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482 Relationship Between Tumor MET Expression and Clinical Outcomes in Cancer Patients Treated with Tivantinib
Poster Session – Biomarkers plasma gCYC were not associated (r2 =0.18), whereas KRAS levels were significantly correlated (r2 =0.83). The correlation between gCYC and KRAS in serum was poor (r2 =0.23) as compared to plasma (r2 =0.55). Linear regression between gCYC and KRAS revealed a difference in slopes between plasma and serum. In plasma the slope was 0.085 (95% confidence interval (CI) 0.075–0.095) whereas in serum the slope was 0.037 (95% CI 0.027–0.047) suggesting a lower proportion of cfDNA in serum than in plasma originate from the tumor. Surprisingly, a few samples with high cfDNA levels did not habor mutated DNA. Previous reports indicate that synchronous tumors may be divergent with respect to mutational status. If samples with no KRAS mutation were omitted from the analysis the correlation between gCYC and KRAS increased in plasma (r2 =0.73) but was lower in serum (r2 =0.19). Conclusions: The results highlight significant differences between plasma and serum. Mutations were detected with a significantly higher sensitivity in plasma than in serum. The median values and the fraction of KRAS mutated alleles detected were both different in the two materials. Plasma analyses seem to give a better measure of tumor dynamics and should be preferred over serum in cfDNA measurements. 480 POSTER Detection by Immunohistochemistry of Prostate Stem Cell Antigen (PSCA) in Tumors is Not a Predictive Biomarker for the Anti-PSCa Monoclonal Antibody AGS-1C4D4: Identification of Alternative Predictive Biomarkers 1 F. Donate ˜ , A. Hartford1 , K. Morrison1 , L. da Cruz1 , J. Nater1 , T. Brooks1 , J. Ou1 , P. Chalita-Eid1 , D. Stover1 , L. Reyno1 . 1 Agensys, Santa Monica, USA
Background: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell surface protein highly expressed in prostate, pancreatic and bladder cancers. AGS-1C4D4 is a fully-human IgG1ú monoclonal antibody against PSCA. Preclinical work suggested antitumor activity for AGS-1C4D4 alone and in combination with gemcitabine. Methods: In a Phase 2 study in metastatic pancreatic adenocarcinoma, patients were randomized 1:2 to gemcitabine or gemcitabine plus AGS1C4D4, respectively. The primary endpoint was 6-month survival rate (SR), an early surrogate for overall survival (OS), with OS as a secondary endpoint. Archived tumor samples were collected for preplanned PSCA expression exploratory analyses using IHC. Independent of this clinical trial, other potential predictive biomarkers were investigated preclinically. Results: The 6-month SR was 44.4% (95% CI, 31.9–57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1–69.2) in the gemcitabine plus AGS-1C4D4 arm (CMH test p-value, 0.02). The median OS was 5.5 months versus 7.6 months (hazard ratio (HR), 0.78; 95% CI, 0.56–1.07; log-rank p-value, 0.12). Archived tumor samples were obtained for 118 patients of the total 196 to investigate the hypothesis that moderate-strong PSCA expression would result in greater benefit with AGS-1C4D4. However, subgroup analyses of OS did not provide evidence that moderate-strong PSCA expression in the tumor samples could select for patients who would benefit from AGS-1C4D4 (moderate-strong: HR 0.82; log-rank p-value, 0.26) (nonexpressers: HR 0.84; log-rank p-value, 0.27). Other potential predictive biomarkers have been investigated preclinically: markers of sensitivity to gemcitabine (hENT1) together with PSCA expression by IHC in tumor samples; and genotyping for the rs2294008 PSCA SNP, since minimal PSCA protein expression in the membrane with the CC genotype was observed in transfected cell lines and tissues. Conclusions: Addition of AGS-1C4D4 to gemcitabine administered to patients with metastatic pancreatic adenocarcinoma resulted in an improved 6-month SR, which was the primary end point of the Phase 2 study. The PSCA IHC assay in archived tumor samples failed to discriminate which patients would benefit from AGS-1C4D4. Alternatively, other predictive biomarkers have been identified and are awaiting clinical validation. 481 POSTER Osteopontin Overexpression Synergistically Interacts with Aurora A Overexpression, and is Associated with Tumor Progression, Early Tumor Recurrence, and Poor Prognosis in Hepatocellular Carcinoma Z. Lin1 , H. Pan2 , N. Sun1 , Y. Jeng2 , A. Cheng1 , H. Hsu2 . 1 National Taiwan University Hospital, Oncology, Taipei City, Taiwan; 2 National Taiwan University Hospital, Pathology, Taipei City, Taiwan Background: We previously identified several prognostic factors, including osteopontin, Aurora A, and Aurora B, correlating to tumor progression of hepatocellular carcinoma (HCC). In this study, we sought to analyze the interactions of these molecular factors, as well as the prognostic significance of the interactions in HCC.
Friday 9 November 2012 149 Method: Osteopontin/Aurora A/Aurora B mRNA levels were measured in 203 HCC and paired non-tumorous liver tissues by reverse transcriptionPCR. The mRNA levels were determined by the ratio of signal intensity of target genes to that of S26, and categorized as overexpression if the ratio >1.0. Results: Overexpressions of these three markers were all associated with higher grade, and more advanced stage of the tumors, as well as high a-fetoprotein levels (>200 ng/mL) and early tumor recurrence (<1 year). Overexpression of each of the markers significantly correlated with overexpression of the other two. The coexistence of overexpressions of osteopontin and Aurora A were especially associated with worse survival outcomes of the HCC patients. In multivariate analysis, early tumor recurrence, stage, osteopontin overexpression, and liver cirrhosis were identified as independent prognostic factors. Conclusions: Overexpressions of osteopontin, Aurora A, and Aurora B are frequently found in HCC, and these three molecular factors had intimate interactions. Overexpressions of osteopontin and Aurora A synergistically led to poor prognosis for HCC patients. 482 POSTER Relationship Between Tumor MET Expression and Clinical Outcomes in Cancer Patients Treated with Tivantinib H. Zahir1 , S. Rodig2 , L.V. Sequist3 , L. Rimassa4 , C. Eng5 , A.B. Halim6 , Y. Wang7 , R. von Roemeling8 , Y. Chen9 , B. Schwartz9 . 1 Daiichi Sankyo Inc., Clinical Pharmacology, Edison, USA; 2 Brigham and Women’s Hospital and Harvard Medical School, Department of Pathology, Boston, USA; 3 Massachusetts General Hospital Cancer Center and Harvard Medical School, Department of Medicine, Boston, USA; 4 Humanitas Cancer Center Istituto Clinico Humanitas IRCCS, Medical Oncology Unit, Rozzano (Milano), Italy; 5 The University of Texas M.D. Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Houston, USA; 6 Daiichi Sankyo Inc., Clinical Biomarkers, Edison, USA; 7 Daiichi Sankyo Inc., Clinical Development, Edison, USA; 8 Daiichi Sankyo Inc., Clinical Development − Oncology, Edison, USA; 9 ArQule Inc., Clinical Development, Woburn, USA Background: Expression of the MET receptor tyrosine kinase is associated with a poor prognosis in multiple tumor types. Further evaluation of the relationship between MET expression and clinical outcomes in patients (pts) treated with the selective MET inhibitor tivantinib may support identification of a population most likely to benefit from treatment. MET protein expression was assessed by immunohistochemistry (IHC) in archival tumor samples from pts enrolled in 3 randomized, placebo-controlled, phase 2 studies in non-small cell lung cancer (NSCLC; tivantinib + erlotinib [TE]), hepatocellular carcinoma (HCC; tivantinib monotherapy), or KRAS wildtype colorectal cancer (CRC; tivantinib + cetuximab + irinotecan). Materials and Methods: IHC was conducted using the anti-total c-MET (SP44) rabbit monoclonal antibody (Spring Biosciences and Ventana Medical Systems). Staining intensity was scored on a scale of 0, 1+, 2+, or 3+. Samples with a staining intensity 2+ in 50% of tumor cells were considered MET-high. Results: In nonclinical assays, the MET IHC assay robustly differentiated between high, moderate, and low levels of MET expression in tumor cell lines. The inter-assay correlation of variance was 20%. Tissue samples were available from 50 of 167 (30%) NSCLC pts and 77 of 107 (72%) HCC pts. The CRC study is ongoing. A total of 27 (54%) NSCLC samples were MET-high. Among the 33 (66%) pts with nonsquamous tumors, 25 (76%) were MET-high, whereas 2 of 17 (12%) squamous tumors were MET-high. Among HCC tumors tested, 37 (48%) samples were MET-high. Among nonsquamous NSCLC pts with MET-high tumors, treatment with TE was associated with median progression-free survival (PFS) of 5.5 vs 2.3 months (HR = 0.63; P = 0.35) and median overall survival (OS) of 10.3 vs 6.9 months (HR = 0.50; P = 0.22) compared with placebo + erlotinib (PE). Among nonsquamous NSCLC pts with MET-low tumors, TE vs PE treatment yielded median PFS of 3.6 vs 1.8 months, respectively (HR = 0.53; P = 0.20), and median OS of 5.5 vs 6.4 months, respectively (HR = 1.53; P = 0.39). Among HCC pts with MET-high tumors, tivantinib monotherapy yielded median time to progression (TTP) of 2.7 vs 1.4 months with placebo (HR = 0.43; P = 0.03) and median OS of 7.2 vs 3.8 months with placebo (HR = 0.38; P = 0.01). In pts with MET-low tumors, tivantinib vs placebo yielded median TTP of 1.5 vs 1.4 months, respectively (HR = 0.96; P = 0.92), and median OS of 5.0 vs 9.0 months, respectively (HR = 1.33; P = 0.50). Analysis of pts in the placebo group with METhigh (n = 15) vs MET-low tumors (n = 13) was consistent with the body of evidence indicating that MET expression is associated with shorter OS (median, 3.8 vs 9.0 months; P = 0.02). Conclusions: Although sample sizes are small, the MET IHC assay used in these studies may be a useful prognostic and predictive biomarker in future clinical trials. Testing and analysis of larger populations are ongoing to confirm this hypothesis.
Background: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell surface protein highly expressed in prostate, pancreatic and bladder cancers. AGS-1C4D4 is a fully-human IgG1ú monoclonal antibody against PSCA. Preclinical work suggested antitumor activity for AGS-1C4D4 alone and in combination with gemcitabine. Methods: In a Phase 2 study in metastatic pancreatic adenocarcinoma, patients were randomized 1:2 to gemcitabine or gemcitabine plus AGS1C4D4, respectively. The primary endpoint was 6-month survival rate (SR), an early surrogate for overall survival (OS), with OS as a secondary endpoint. Archived tumor samples were collected for preplanned PSCA expression exploratory analyses using IHC. Independent of this clinical trial, other potential predictive biomarkers were investigated preclinically. Results: The 6-month SR was 44.4% (95% CI, 31.9–57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1–69.2) in the gemcitabine plus AGS-1C4D4 arm (CMH test p-value, 0.02). The median OS was 5.5 months versus 7.6 months (hazard ratio (HR), 0.78; 95% CI, 0.56–1.07; log-rank p-value, 0.12). Archived tumor samples were obtained for 118 patients of the total 196 to investigate the hypothesis that moderate-strong PSCA expression would result in greater benefit with AGS-1C4D4. However, subgroup analyses of OS did not provide evidence that moderate-strong PSCA expression in the tumor samples could select for patients who would benefit from AGS-1C4D4 (moderate-strong: HR 0.82; log-rank p-value, 0.26) (nonexpressers: HR 0.84; log-rank p-value, 0.27). Other potential predictive biomarkers have been investigated preclinically: markers of sensitivity to gemcitabine (hENT1) together with PSCA expression by IHC in tumor samples; and genotyping for the rs2294008 PSCA SNP, since minimal PSCA protein expression in the membrane with the CC genotype was observed in transfected cell lines and tissues. Conclusions: Addition of AGS-1C4D4 to gemcitabine administered to patients with metastatic pancreatic adenocarcinoma resulted in an improved 6-month SR, which was the primary end point of the Phase 2 study. The PSCA IHC assay in archived tumor samples failed to discriminate which patients would benefit from AGS-1C4D4. Alternatively, other predictive biomarkers have been identified and are awaiting clinical validation. 481 POSTER Osteopontin Overexpression Synergistically Interacts with Aurora A Overexpression, and is Associated with Tumor Progression, Early Tumor Recurrence, and Poor Prognosis in Hepatocellular Carcinoma Z. Lin1 , H. Pan2 , N. Sun1 , Y. Jeng2 , A. Cheng1 , H. Hsu2 . 1 National Taiwan University Hospital, Oncology, Taipei City, Taiwan; 2 National Taiwan University Hospital, Pathology, Taipei City, Taiwan Background: We previously identified several prognostic factors, including osteopontin, Aurora A, and Aurora B, correlating to tumor progression of hepatocellular carcinoma (HCC). In this study, we sought to analyze the interactions of these molecular factors, as well as the prognostic significance of the interactions in HCC.
Friday 9 November 2012 149 Method: Osteopontin/Aurora A/Aurora B mRNA levels were measured in 203 HCC and paired non-tumorous liver tissues by reverse transcriptionPCR. The mRNA levels were determined by the ratio of signal intensity of target genes to that of S26, and categorized as overexpression if the ratio >1.0. Results: Overexpressions of these three markers were all associated with higher grade, and more advanced stage of the tumors, as well as high a-fetoprotein levels (>200 ng/mL) and early tumor recurrence (<1 year). Overexpression of each of the markers significantly correlated with overexpression of the other two. The coexistence of overexpressions of osteopontin and Aurora A were especially associated with worse survival outcomes of the HCC patients. In multivariate analysis, early tumor recurrence, stage, osteopontin overexpression, and liver cirrhosis were identified as independent prognostic factors. Conclusions: Overexpressions of osteopontin, Aurora A, and Aurora B are frequently found in HCC, and these three molecular factors had intimate interactions. Overexpressions of osteopontin and Aurora A synergistically led to poor prognosis for HCC patients. 482 POSTER Relationship Between Tumor MET Expression and Clinical Outcomes in Cancer Patients Treated with Tivantinib H. Zahir1 , S. Rodig2 , L.V. Sequist3 , L. Rimassa4 , C. Eng5 , A.B. Halim6 , Y. Wang7 , R. von Roemeling8 , Y. Chen9 , B. Schwartz9 . 1 Daiichi Sankyo Inc., Clinical Pharmacology, Edison, USA; 2 Brigham and Women’s Hospital and Harvard Medical School, Department of Pathology, Boston, USA; 3 Massachusetts General Hospital Cancer Center and Harvard Medical School, Department of Medicine, Boston, USA; 4 Humanitas Cancer Center Istituto Clinico Humanitas IRCCS, Medical Oncology Unit, Rozzano (Milano), Italy; 5 The University of Texas M.D. Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Houston, USA; 6 Daiichi Sankyo Inc., Clinical Biomarkers, Edison, USA; 7 Daiichi Sankyo Inc., Clinical Development, Edison, USA; 8 Daiichi Sankyo Inc., Clinical Development − Oncology, Edison, USA; 9 ArQule Inc., Clinical Development, Woburn, USA Background: Expression of the MET receptor tyrosine kinase is associated with a poor prognosis in multiple tumor types. Further evaluation of the relationship between MET expression and clinical outcomes in patients (pts) treated with the selective MET inhibitor tivantinib may support identification of a population most likely to benefit from treatment. MET protein expression was assessed by immunohistochemistry (IHC) in archival tumor samples from pts enrolled in 3 randomized, placebo-controlled, phase 2 studies in non-small cell lung cancer (NSCLC; tivantinib + erlotinib [TE]), hepatocellular carcinoma (HCC; tivantinib monotherapy), or KRAS wildtype colorectal cancer (CRC; tivantinib + cetuximab + irinotecan). Materials and Methods: IHC was conducted using the anti-total c-MET (SP44) rabbit monoclonal antibody (Spring Biosciences and Ventana Medical Systems). Staining intensity was scored on a scale of 0, 1+, 2+, or 3+. Samples with a staining intensity 2+ in 50% of tumor cells were considered MET-high. Results: In nonclinical assays, the MET IHC assay robustly differentiated between high, moderate, and low levels of MET expression in tumor cell lines. The inter-assay correlation of variance was 20%. Tissue samples were available from 50 of 167 (30%) NSCLC pts and 77 of 107 (72%) HCC pts. The CRC study is ongoing. A total of 27 (54%) NSCLC samples were MET-high. Among the 33 (66%) pts with nonsquamous tumors, 25 (76%) were MET-high, whereas 2 of 17 (12%) squamous tumors were MET-high. Among HCC tumors tested, 37 (48%) samples were MET-high. Among nonsquamous NSCLC pts with MET-high tumors, treatment with TE was associated with median progression-free survival (PFS) of 5.5 vs 2.3 months (HR = 0.63; P = 0.35) and median overall survival (OS) of 10.3 vs 6.9 months (HR = 0.50; P = 0.22) compared with placebo + erlotinib (PE). Among nonsquamous NSCLC pts with MET-low tumors, TE vs PE treatment yielded median PFS of 3.6 vs 1.8 months, respectively (HR = 0.53; P = 0.20), and median OS of 5.5 vs 6.4 months, respectively (HR = 1.53; P = 0.39). Among HCC pts with MET-high tumors, tivantinib monotherapy yielded median time to progression (TTP) of 2.7 vs 1.4 months with placebo (HR = 0.43; P = 0.03) and median OS of 7.2 vs 3.8 months with placebo (HR = 0.38; P = 0.01). In pts with MET-low tumors, tivantinib vs placebo yielded median TTP of 1.5 vs 1.4 months, respectively (HR = 0.96; P = 0.92), and median OS of 5.0 vs 9.0 months, respectively (HR = 1.33; P = 0.50). Analysis of pts in the placebo group with METhigh (n = 15) vs MET-low tumors (n = 13) was consistent with the body of evidence indicating that MET expression is associated with shorter OS (median, 3.8 vs 9.0 months; P = 0.02). Conclusions: Although sample sizes are small, the MET IHC assay used in these studies may be a useful prognostic and predictive biomarker in future clinical trials. Testing and analysis of larger populations are ongoing to confirm this hypothesis.