- Email: [email protected]
Computational model to predict response rate of clinical trials
abstracts
1934P
Encyclopedic tumor analysis for organ agnostic treatment with axitinib in combination regimens for advanced cancers
T. Crook1, D. Akolkar2, D. Patil2, A. Bhatt3, A. Ranade4, V. Datta2, S. Schuster2, A. Srinivasan2, R. Datar2 1 St. Luke’s Cancer Center, Royal Surrey County Hospital, Guildford, UK, 2Research and Innovations, Datar Cancer Genetics Limited, Nasik, India, 3Medical Oncology, Avinash Cancer Clinic, Pune, India, 4Medical Oncology, Jupiter Hospital, Pune, India Background: Anti-angiogenic agents are approved for treatment of various cancers like Colon, Ovary, Breast, Glioma, Lung, Kidney and Liver. Axitinib, a selective inhibitor of Vascular Endothelial Growth Factor Receptors (VEGFR 1 / 2 / 3) was initially approved as a single agent for treatment of advanced Renal Cell Carcinomas (RCC), following failure of one prior line of systemic therapy, and recently as frontline treatment for RCC in combination with Pembrolizumab. Currently, Axitinib is not approved by US FDA or recommended by NCCN for use in combination with cytotoxic/targeted or endocrine therapies. We show that Axitinib can be combined for treatment of advanced solid organ tumors based upon Encyclopedic Tumor Analysis (ETA) with clinical benefit. Methods: Between January 1, 2017 and November 30, 2018, 191 patients obtained ETA for considering precision treatment options to treat advanced broadly refractory solid organ tumors. Fresh tumor biopsies were submitted for evaluation. In a cohort of 30 patients who received combination treatment with Axitinib and cytotoxic and/or targeted and/or endocrine agents based on ETA, treatment response was evaluated as per RECIST 1.1 criteria. Objective Response Rate (ORR), Clinical Benefit Rate (CBR) and Progression Free Survival (PFS) were retrospectively determined. Therapy related adverse events were reviewed from clinical records. Results: Out of 30 patients treated with combinations of Axitinib and either targeted, cytotoxic or endocrine drugs Partial Response (PR) was observed in 13 (43.3%) patients and Stable Disease (SD) was observed in 17 (56.7%) patients. ORR was 45.7% and CBR was 97.1%. Median PFS was 125 days (Range 35-368 days). There were no Grade IV treatment related Adverse Events (AEs) or any treatment related deaths. The most common Grade III treatment related AEs were anorexia, fatigue, and neutropenia. Conclusions: Axitinib in combination with appropriate targeted and/or cytotoxic and/ or endocrine drugs determined by ETA is well tolerated and is a potent precision therapeutic option for advanced broadly refractory solid organ cancers irrespective of the organ of origin. Legal entity responsible for the study: The authors. Funding: Datar Cancer Genetics Limited. Disclosure: T. Crook: Advisory / Consultancy: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. A. Bhatt: Advisory / Consultancy: Datar Cancer Genetics Limited. A. Ranade: Advisory / Consultancy: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. S. Schuster: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Officer / Board of Directors: Datar Cancer Genetics Limited.
1935P
Computational model to predict response rate of clinical trials
O. Lorincz1, J. Toth2, M. Megyesi1, K. Pantya1, I. Miklos3, E. Somogyi1, Z. Csiszovszki1, oke1 P. Pales1, L. Molnar2, E.R. T} 1 Product Development, Treos Bio Zrt., Veszprem, Hungary, 2Bioinformatics, Treos Bio Zrt., Veszprem, Hungary, 3Department of Stochastics, MTA Re´nyi Institute, Budapest, Hungary Background: Most therapeutic vaccine clinical trials (CTs) have failed to prove efficacy, even if immunogenicity was confirmed earlier. It was already shown that immune responses generated against multiple antigens are indicative of clinical responses. We aimed to find association between the heterogeneity of immune response and clinical
v780 | Translational Research
efficacy and, based on this develop a tool that can predict the clinical outcome of cancer vaccines. Methods: In an extensive literature search we collected the immune- and objective response rates (IRR, ORR) of 94 CTs in which 2,338 patients were treated with 64 different vaccines. Vaccine sequences were used to predict personal epitopes (PEPIs) that bind to at least 3 HLA alleles of the same subject, for all patients of a representative model population. Then we determined the percentage of subjects with at least 1 vaccine specific PEPIs (PEPI Score) and at least 2 vaccine specific PEPIs derived from different antigens (MultiAg PEPI-Score) and compared to the published IRR and ORR. Results: PEPI Score was able to predict the immunogenicity of therapeutic vaccines; significant correlation was found with IRR (p ¼ 0.002). As expected, no correlation was found between ORR and IRR (p ¼ 0.294), neither between PEPI Score and ORR (p ¼ 0.302), suggesting, that immune response against a single epitope is not enough for efficient tumor response. However, we found that MultiAg PEPI-Score significantly correlates with ORR (p < 0.0001) consistent with earlier findings that the targeting of multiple antigens is required for tumor shrinkage. Conclusions: Our results demonstrate that both IRR and ORR can be predicted by PEPIs. For clinical efficacy it is crucial to target and generate immune response against multiple antigens. Based on our analysis our computational model is useful and accurate for the prediction of the clinical outcome of cancer vaccines and can even be suitable for rescuing CTs with insufficient or missing responder selection. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: O. Lorincz: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. J. Toth: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. M. Megyesi: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. K. Pantya: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. E. Somogyi: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. Z. Csiszovszki: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. P. Pales: Full / Part-time employment: Treos Bio Zrt. L. Molnar: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. E.R. T} oke: Shareholder / Stockholder / Stock options, Officer / Board of Directors: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. All other authors have declared no conflicts of interest.
1936P
Analysis of BRCA genes and homologous recombination deficiency (HRD) scores in tumours from patients (pts) with metastatic breast cancer (mBC) in the OlympiAD trial
M. Robson1, Z. Lai2, S. Dearden3, J.C. Barrett2, E.A. Harrington3, K. Timms4, J. Lanchbury4, W. Wu5, A. Allen5, C. Goessl5, E. Senkus6, S. Domchek7, D. Hodgson2 1 Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 2AstraZeneca, Boston, MA, USA, 3AstraZeneca, Cambridge, UK, 4Myriad Genetics, Salt Lake City, UT, USA, 5 AstraZeneca, Gaithersburg, MD, USA, 6Medical University of Gda nsk, Gdansk, Poland, 7 Basser Center, University of Pennsylvania, Philadelphia, PA, USA Background: We conducted tumour testing in pts with germline mutations in BRCA1 and/or BRCA2 (gBRCAm) and HER2-negative mBC in the OlympiAD study (NCT02000622). Methods: Tumour tissue of gBRCAm pts was analysed with Myriad myChoice HRD Plus, including determination of tumor (t) BRCAm, HRD score and gene-specific loss of heterozygosity (LOH). Results: Tissue was available from 161/302 pts: tBRCAm status n ¼ 143 (47%); HRD score n ¼ 129 (43%); LOH n ¼ 125 (41%). Concordance of gBRCAm and tBRCAm was 99% (141/142). Absence of LOH was observed in 7/125 pts (6%): 4/49 (8%) BRCA2m, 3/76 (4%) BRCA1m; 2 had a 2nd mutation event (Table). Low HRD scores (<42) were seen in 16% of pts (21/129), with higher rates in BRCA2m vs BRCA1m pts (14/51 [27%] vs 7/78 [9%]) and hormone receptor positive (HRþ) vs triple negative (TN; 13/59 [22%] vs 8/70 [11%]). In olaparib (ola) pts with a BRCAm, ORR was 60% (6/10) and 57% (37/65) in pts with HRD score <42 and 42, respectively. Hazard ratio for PFS favoured ola vs treatment of physician’s choice (TPC) when HRD score was <42 or 42. Conclusions: Tumour testing detected almost all gBRCAm in the study. In this mBC population, absence of LOH was uncommon, indicating a high rate of biallelic inactivation. There was no evidence for a reduction in ola efficacy in the small number of pts with BRCAm HER2-negative mBC whose tumors lack LOH and/or have HRD score <42. Clinical trial identification: NCT02000622. Editorial acknowledgement: Medical writing assistance was provided by Debbi Gorman, PhD, from Mudskipper Business, Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD). Legal entity responsible for the study: AstraZeneca. Funding: This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck & Co, Inc. Disclosure: M. Robson: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Uncompensated: Daiichi-Sankyo; Advisory / Consultancy: McKesson; Advisory / Consultancy, Uncompensated: Merck; Advisory / Consultancy, Research grant / Funding (institution), Consulting/advisory: Uncompensated; other transfer of value (editorial services): Pfizer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Invitae; Research grant / Funding (institution):
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz268.062/5576816 by guest on 26 October 2019
CMYC, BCL2, and BCL6 showed high protein expression in 50.6% (n ¼ 44), 55.2% (n ¼ 48), and 54% (n ¼ 47) respectively. Cases with DEL constituted 44.8% of sample (n ¼ 39), where DEL was significantly higher in patients with poor performance status (PS > 1). Neither of the associations between DEL and other patients’ or disease’s characteristics (age, gender, smoking history, family history, comorbidities, B symptoms, LDH, B2 microglobulin, stage, BM infiltration, presence of more than one extranodal site, IPI, and risk group) tested positive. There were no associations between DEL and response, PFS, DFS, or OS. Conclusions: DEL is not uncommon among studied sample constituting around 44.8% of cases. This positive protein expression was commonly found in patients with poor performance status creating a particular therapeutic challenge. DEL did not correlate with other variables including known prognostic factors for DLBCL. DEL did not also show effect on further treatment outcomes including response and survival. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
1934P
Encyclopedic tumor analysis for organ agnostic treatment with axitinib in combination regimens for advanced cancers
T. Crook1, D. Akolkar2, D. Patil2, A. Bhatt3, A. Ranade4, V. Datta2, S. Schuster2, A. Srinivasan2, R. Datar2 1 St. Luke’s Cancer Center, Royal Surrey County Hospital, Guildford, UK, 2Research and Innovations, Datar Cancer Genetics Limited, Nasik, India, 3Medical Oncology, Avinash Cancer Clinic, Pune, India, 4Medical Oncology, Jupiter Hospital, Pune, India Background: Anti-angiogenic agents are approved for treatment of various cancers like Colon, Ovary, Breast, Glioma, Lung, Kidney and Liver. Axitinib, a selective inhibitor of Vascular Endothelial Growth Factor Receptors (VEGFR 1 / 2 / 3) was initially approved as a single agent for treatment of advanced Renal Cell Carcinomas (RCC), following failure of one prior line of systemic therapy, and recently as frontline treatment for RCC in combination with Pembrolizumab. Currently, Axitinib is not approved by US FDA or recommended by NCCN for use in combination with cytotoxic/targeted or endocrine therapies. We show that Axitinib can be combined for treatment of advanced solid organ tumors based upon Encyclopedic Tumor Analysis (ETA) with clinical benefit. Methods: Between January 1, 2017 and November 30, 2018, 191 patients obtained ETA for considering precision treatment options to treat advanced broadly refractory solid organ tumors. Fresh tumor biopsies were submitted for evaluation. In a cohort of 30 patients who received combination treatment with Axitinib and cytotoxic and/or targeted and/or endocrine agents based on ETA, treatment response was evaluated as per RECIST 1.1 criteria. Objective Response Rate (ORR), Clinical Benefit Rate (CBR) and Progression Free Survival (PFS) were retrospectively determined. Therapy related adverse events were reviewed from clinical records. Results: Out of 30 patients treated with combinations of Axitinib and either targeted, cytotoxic or endocrine drugs Partial Response (PR) was observed in 13 (43.3%) patients and Stable Disease (SD) was observed in 17 (56.7%) patients. ORR was 45.7% and CBR was 97.1%. Median PFS was 125 days (Range 35-368 days). There were no Grade IV treatment related Adverse Events (AEs) or any treatment related deaths. The most common Grade III treatment related AEs were anorexia, fatigue, and neutropenia. Conclusions: Axitinib in combination with appropriate targeted and/or cytotoxic and/ or endocrine drugs determined by ETA is well tolerated and is a potent precision therapeutic option for advanced broadly refractory solid organ cancers irrespective of the organ of origin. Legal entity responsible for the study: The authors. Funding: Datar Cancer Genetics Limited. Disclosure: T. Crook: Advisory / Consultancy: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. A. Bhatt: Advisory / Consultancy: Datar Cancer Genetics Limited. A. Ranade: Advisory / Consultancy: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. S. Schuster: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Officer / Board of Directors: Datar Cancer Genetics Limited.
1935P
Computational model to predict response rate of clinical trials
O. Lorincz1, J. Toth2, M. Megyesi1, K. Pantya1, I. Miklos3, E. Somogyi1, Z. Csiszovszki1, oke1 P. Pales1, L. Molnar2, E.R. T} 1 Product Development, Treos Bio Zrt., Veszprem, Hungary, 2Bioinformatics, Treos Bio Zrt., Veszprem, Hungary, 3Department of Stochastics, MTA Re´nyi Institute, Budapest, Hungary Background: Most therapeutic vaccine clinical trials (CTs) have failed to prove efficacy, even if immunogenicity was confirmed earlier. It was already shown that immune responses generated against multiple antigens are indicative of clinical responses. We aimed to find association between the heterogeneity of immune response and clinical
v780 | Translational Research
efficacy and, based on this develop a tool that can predict the clinical outcome of cancer vaccines. Methods: In an extensive literature search we collected the immune- and objective response rates (IRR, ORR) of 94 CTs in which 2,338 patients were treated with 64 different vaccines. Vaccine sequences were used to predict personal epitopes (PEPIs) that bind to at least 3 HLA alleles of the same subject, for all patients of a representative model population. Then we determined the percentage of subjects with at least 1 vaccine specific PEPIs (PEPI Score) and at least 2 vaccine specific PEPIs derived from different antigens (MultiAg PEPI-Score) and compared to the published IRR and ORR. Results: PEPI Score was able to predict the immunogenicity of therapeutic vaccines; significant correlation was found with IRR (p ¼ 0.002). As expected, no correlation was found between ORR and IRR (p ¼ 0.294), neither between PEPI Score and ORR (p ¼ 0.302), suggesting, that immune response against a single epitope is not enough for efficient tumor response. However, we found that MultiAg PEPI-Score significantly correlates with ORR (p < 0.0001) consistent with earlier findings that the targeting of multiple antigens is required for tumor shrinkage. Conclusions: Our results demonstrate that both IRR and ORR can be predicted by PEPIs. For clinical efficacy it is crucial to target and generate immune response against multiple antigens. Based on our analysis our computational model is useful and accurate for the prediction of the clinical outcome of cancer vaccines and can even be suitable for rescuing CTs with insufficient or missing responder selection. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: O. Lorincz: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. J. Toth: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. M. Megyesi: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. K. Pantya: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. E. Somogyi: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. Z. Csiszovszki: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. P. Pales: Full / Part-time employment: Treos Bio Zrt. L. Molnar: Shareholder / Stockholder / Stock options: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. E.R. T} oke: Shareholder / Stockholder / Stock options, Officer / Board of Directors: Treos Bio Ltd; Full / Part-time employment: Treos Bio Zrt. All other authors have declared no conflicts of interest.
1936P
Analysis of BRCA genes and homologous recombination deficiency (HRD) scores in tumours from patients (pts) with metastatic breast cancer (mBC) in the OlympiAD trial
M. Robson1, Z. Lai2, S. Dearden3, J.C. Barrett2, E.A. Harrington3, K. Timms4, J. Lanchbury4, W. Wu5, A. Allen5, C. Goessl5, E. Senkus6, S. Domchek7, D. Hodgson2 1 Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 2AstraZeneca, Boston, MA, USA, 3AstraZeneca, Cambridge, UK, 4Myriad Genetics, Salt Lake City, UT, USA, 5 AstraZeneca, Gaithersburg, MD, USA, 6Medical University of Gda nsk, Gdansk, Poland, 7 Basser Center, University of Pennsylvania, Philadelphia, PA, USA Background: We conducted tumour testing in pts with germline mutations in BRCA1 and/or BRCA2 (gBRCAm) and HER2-negative mBC in the OlympiAD study (NCT02000622). Methods: Tumour tissue of gBRCAm pts was analysed with Myriad myChoice HRD Plus, including determination of tumor (t) BRCAm, HRD score and gene-specific loss of heterozygosity (LOH). Results: Tissue was available from 161/302 pts: tBRCAm status n ¼ 143 (47%); HRD score n ¼ 129 (43%); LOH n ¼ 125 (41%). Concordance of gBRCAm and tBRCAm was 99% (141/142). Absence of LOH was observed in 7/125 pts (6%): 4/49 (8%) BRCA2m, 3/76 (4%) BRCA1m; 2 had a 2nd mutation event (Table). Low HRD scores (<42) were seen in 16% of pts (21/129), with higher rates in BRCA2m vs BRCA1m pts (14/51 [27%] vs 7/78 [9%]) and hormone receptor positive (HRþ) vs triple negative (TN; 13/59 [22%] vs 8/70 [11%]). In olaparib (ola) pts with a BRCAm, ORR was 60% (6/10) and 57% (37/65) in pts with HRD score <42 and 42, respectively. Hazard ratio for PFS favoured ola vs treatment of physician’s choice (TPC) when HRD score was <42 or 42. Conclusions: Tumour testing detected almost all gBRCAm in the study. In this mBC population, absence of LOH was uncommon, indicating a high rate of biallelic inactivation. There was no evidence for a reduction in ola efficacy in the small number of pts with BRCAm HER2-negative mBC whose tumors lack LOH and/or have HRD score <42. Clinical trial identification: NCT02000622. Editorial acknowledgement: Medical writing assistance was provided by Debbi Gorman, PhD, from Mudskipper Business, Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD). Legal entity responsible for the study: AstraZeneca. Funding: This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck & Co, Inc. Disclosure: M. Robson: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Uncompensated: Daiichi-Sankyo; Advisory / Consultancy: McKesson; Advisory / Consultancy, Uncompensated: Merck; Advisory / Consultancy, Research grant / Funding (institution), Consulting/advisory: Uncompensated; other transfer of value (editorial services): Pfizer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Invitae; Research grant / Funding (institution):
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz268.062/5576816 by guest on 26 October 2019
CMYC, BCL2, and BCL6 showed high protein expression in 50.6% (n ¼ 44), 55.2% (n ¼ 48), and 54% (n ¼ 47) respectively. Cases with DEL constituted 44.8% of sample (n ¼ 39), where DEL was significantly higher in patients with poor performance status (PS > 1). Neither of the associations between DEL and other patients’ or disease’s characteristics (age, gender, smoking history, family history, comorbidities, B symptoms, LDH, B2 microglobulin, stage, BM infiltration, presence of more than one extranodal site, IPI, and risk group) tested positive. There were no associations between DEL and response, PFS, DFS, or OS. Conclusions: DEL is not uncommon among studied sample constituting around 44.8% of cases. This positive protein expression was commonly found in patients with poor performance status creating a particular therapeutic challenge. DEL did not correlate with other variables including known prognostic factors for DLBCL. DEL did not also show effect on further treatment outcomes including response and survival. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology