The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab–FOLFOX4 significantly improved ...progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study.
Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled.
A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months 95% confidence interval (CI) 9.3–11.4 months for arm 1 and 8.6 months (95% CI 7.5–9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67–0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3–27.7 months) for arm 1 and 19.7 months (95% CI 17.6–22.7 months) for arm 2; HR = 0.88; 95% CI 0.73–1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70–0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis.
In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab–FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab–FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.
Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin ...αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part).
Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500mg (arm A) or 1000mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed.
Phase I showed that abituzumab doses up to 1000mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 95% confidence interval (CI) 0.78–1.64; arm B versus SoC, HR 1.11 (95% CI 0.77–1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54–1.28); arm B versus SoC, HR 0.80 (95% CI 0.52–1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvβ6 expression was associated with longer OS in arms A HR 0.55 (0.30–1.00) and B HR 0.41 (0.21–0.81) than in arm C.
The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted.
NCT01008475
To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study.
Three hundred sixty-eight ...patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life.
The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P =.376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms.
Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.
Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin ...αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part).
Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500mg (arm A) or 1000mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed.
Phase I showed that abituzumab doses up to 1000mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 95% confidence interval (CI) 0.78-1.64; arm B versus SoC, HR 1.11 (95% CI 0.77-1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54-1.28); arm B versus SoC, HR 0.80 (95% CI 0.52-1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvβ6 expression was associated with longer OS in arms A HR 0.55 (0.30-1.00) and B HR 0.41 (0.21-0.81) than in arm C.
The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. CLINICALTRIALS.
NCT01008475.
Abstract
Aim: Abituzumab (EMD 525797, DI17E6) is a humanized monoclonal IgG2 antibody specifically targeting the αν subunit of integrin receptors. POSEIDON is a Phase I/II open-label, randomized, ...controlled, multicenter trial (NCT01008475). Abituzumab ≤1000 mg combined with standard of care (SoC) revealed no dose-limiting toxicities in Phase I; here Phase II results are reported.
Methods: Pts were randomized 1:1:1 to abituzumab 500 mg (Arm A) or 1000 mg (Arm B) i.v. every 2-week cycle, combined with SoC (cetuximab 400 mg/m2, day 1 cycle 1; then 250 mg/m2 weekly plus irinotecan 180 mg/m2/cycle), or SoC alone (Arm C). Primary endpoint was investigator-assessed progression-free survival (PFS). Other objectives included overall survival (OS), safety and tolerability, and biomarker analysis. Eligible pts had confirmed KRAS wild-type colorectal cancer with distant metastasis and failure after oxaliplatin/fluoropyrimidine-containing treatment.
Results: In total, 216 pts were randomized: 73 to Arm A, 71 to Arm B, and 72 to Arm C; baseline characteristics were matched. Median PFS (investigator assessed) was 5.4 vs 5.6 mo for Arm A vs Arm C, respectively (HR, 1.13 95% CI, 0.78, 1.64) and 5.6 mo with Arm B (HR, 1.11 95% CI, 0.77, 1.61). A trend for longer median OS was observed in Arms A and B, vs Arm C (15.0 and 14.4, vs 11.6 mo, respectively); response rates (RRs) were 27.4%, 25.4%, and 26.4%, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) were observed in 72%, 78%, and 67% of pts in Arms A, B, and C, respectively, and 13%, 10%, and 8% of TEAEs resulted in death (none considered abituzumab related). High integrin αvβ6 expression in the tumor tissue (98/197 analyzed pts) was associated with longer OS (HR, 0.48 95% CI, 0.28, 0.82) and better RR (31% vs 16%) for abituzumab-treated pts vs SoC. Additional data on circulating plasma proteins as candidate biomarkers and pharmacokinetics will be presented.
Conclusions: Although no difference in PFS was observed with the addition of abituzumab to SoC, abituzumab did prolong OS and doubled RR in pts with high tumor expression of αvβ6. The overall safety profile of abituzumab combined with SoC was acceptable.
Disclosure: C. Bokemeyer: Advisory Board: Merck-Serono, Sanofi Aventis Corporate-sponsored research: Merck Serono, Roche Pharma;E. Van Cutsem: Corporate-sponsored research: Research funding paid to my institution by Merckserono; B. Melichar: Advisory board: Merck, Roche, Sanofi, Lilly Other substantive relationships: honoraria for speeches Merck, Roche, Sanofi, Lilly;F. Rivera: Advisory board: Merck Serono Corporate-sponsored research: Merck Serono;J. Straub: Other substantive relationships: Employee of the trial sponsor; R. Bruns: Other substantive relationships: Employee of Merck KgaA; S. Quaratino: Other substantive relationships: Employee of Merck KgaA; J. Tabernero: Advisory board: Amgen, Imclone, Lilly, Merck KGaA, Millennium, Novartis, Roche, Sanofi, Celgene, Chugai and Taiho Other substantive relationships: Honoraria for presentations: Amgen, Merck KGaA, Novartis, Roche and Sanofi.All other authors have declared no conflicts of interest.
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