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Comprehensive genomic profiling and clinical outcomes in patients (pts) with fibroblast growth factor receptor rearrangement-positive (FGFR2+) cholangiocarcinoma (CCA) treated with pemigatinib in the fight-202 trial
abstracts 720P
Comprehensive genomic profiling and clinical outcomes in patients (pts) with fibroblast growth factor receptor rearrangement-positive (FGFR21) cholangiocarcinoma (CCA) treated with pemigatinib in the fight-202 trial
Background: Fight-202 is a phase 2 study (NCT02924376) of pemigatinib (INCB054828), a selective, potent, oral inhibitor of FGFR1, 2, and 3 in pts with advanced CCA. Interim results from the first 47 FGFR2þ CCA pts with 8 months (mo) of follow-up demonstrated an objective response rate (ORR) of 40.4%, disease control rate (DCR) of 85%, median progression-free survival (mPFS) of 9.2 mo, and median overall survival (mOS) of 15.8 mo, based on independent central review. Here we report the frequency of FGFR2 rearrangement partners and co-occurring alterations and their impact on clinical outcomes. Methods: Comprehensive genomic profiling was performed in all pts prescreened and/ or enrolled in fight-202 using FoundationOne. Clinical data were reported previously. Results: Among 118 FGFR2þ pts identified, 54 unique FGFR2 rearrangement partners were observed, of which 74.1% (n ¼ 40) were unique to a single patient. BICC1 was the most frequent FGFR2 rearrangement partner (29.7% [n ¼ 35]). FGFR2þ pts had fewer genomic alterations (3.36 alterations/pt) than unaltered pts (4.6 alterations/pt). The most frequently co-altered gene, BAP1, was altered in 39.8% (n ¼ 47) of FGFR2þ pts. As of the data cutoff date (July 24, 2018), 47 FGFR2þ pts were treated with pemigatinib and followed for 8 mo. There were no meaningful differences in ORR (42.9% vs 39.4%), mPFS (8.9 mo vs 9.6 mo), or mOS (not reached [NR] vs 15.8 mo) in patients with FGFR2-BICC1 (n ¼ 14) versus other FGFR2 rearrangements. Similarly, no meaningful difference in ORR (53.3% vs 34.4%), mPFS (8.9 mo vs NR), or mOS (NR vs 15.8 mo) was observed in pts with BAP1 loss-of-function mutations (n ¼ 15). Among other co-occurring genomic alterations, pts with TP53 alterations (n ¼ 5) had no objective responses (0% vs 45.2%) and shorter mPFS (6.2 mo vs NR) and mOS (10.5 mo vs NR). Conclusions: Despite myriad FGFR2 rearrangement partners identified in the study, an interim analysis did not indicate a difference in ORR, mPFS, or mOS between the most common rearrangement partner (BICC1) and other partner genes. Alterations in TP53, but not BAP1, were associated with decreased clinical benefit. Editorial acknowledgement: Simon J. Slater, PhD, CMPP, of Envision Pharma Group (Philadelphia, PA), funded by Incyte Corporation. Legal entity responsible for the study: Incyte Corporation. Funding: Incyte Corporation. Disclosure: A. Hollebecque: Consulting/Advisory Role, Travel/Accommodation/Expenses, Courses/Trainings: Amgen; Consulting/Advisory Role: Spectrum Pharmaceuticals; Consulting/ Advisory Role, Travel/Accommodation/Expenses: Lilly; Consulting/Advisory Role, Travel/ Accommodation/Expenses: Debiopharm; Travel/Accommodation/Expenses: Servier; Travel/ Accommodation/Expenses: Incyte; Courses/Trainings: Bayer; Courses/Trainings: Eisai; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Janssen Cilag; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Sanofi. I.M. Silverman: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. S. Owens: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. L. Fe´liz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. C.F. Lihou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. H. Zhen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. R.C. Newton: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. T.C. Burn: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. D. Melisi: Research Grants (Institution), Advisory/Consultancy Role: Shire; Research Grants (Institution), Advisory/Consultancy Role: Incyte; Research Grants (Institution), Advisory/Consultancy Role: Evotec; Research Grants (Institution): Celgene; Advisory/Consultancy Role: Eli Lilly; Advisory/ Consultancy: Baxter. All other authors have declared no conflicts of interest.
721P
Efficacy of derazantinib (DZB) in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) expressing FGFR2-fusion or FGFR2 mutations/amplifications
M. Droz Dit Busset1, S. Braun2, B. El-Rayes3, W.P. Harris4, N. Damjanov5, G. Masi6, L. Rimassa7, S. Bhoori8, M. Niger9, N. Personeni10, F. Braiteh11, S. Lonardi12, M. Engelhardt2, M. Saulay2, B. Schwartz13, W.L. Shaib14, V. Mazzaferro15, K.P. Papadopoulos16 1 Department of Surgery and Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 2Development, Basilea Pharmaceutica AG, Basel, Switzerland, 3 Department of Hematology and Medical Oncology, Winship Cancer Institute, Atlanta, GA, USA, 4Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA, 5Section Chief Hematology/Oncology, VA Medical Center, Abramson Cancer Center, Philadelphia, PA, USA, 6Oncology, Azienda Ospedaliera Universitaria S.Chiara, Pisa, Italy, 7Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy, 8S.c. Medicina Nucleare, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 9Oncology, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, Italy, 10Oncology, Istituto Clinico Humanitas, Rozzano, Italy, 11Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA, 12Medical Oncology 1 Unit, Istituto Oncologico Veneto IRCCS, Padua, Italy, 13ArQule Inc., Burlington, MA, USA, 14 Hematology and Oncology, Emory University, Atlanta, GA, USA, 15Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 16Clinical Research, South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA Background: FGFR2 gene aberrations (GA) include fusions and mutations/amplifications, with an estimated prevalence of approximately 15% and 5% in iCCA, respectively. While FGFR2 fusions are acknowledged oncogenic drivers, the oncogenic potential of FGFR2 mutations and amplifications is less well defined, due to ambiguous available preclinical and clinical data. In a non-comparative Phase 2a study (NCT01752920), the potent pan-FGFR inhibitor DZB was administered to iCCA pts expressing either FGFR2-fusion (N ¼ 29), FGFR2 mutations/amplifications (N ¼ 6) or no FGFR gene aberration (N ¼ 9). Here, we present a post-hoc analysis of outcomes of iCCA pts expressing FGFR mutations/amplifications (N ¼ 6) or no FGFR GA (N ¼ 9) as compared to previously reported data of iCCA pts (N ¼ 29) expressing FGFR2 fusions (Mazzaferro et al. 2018 BJC). Methods: Pts received 300 mg DZB QD PO. Eligibility criteria included a locally confirmed (FISH or NGS) testing of FGFR2 GA (fusions vs mutations/amplifications or no aberrations). Objective responses were determined per RECIST 1.1. Disease control rate (DCR) was defined by the summation of CR, PR and SD, and PFS, calculated from treatment initiation until disease progression or death. Results: The table shows the efficacy outcomes in the 3 patient groups. Types of drugrelated adverse events were similar across groups. No new safety signals were identified.
Table: 721P iCCA patient group
FGFR2 fusion N ¼ 29
FGFR2 mutation/ amplification N¼6
No FGFR2 genomic aberration N¼9
Objective response rate (RECIST 1.1) DCR (PR or SD) Any target lesion diameter reduction Median (95% CI) Progression free survival (PFS), months % PFS at 3 months % PFS at 6 months
6 (21%) 24 (83%) 18 (62%) 5.7 (4.0-9.2) 83% 47%
0 (0%) 4 (67%) 4 (67%) 6.7 (1.0-14.7) 67% 50%
0 (0%) 2 (22%) 0 (0%) 1.5 (0.7 – NA) 0% 0%
Conclusions: Anti-tumor efficacy of DZB as measured by DCR and PFS in iCCA patients harboring an FGFR2 GA seems to be similar for patients with FGFR2 fusions and FGFR2 mutations/amplifications, while patients without any detectable FGFR GA appear to derive no benefit from DZB treatment. While the influence of prognostic variables still has to be confirmed, the anti-tumor efficacy of DZB seen in pts with FGFR2 GA other than fusions warrant further clinical investigation. Legal entity responsible for the study: Basilea Pharmaceutica International Ltd. Funding: Basilea Pharmaceutica International Ltd. Disclosure: S. Braun: Full / Part-time employment: Basilea Pharmaceutica Int. Ltd.; Shareholder / Stockholder / Stock options: Ipsen. B. El-Rayes: Advisory / Consultancy: Merrimack; Advisory / Consultancy: BTG; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: RTI Health Solutions; Honoraria (self), Speaker Bureau / Expert testimony: Lexicon; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Cleave Biosciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): AVEO; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Hoosier Cancer Research Network; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): PPD; Research grant / Funding (institution): Merck; Research grant / Funding (institution): ICON Clinical Research. W.P. Harris: Advisory / Consultancy: Neo Therma; Advisory / Consultancy, Research grant / Funding
v276 | Gastrointestinal Tumours, Non-Colorectal
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz247.047/5576533 by guest on 26 October 2019
A. Hollebecque1, I. Silverman2, S. Owens2, L. Fe´liz3, C. Lihou3, H. Zhen4, R. Newton2, T. Burn2, D. Melisi5 1 Department of Adult Medicine, Gustave Roussy, Villejuif, France, 2Translational Sciences, Incyte Research Institute, Incyte Corporation, Wilmington, DE, USA, 3Clinical Development, Incyte Corporation, Wilmington, DE, USA, 4Biostatistics, Incyte Corporation, Wilmington, DE, USA, 5Digestive Molecular and Clinical Oncology Research Unit, Department of Medicine, Universit a degli Studi di Verona, Verona, Italy
Annals of Oncology
Comprehensive genomic profiling and clinical outcomes in patients (pts) with fibroblast growth factor receptor rearrangement-positive (FGFR21) cholangiocarcinoma (CCA) treated with pemigatinib in the fight-202 trial
Background: Fight-202 is a phase 2 study (NCT02924376) of pemigatinib (INCB054828), a selective, potent, oral inhibitor of FGFR1, 2, and 3 in pts with advanced CCA. Interim results from the first 47 FGFR2þ CCA pts with 8 months (mo) of follow-up demonstrated an objective response rate (ORR) of 40.4%, disease control rate (DCR) of 85%, median progression-free survival (mPFS) of 9.2 mo, and median overall survival (mOS) of 15.8 mo, based on independent central review. Here we report the frequency of FGFR2 rearrangement partners and co-occurring alterations and their impact on clinical outcomes. Methods: Comprehensive genomic profiling was performed in all pts prescreened and/ or enrolled in fight-202 using FoundationOne. Clinical data were reported previously. Results: Among 118 FGFR2þ pts identified, 54 unique FGFR2 rearrangement partners were observed, of which 74.1% (n ¼ 40) were unique to a single patient. BICC1 was the most frequent FGFR2 rearrangement partner (29.7% [n ¼ 35]). FGFR2þ pts had fewer genomic alterations (3.36 alterations/pt) than unaltered pts (4.6 alterations/pt). The most frequently co-altered gene, BAP1, was altered in 39.8% (n ¼ 47) of FGFR2þ pts. As of the data cutoff date (July 24, 2018), 47 FGFR2þ pts were treated with pemigatinib and followed for 8 mo. There were no meaningful differences in ORR (42.9% vs 39.4%), mPFS (8.9 mo vs 9.6 mo), or mOS (not reached [NR] vs 15.8 mo) in patients with FGFR2-BICC1 (n ¼ 14) versus other FGFR2 rearrangements. Similarly, no meaningful difference in ORR (53.3% vs 34.4%), mPFS (8.9 mo vs NR), or mOS (NR vs 15.8 mo) was observed in pts with BAP1 loss-of-function mutations (n ¼ 15). Among other co-occurring genomic alterations, pts with TP53 alterations (n ¼ 5) had no objective responses (0% vs 45.2%) and shorter mPFS (6.2 mo vs NR) and mOS (10.5 mo vs NR). Conclusions: Despite myriad FGFR2 rearrangement partners identified in the study, an interim analysis did not indicate a difference in ORR, mPFS, or mOS between the most common rearrangement partner (BICC1) and other partner genes. Alterations in TP53, but not BAP1, were associated with decreased clinical benefit. Editorial acknowledgement: Simon J. Slater, PhD, CMPP, of Envision Pharma Group (Philadelphia, PA), funded by Incyte Corporation. Legal entity responsible for the study: Incyte Corporation. Funding: Incyte Corporation. Disclosure: A. Hollebecque: Consulting/Advisory Role, Travel/Accommodation/Expenses, Courses/Trainings: Amgen; Consulting/Advisory Role: Spectrum Pharmaceuticals; Consulting/ Advisory Role, Travel/Accommodation/Expenses: Lilly; Consulting/Advisory Role, Travel/ Accommodation/Expenses: Debiopharm; Travel/Accommodation/Expenses: Servier; Travel/ Accommodation/Expenses: Incyte; Courses/Trainings: Bayer; Courses/Trainings: Eisai; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Janssen Cilag; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Sanofi. I.M. Silverman: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. S. Owens: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. L. Fe´liz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. C.F. Lihou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. H. Zhen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. R.C. Newton: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. T.C. Burn: Shareholder / Stockholder / Stock options, Full / Part-time employment: ): Incyte Research Institute, Incyte Corporation. D. Melisi: Research Grants (Institution), Advisory/Consultancy Role: Shire; Research Grants (Institution), Advisory/Consultancy Role: Incyte; Research Grants (Institution), Advisory/Consultancy Role: Evotec; Research Grants (Institution): Celgene; Advisory/Consultancy Role: Eli Lilly; Advisory/ Consultancy: Baxter. All other authors have declared no conflicts of interest.
721P
Efficacy of derazantinib (DZB) in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) expressing FGFR2-fusion or FGFR2 mutations/amplifications
M. Droz Dit Busset1, S. Braun2, B. El-Rayes3, W.P. Harris4, N. Damjanov5, G. Masi6, L. Rimassa7, S. Bhoori8, M. Niger9, N. Personeni10, F. Braiteh11, S. Lonardi12, M. Engelhardt2, M. Saulay2, B. Schwartz13, W.L. Shaib14, V. Mazzaferro15, K.P. Papadopoulos16 1 Department of Surgery and Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 2Development, Basilea Pharmaceutica AG, Basel, Switzerland, 3 Department of Hematology and Medical Oncology, Winship Cancer Institute, Atlanta, GA, USA, 4Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA, 5Section Chief Hematology/Oncology, VA Medical Center, Abramson Cancer Center, Philadelphia, PA, USA, 6Oncology, Azienda Ospedaliera Universitaria S.Chiara, Pisa, Italy, 7Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy, 8S.c. Medicina Nucleare, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 9Oncology, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, Italy, 10Oncology, Istituto Clinico Humanitas, Rozzano, Italy, 11Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA, 12Medical Oncology 1 Unit, Istituto Oncologico Veneto IRCCS, Padua, Italy, 13ArQule Inc., Burlington, MA, USA, 14 Hematology and Oncology, Emory University, Atlanta, GA, USA, 15Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 16Clinical Research, South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA Background: FGFR2 gene aberrations (GA) include fusions and mutations/amplifications, with an estimated prevalence of approximately 15% and 5% in iCCA, respectively. While FGFR2 fusions are acknowledged oncogenic drivers, the oncogenic potential of FGFR2 mutations and amplifications is less well defined, due to ambiguous available preclinical and clinical data. In a non-comparative Phase 2a study (NCT01752920), the potent pan-FGFR inhibitor DZB was administered to iCCA pts expressing either FGFR2-fusion (N ¼ 29), FGFR2 mutations/amplifications (N ¼ 6) or no FGFR gene aberration (N ¼ 9). Here, we present a post-hoc analysis of outcomes of iCCA pts expressing FGFR mutations/amplifications (N ¼ 6) or no FGFR GA (N ¼ 9) as compared to previously reported data of iCCA pts (N ¼ 29) expressing FGFR2 fusions (Mazzaferro et al. 2018 BJC). Methods: Pts received 300 mg DZB QD PO. Eligibility criteria included a locally confirmed (FISH or NGS) testing of FGFR2 GA (fusions vs mutations/amplifications or no aberrations). Objective responses were determined per RECIST 1.1. Disease control rate (DCR) was defined by the summation of CR, PR and SD, and PFS, calculated from treatment initiation until disease progression or death. Results: The table shows the efficacy outcomes in the 3 patient groups. Types of drugrelated adverse events were similar across groups. No new safety signals were identified.
Table: 721P iCCA patient group
FGFR2 fusion N ¼ 29
FGFR2 mutation/ amplification N¼6
No FGFR2 genomic aberration N¼9
Objective response rate (RECIST 1.1) DCR (PR or SD) Any target lesion diameter reduction Median (95% CI) Progression free survival (PFS), months % PFS at 3 months % PFS at 6 months
6 (21%) 24 (83%) 18 (62%) 5.7 (4.0-9.2) 83% 47%
0 (0%) 4 (67%) 4 (67%) 6.7 (1.0-14.7) 67% 50%
0 (0%) 2 (22%) 0 (0%) 1.5 (0.7 – NA) 0% 0%
Conclusions: Anti-tumor efficacy of DZB as measured by DCR and PFS in iCCA patients harboring an FGFR2 GA seems to be similar for patients with FGFR2 fusions and FGFR2 mutations/amplifications, while patients without any detectable FGFR GA appear to derive no benefit from DZB treatment. While the influence of prognostic variables still has to be confirmed, the anti-tumor efficacy of DZB seen in pts with FGFR2 GA other than fusions warrant further clinical investigation. Legal entity responsible for the study: Basilea Pharmaceutica International Ltd. Funding: Basilea Pharmaceutica International Ltd. Disclosure: S. Braun: Full / Part-time employment: Basilea Pharmaceutica Int. Ltd.; Shareholder / Stockholder / Stock options: Ipsen. B. El-Rayes: Advisory / Consultancy: Merrimack; Advisory / Consultancy: BTG; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: RTI Health Solutions; Honoraria (self), Speaker Bureau / Expert testimony: Lexicon; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Cleave Biosciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): AVEO; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Hoosier Cancer Research Network; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): PPD; Research grant / Funding (institution): Merck; Research grant / Funding (institution): ICON Clinical Research. W.P. Harris: Advisory / Consultancy: Neo Therma; Advisory / Consultancy, Research grant / Funding
v276 | Gastrointestinal Tumours, Non-Colorectal
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz247.047/5576533 by guest on 26 October 2019
A. Hollebecque1, I. Silverman2, S. Owens2, L. Fe´liz3, C. Lihou3, H. Zhen4, R. Newton2, T. Burn2, D. Melisi5 1 Department of Adult Medicine, Gustave Roussy, Villejuif, France, 2Translational Sciences, Incyte Research Institute, Incyte Corporation, Wilmington, DE, USA, 3Clinical Development, Incyte Corporation, Wilmington, DE, USA, 4Biostatistics, Incyte Corporation, Wilmington, DE, USA, 5Digestive Molecular and Clinical Oncology Research Unit, Department of Medicine, Universit a degli Studi di Verona, Verona, Italy
Annals of Oncology