−4 skin toxicity had longer median OS and PFS in both arms (Table). Conclusions: Consistent with previous anti-EGFR therapy analyses, this study demonstrates that higher grade skin toxicity (worst grade 2−4) is associated with better survival outcome compared to no or low grade (worst grade 1) in patients with WT KRAS mCRC treated with pmab or cmab.
Median OS, months (95% CI) HR (95% CI) Median PFS, months (95% CI) HR (95% CI)
Pmab
Cmab
Skin toxicity Skin toxicity worst grade 2−4 worst grade 1 N = 263 N = 233
Skin toxicity Skin toxicity worst grade 2−4 worst grade 1 N = 266 N = 237
14.2 (12.6–15.5) 7.1 (6.0−8.2) 0.45 (0.37–0.56) 5.1 (4.9−6.4) 2.9 (1.9−3.0) 0.46 (0.38–0.56)
12.6 (10.9–14.0) 8.3 (6.8−9.3) 0.58 (0.48–0.71) 4.9 (4.8−5.0) 3.0 (3.0−3.1) 0.65 (0.54–0.78)
Conflict of interest: Ownership: XG, TH, and YH are employees and stockholders of Amgen Inc. Advisory Board: TP (uncompensated) for Amgen Inc., Merck, and Roche. TWK for Bayer and Merck. SC for Amgen Inc. MP for Amgen Inc., Bayer, Roche, Merck, and Sanofi. Corporatesponsored Research: JL for Merck. PR for Amgen Inc. MP for Amgen Inc., Bayer, and Roche. Other Substantive Relationships: ST participated on Speakers Bureaus for AstraZeneca, Pfizer, and Sanofi-Aventis.
2111 POSTER A randomized, double-blind, placebo-controlled, multicenter Phase II clinical trial of fruquintinib in patients with metastatic colorectal cancer (mCRC) J. Li1 , R. Xu2 , Y. Bai3 , J. Xu4 , T. Liu5 , L. Shen6 , L. Wang7 , H. Pan8 , S. Fan9 , Y. Hua10 , W. Su11 , C. Hugg12 . 1 Fudan University Shanghai Cancer Center, Shanghai Medical College, Department of Medical Oncology, Shanghai, China; 2 Sun Yat-sen University Cancer Center, Department of medical oncology, Guangzhou, China; 3 Harbin Medical University Cancer Hospital, Department of medical oncology, Heilongjiang, China; 4 307th hospital of Chinese PLA, the affiliated hospital of Military Medical Sciences, Department of medical oncology, Beijing, China; 5 Fudan University Zhongshan Hospital, Shanghai Medical College, Department of Medical Oncology, Shanghai, China; 6 Beijing University Cancer Center, Department of medical oncology, Beijing, China; 7 Shanghai Jiaotong University affiliated1st people hospital, Department of medical oncology, Shanghai, China; 8 SIR RUN RUN SHAW hospital, college of medicine, Zhejiang University, Department of medical oncology, Hangzhou, China; 9 Hutchison MediParma Ltd, clinical and regulatory affair, Shanghai, China; 10 Hutchison MediPharma Ltd, clinical and regulatory affair, Shanghai, China; 11 Hutchison MediPharma Ltd., Research, Shanghai, China; 12 Hutchison MediPharma Ltd., Corporate office, Shanghai, China Background: Fruquintinib is a novel, potent and highly selective oral small molecule VEGF receptor inhibitor. In a Phase 1b study (ASCO 2014 #126686), fruquintinib administered at 5mg once daily in cycles of three weeks on and one week off (3/1 wk) was well tolerated and demonstrated encouraging preliminary clinical efficacy in mCRC patients. Methods: This is a randomized, double-blind, placebo-controlled, multicenter Phase II clinical trial to compare the efficacy of fruquintinib plus best supportive care (BSC) vs. placebo plus BSC in mCRC patients who failed at least 2 prior therapies, including fluorouracil, oxaliplatin and irinotecan.Patients were randomized to receive fruquintinib 5mg orally 3/1 wk or placebo at 2:1 ratio. Treatment was given in 28-day cycles until disease progression or non-tolerable toxicity occurs. Tumor assessments were conducted using RECIST 1.1 criteria. Primary efficacy endpoint for the trial was Progression Free Survival (PFS). Secondary efficacy endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and Overall Survival (OS).Safety endpoints included Adverse Event (AE), laboratory tests, vital signs and ECG. Data were analyzed up to February 11, 2015, approximately 6 months post last patient enrolled. Results: A total of 71 patients were enrolled in the Phase 2mCRC trial,47 in the fruquintinibarm and 24 in the placebo arm, respectively. Patient baseline characteristics were similar between the two treatment arms. The median fruquintinibexposure was 84 (range: 13–188) days whereas the median was 21(range: 19,191) days in the placebo arm.Median PFS was 4.7 months in the fruquitinib arm compared with 1.0 month in the placebo arm (Hazard Ratio of PFS=0.30 (p < 0.001)). The Disease Control Rate (DCR) in the fruquintinib arm is 68.1%, compared with 20.8% DCR in the placebo arm (p < 0.001). Twenty-two and 15 patients died in the fruquintinib and placebo arm, respectively, by the time of data cut-off, with a median OS of 7.6 months and 5.5 months in the fruquintiniband placebo arm, respectively. The 5 most common fruquintinib treatment-related adverse events (AE) were hand-foot syndrome (61.7%), hypertension (51.4%), dysphonia (46.8%), proteinuria (44.7%) and AST elevation (27.7%). Dose interruption and dose reduction due to AE was reported in 29.8% and 27.7%, respectively, in the fruquintinib arm patients. Conclusions: Fruquintinib 5mg 3/1 wk treatment demonstrated superior PFS in patients with metastatic CRC as compared with placebo. Fruquintinib was well tolerated and the safety profile appeared to be consistent with that of the TKI class. Further confirmatory clinical studies are warranted. Conflict of interest: Board of Directors: Christian Hogg. Corporatesponsored Research: Hutchison MediPharma Ltd.
Abstracts
2110 POSTER Efficacy outcomes by severity of skin toxicity from ASPECCT: Randomized phase 3 study of panitumumab (pmab) versus cetuximab (cmab) in chemorefractory wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) T. Price1 , T.W. Kim2 , J. Li3 , S. Cascinu4 , P. Ruff5 , A.S. Suresh6 , A. Thomas7 , S. Tjulandin8 , X. Guan9 , T. Hoang10 , Y.J. Hei10 , M. Peeters11 . 1 The Queen Elizabeth Hospital and University of Adelaide, Hematology/Oncology and Clinical Cancer Research, Woodville, Australia; 2 Asan Medical Center − University of Ulsan, Oncology, Seoul, Korea; 3 Fudan University Cancer Hospital, Medical Oncology, Shanghai, China; 4 Universita Politecnica delle Marche, Medical Oncology, Ancona, Italy; 5 University of Witwatersrand Faculty of Health Sciences, Medical Oncology, Johannesburg, South Africa; 6 Apollo Hospital, Medical Oncology, Hyderabad, India; 7 Leicester Royal Infirmary, Cancer Studies and Molecular Medicine, Leicester, United Kingdom; 8 N. N. Blokhin Cancer Research Center of RAMS, Department of Clinical Pharmacology and Chemotherapy, Moscow, Russian Federation; 9 Amgen Inc., Global Biostatistical Science, Thousand Oaks, USA; 10 Amgen Inc., Global Development − Hematology/Oncology, Thousand Oaks, USA; 11 Antwerp University Hospital, Oncology, Edegem, Belgium Background: The primary analysis of ASPECCT (NCT01001377; Sponsor: Amgen Inc.) demonstrated that pmab was non-inferior to cmab for overall survival (OS) in chemorefractory WT KRAS mCRC. Skin toxicity is the most common adverse event associated with EGFR inhibitors and prior studies with pmab or cmab suggested skin toxicity was associated with better outcome. Here we report skin toxicity and the relationship between severity and survival in patients treated with pmab versus cmab in ASPECCT. Materials and Methods: Patients were randomized 1:1 to receive pmab 6 mg/kg Q2W or cmab 400 mg/m2 followed by 250 mg/m2 QW. The primary endpoint was OS assessed for non-inferiority. Secondary endpoints included progression free survival (PFS) and safety. A retrospective analysis was conducted to evaluate the effect of skin toxicity severity (worst grade 1 versus worst grade 2−4) on efficacy (OS and PFS) from the primary analysis data of ASPECCT. Hazard ratios (HR) were estimated using a stratified Cox proportional hazards model. Skin toxicity was defined as any treatment emergent skin-related adverse event. Results: 496 patients were treated with pmab versus 503 with cmab. The incidence of worst grade skin toxicity by any grade (1−4), grade 1, and grade 2−4 was similar between arms: 87%, 47%, and 53%, respectively. Worst grade 3−4 skin toxicity was 12.5% in the pmab arm and 9.5% in the cmab arm. Median time to first event (any grade) was 10 days (range, 1 to 236) in the pmab arm and 11 days (range, 1 to 367) in the cmab arm. Median time to resolution after the last dose was 37 days in the pmab arm and 35 days in the cmab arm. Demographics and baseline characteristics were generally balanced between patients with worst grade 2−4 and worst grade 1 skin toxicity with the following exceptions: a higher percentage of patients with worst grade 2−4 skin toxicity were white, male, or Western (9% to 11% higher in either arm) and had ECOG performance status of 0 (11%, pmab arm only). Patients with worst grade 2−4 skin toxicity had longer median OS and PFS in both arms (Table). Conclusions: Consistent with previous anti-EGFR therapy analyses, this study demonstrates that higher grade skin toxicity (worst grade 2−4) is associated with better survival outcome compared to no or low grade (worst grade 1) in patients with WT KRAS mCRC treated with pmab or cmab.
Median OS, months (95% CI) HR (95% CI) Median PFS, months (95% CI) HR (95% CI)
Pmab
Cmab
Skin toxicity Skin toxicity worst grade 2−4 worst grade 1 N = 263 N = 233
Skin toxicity Skin toxicity worst grade 2−4 worst grade 1 N = 266 N = 237
14.2 (12.6–15.5) 7.1 (6.0−8.2) 0.45 (0.37–0.56) 5.1 (4.9−6.4) 2.9 (1.9−3.0) 0.46 (0.38–0.56)
12.6 (10.9–14.0) 8.3 (6.8−9.3) 0.58 (0.48–0.71) 4.9 (4.8−5.0) 3.0 (3.0−3.1) 0.65 (0.54–0.78)
Conflict of interest: Ownership: XG, TH, and YH are employees and stockholders of Amgen Inc. Advisory Board: TP (uncompensated) for Amgen Inc., Merck, and Roche. TWK for Bayer and Merck. SC for Amgen Inc. MP for Amgen Inc., Bayer, Roche, Merck, and Sanofi. Corporatesponsored Research: JL for Merck. PR for Amgen Inc. MP for Amgen Inc., Bayer, and Roche. Other Substantive Relationships: ST participated on Speakers Bureaus for AstraZeneca, Pfizer, and Sanofi-Aventis.
2111 POSTER A randomized, double-blind, placebo-controlled, multicenter Phase II clinical trial of fruquintinib in patients with metastatic colorectal cancer (mCRC) J. Li1 , R. Xu2 , Y. Bai3 , J. Xu4 , T. Liu5 , L. Shen6 , L. Wang7 , H. Pan8 , S. Fan9 , Y. Hua10 , W. Su11 , C. Hugg12 . 1 Fudan University Shanghai Cancer Center, Shanghai Medical College, Department of Medical Oncology, Shanghai, China; 2 Sun Yat-sen University Cancer Center, Department of medical oncology, Guangzhou, China; 3 Harbin Medical University Cancer Hospital, Department of medical oncology, Heilongjiang, China; 4 307th hospital of Chinese PLA, the affiliated hospital of Military Medical Sciences, Department of medical oncology, Beijing, China; 5 Fudan University Zhongshan Hospital, Shanghai Medical College, Department of Medical Oncology, Shanghai, China; 6 Beijing University Cancer Center, Department of medical oncology, Beijing, China; 7 Shanghai Jiaotong University affiliated1st people hospital, Department of medical oncology, Shanghai, China; 8 SIR RUN RUN SHAW hospital, college of medicine, Zhejiang University, Department of medical oncology, Hangzhou, China; 9 Hutchison MediParma Ltd, clinical and regulatory affair, Shanghai, China; 10 Hutchison MediPharma Ltd, clinical and regulatory affair, Shanghai, China; 11 Hutchison MediPharma Ltd., Research, Shanghai, China; 12 Hutchison MediPharma Ltd., Corporate office, Shanghai, China Background: Fruquintinib is a novel, potent and highly selective oral small molecule VEGF receptor inhibitor. In a Phase 1b study (ASCO 2014 #126686), fruquintinib administered at 5mg once daily in cycles of three weeks on and one week off (3/1 wk) was well tolerated and demonstrated encouraging preliminary clinical efficacy in mCRC patients. Methods: This is a randomized, double-blind, placebo-controlled, multicenter Phase II clinical trial to compare the efficacy of fruquintinib plus best supportive care (BSC) vs. placebo plus BSC in mCRC patients who failed at least 2 prior therapies, including fluorouracil, oxaliplatin and irinotecan.Patients were randomized to receive fruquintinib 5mg orally 3/1 wk or placebo at 2:1 ratio. Treatment was given in 28-day cycles until disease progression or non-tolerable toxicity occurs. Tumor assessments were conducted using RECIST 1.1 criteria. Primary efficacy endpoint for the trial was Progression Free Survival (PFS). Secondary efficacy endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and Overall Survival (OS).Safety endpoints included Adverse Event (AE), laboratory tests, vital signs and ECG. Data were analyzed up to February 11, 2015, approximately 6 months post last patient enrolled. Results: A total of 71 patients were enrolled in the Phase 2mCRC trial,47 in the fruquintinibarm and 24 in the placebo arm, respectively. Patient baseline characteristics were similar between the two treatment arms. The median fruquintinibexposure was 84 (range: 13–188) days whereas the median was 21(range: 19,191) days in the placebo arm.Median PFS was 4.7 months in the fruquitinib arm compared with 1.0 month in the placebo arm (Hazard Ratio of PFS=0.30 (p < 0.001)). The Disease Control Rate (DCR) in the fruquintinib arm is 68.1%, compared with 20.8% DCR in the placebo arm (p < 0.001). Twenty-two and 15 patients died in the fruquintinib and placebo arm, respectively, by the time of data cut-off, with a median OS of 7.6 months and 5.5 months in the fruquintiniband placebo arm, respectively. The 5 most common fruquintinib treatment-related adverse events (AE) were hand-foot syndrome (61.7%), hypertension (51.4%), dysphonia (46.8%), proteinuria (44.7%) and AST elevation (27.7%). Dose interruption and dose reduction due to AE was reported in 29.8% and 27.7%, respectively, in the fruquintinib arm patients. Conclusions: Fruquintinib 5mg 3/1 wk treatment demonstrated superior PFS in patients with metastatic CRC as compared with placebo. Fruquintinib was well tolerated and the safety profile appeared to be consistent with that of the TKI class. Further confirmatory clinical studies are warranted. Conflict of interest: Board of Directors: Christian Hogg. Corporatesponsored Research: Hutchison MediPharma Ltd.