Prognostic and clinicopathological significance of PD-L1 in patients with cervical cancer: A meta-analysis

abstracts

Annals of Oncology

Table: 1052P

1053P

Primary results from CECILIA, a global single-arm phase II study evaluating bevacizumab (BEV), carboplatin (C) and paclitaxel (P) for advanced cervical cancer (aCC)

A. Redondo1, N. Colombo2, L.M. Dreosti3, M. McCormack4, A. Nogueira Rodrigues5, G. Scambia6, A. Roszak7, M. Donica8, B. Ulker9, A. Gonzalez Martın10 1 Department Oncologia Medica, Hospital Universitario La Paz, Madrid, Spain, 2 Department of Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy, 3Department of Medical Oncology, University of Pretoria, Pretoria, South Africa, 4Department of Oncology, University College London Hospitals, London, UK, 5Medical Oncology Department, Federal University of Minas Gerais Brazil and Brazilian Group of Gynecologic Oncology, Belo Horizonte, Brazil, 6Policlinico Universitario ‘Agostino Gemelli’, Universit a Cattolica del Sacro Cuore, Rome, Italy, 7 Apteka Szpitalna, Wielkopolskie Centrum Onkologii im. Marii Skłodowskiej- Curie, 8 Pozna n, Poland, Product Development Medical Affairs Biometrics, Hoffmann-La Roche Ltd, Basel, Switzerland, 9Product Development Medical Affairs, F Hoffmann-La Roche Ltd, Basel, Switzerland, 10Medical Oncology Department, Clınica Universidad de Navarra, Madrid, Spain Background: Adding BEV to P þ cisplatin/topotecan for aCC significantly improved overall survival (OS) and progression-free survival (PFS) in the phase 3 GOG240 trial. CECILIA (NCT02467907) evaluated BEV with a more widely used CP backbone. Methods: The primary objective was to determine the safety of BEV þ CP for aCC, defined by the frequency and severity of gastrointestinal (GI) perforation/fistula, GIvaginal fistula and genitourinary (GU) fistula. Eligible patients (pts) had metastatic/ recurrent/persistent CC not amenable to curative surgery and/or radiotherapy (RT). Pts with ongoing bladder/rectal involvement, prior cobalt RT, history of fistula/GI perforation, or bowel resection 6 wk or chemoRT 3 mo before first dose were excluded. Pts received BEV 15 mg/kg, P 175 mg/m2 and C AUC 5 q3w until disease progression (PD), unacceptable toxicity or consent withdrawal. If BEV, C or P was stopped for adverse events (AEs), the remaining drug(s) could be continued alone. Results: From Jul 2015 to Dec 2016, 150 pts began treatment. Disease status at study entry was persistent in 20%, recurrent in 53% and metastatic at diagnosis in 27%; 71% had received prior RT (chemoRT in 58%) and 59% prior platinum. At data cutoff (31

Volume 30 | Supplement 5 | October 2019

Dec 2018), median follow-up was 27.8 mo. The most common reasons for stopping treatment were PD (39%) and AEs (34%). Median BEV duration was 6.7 (range <1– 39) mo; 57% received BEV alone after stopping CP. 17 pts (11.3%, 95% CI 6.7–17.5%) had 1 perforation/fistula event: GI perforation/fistula in 4.7% (1.9–9.4%), GI-vaginal fistula in 4.0% (1.5–8.5%) and GU fistula in 4.7% (1.9–9.4%). All but 1 pt with fistula/ GI perforation had received prior RT; several had ongoing radiation effects. The most common grade 3/4 AEs were neutropenia (21%), anaemia (19%) and hypertension (14%). 5 pts (3%) had fatal AEs. Objective response rate was 61% (95% CI 52–69%), including complete responses in 14%. Median PFS was 10.9 (95% CI 10.1–13.7) mo and median OS 25.0 (20.9–30.4) mo. Conclusions: These results show that BEV can be combined with CP in the CECILIA study population. The fistula/GI perforation incidence is in line with GOG240 and efficacy results are encouraging. Clinical trial identification: NCT02467907. Editorial acknowledgement: Jennifer Kelly (Medi-Kelsey Ltd), funded by F. Hoffmann-La Roche. Legal entity responsible for the study: F. Hoffmann-La Roche. Funding: F. Hoffmann-La Roche. Disclosure: A. Redondo: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche Farma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Research grant / Funding (institution): Eisai. N. Colombo: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy: BIOCAD; Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Non-remunerated activity/ies, ESMO Clinical Guidelines: ESMO; Non-remunerated activity/ies, Scientific Committee Chair: ACTO Onlus. L.M. Dreosti: Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Merck. M. McCormack: Honoraria (self): AstraZeneca; Honoraria (self): Roche. A. Nogueira Rodrigues: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD. M. Donica: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Roche. B. Ulker: Full / Part-time employment: F. Hoffmann-La Roche AG. A. Gonzalez Martın: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Non-remunerated activity/ies, PI of PRIMA: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy, Speaker Bureau / Expert testimony: PharmaMar; Advisory / Consultancy: MSD; Advisory / Consultancy: Genmad. All other authors have declared no conflicts of interest. Scientific clarification

1054P

Prognostic and clinicopathological significance of PD-L1 in patients with cervical cancer: A meta-analysis

X. Gu, Y. Shi Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China Background: Programmed cell death ligand 1 (PD-L1) expression has been shown to associate with poor prognosis in a variety of solid tumors. However, the prognostic value of PD-L1 expression in cervical cancer is still controversial. Therefore, we performed a meta-analysis to investigate the prognostic and clinicopathological impact of PD-L1 in cervical cancer. Methods: A comprehensive literature search was performed in the PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The correlation between PD-L1 expression and overall survival (OS), progression-free survival (PFS), and clinicopathological features was analyzed by hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI).

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Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Bionomics; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Tilray. W. Small: Honoraria (self), Travel / Accommodation / Expenses: Zeiss; Advisory / Consultancy: Merck. S. Thompson: Honoraria (self): Mevion Medical Systems. W. Huh: Honoraria (self): Antiva; Advisory / Consultancy: Inovio. P.A. Disilvestro: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Syros; Research grant / Funding (institution): Janssen. D. Rischin: Advisory / Consultancy, Research grant / Funding (institution), Uncompensated: MSD; Advisory / Consultancy, Research grant / Funding (institution), Uncompensated: Regeneron; Advisory / Consultancy, Research grant / Funding (institution), Uncompensated: GSK; Advisory / Consultancy, Research grant / Funding (institution), Uncompensated: BMS; Research grant / Funding (institution): Roche. M.R. Stockler: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Bionomics; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Tilray. B.J. Monk: Advisory / Consultancy: AbbVie; Advisory / Consultancy: Advaxis; Advisory / Consultancy: Agenus; Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: ChemoCare; Advisory / Consultancy: ChemoID; Honoraria (self), Advisory / Consultancy: Clovis; Advisory / Consultancy: Conjupro; Advisory / Consultancy: Esaias; Advisory / Consultancy: Geistlich; Advisory / Consultancy: Genmab; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Immunomedics; Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Janssen/Johnson & Johnson; Advisory / Consultancy: Merck; Advisory / Consultancy: Myriad; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Tesaro. All other authors have declared no conflicts of interest.

abstracts

Annals of Oncology

1055P

Clinical impact of molecular profiling of cervical cancer (CC) patients (pts) in a dedicated phase I (P1) unit

M. Scaranti1, R. Caldwell1, M. Selvi Miralles1, R. Shinde1, A. Pal1, J.E. Ang1, A. Biondo1, C. Guo1, E. Cojocaru1, S. Gennatas1, F. Lockie1, C. Bertan2, C. Baker2, S. Carreira2, S. Banerjee3, S. Kaye1, J.S. de Bono1, U. Banerji1, A. Minchom1, J. Lopez1 1 Drug Development Unit, The Royal Marsden Foundation Trust and The Institute of Cancer Research, London, UK, 2Cancer Biomarkers Team, The Institute of Cancer Research, London, UK, 3Gynaecology, Royal Marsden Hospital NHS Foundation Trust, London, UK Background: Metastatic CC prognosis remains poor. Molecular characterisation (MC) allows better understanding of the mutations (mut) driving carcinogenesis or treatment resistance. We report the cervical tumour MC of pts in a P1 unit and its clinical implications. Methods: CC pts referred to the P1 unit of The Royal Marsden Hospital from 2011-18 V underwent tumour molecular profiling using OncoCartaTM (Sequenom), TruSeq Cancer Amplicon (Illumina), GeneReadTM custom DNA damage (Qiagen) or V FoundationOne panel. Retrospective data was extracted from electronic medical records. Results: Of the 37 pts (median age: 34.7 years) analysed, 45.9% had squamous histology, and 37.8% were FIGO stage 2 at diagnosis; 34 different pathogenic mut were identified with 70.3% of pts having mut. PIK3CA mut were the most common (32.4%), followed by KRAS (13.5%), APC (8.1%), TP53 (8.1%), PTEN (5.4%), KDR (5.4%), ATM (5.4%), STK11 (5.4%) and BRCA1 (5.4%). 40.5% (15/37) patients had a potentially actionable mutation. Median overall survival (mOS) was 36 months (mo) in study population, 33 mo in KRAS mut, 40 mo in PIK3CA mut, 52 mo in APC mut and 40 mo in the mut-negative group; however, this difference was not statistically significant. In the KRAS mut group, 60% were adenocarcinoma and 40% adenosquamous. All KRAS mut pts had FIGO stage 2/3 at diagnosis. 80% had visceral metastasis when referred to the P1 unit; whereas in the PIK3CA mut group, tumour histologies were 33.3% squamous, 25% adenocarcinoma, 25% adenosquamous, 8.3% mucinous, 8.3% uncommon histologies. In the PIK3CA mut group, 75% were stage 1/2 at diagnosis, and 41.6% had visceral metastasis when referred. 5.4% (2/37) of pts were allocated to a P1 trial based on the finding of a PIK3CA mut with a mOS of 40 mo compared to 36 mo for the total population (p ¼ 0.6). One pt received an AKT inhibitor (i) but developed progressive disease (PD) after 3 cycles; the other received a PI3K i with PD after 4 cycles. Conclusions: Our study corroborates existing knowledge of the association between KRAS mut and adenocarcinoma histology in CC which confers worse prognosis. The high rate of potentially actionable mut indicates the increasing scope for targeted treatment trials in CC, thus prompting early MC which may improve pt allocation to P1 trials. Legal entity responsible for the study: The Institute of Cancer Research and The Royal Marsden Foundation Trust. Funding: The Institute of Cancer Research and The Royal Marsden Foundation Trust. Disclosure: S. Banerjee: Honoraria (self), Research grant / Funding (institution): AstraZeneca; R

R

Honoraria (self), Honoraria/reimbursement: Tesaro; Honoraria (self), Honoraria/reimbursement: Clovis; Honoraria (self), Honoraria/reimbursement: Merck Serono; Honoraria (self), Honoraria/ reimbursement: Nucana; Honoraria (self), Honoraria/reimbursement: Immunogen; Honoraria (self), Honoraria/reimbursement: Seattle Genetics; Honoraria (self), Honoraria/reimbursement: Roche; Honoraria (self), Honoraria/reimbursement: Gamamabs. J.S. de Bono: Honoraria (self), Non-remunerated activity/ies: Astellas Pharma; Honoraria (self), Research grant / Funding (institution), Nonremunerated activity/ies: AstraZeneca; Honoraria (self): Genentech/Roche; Honoraria (self): Pfizer; Honoraria (self), Non-remunerated activity/ies: Sanofi; Honoraria (self): Bayer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck Serono; Honoraria (self): Merck Sharp & Dohme; Non-remunerated activity/ies: Genmab; Non-remunerated activity/ies: GlaxoSmithKline; Nonremunerated activity/ies: Orion Pharma GmbH; Non-remunerated activity/ies: Qiagen; Non-remunerated activity/ies: Taiho Pharmaceutical; Non-remunerated activity/ies: Vertex; Licensing / Royalties, Royalties paid to Institution, no personal income: Abiraterone Rewards to Inventors; Licensing / Royalties, Royalties paid to Institution, no personal income: PARP inhibitors and DNA repair defects. U. Banerji: Honoraria (self), Precision Medicine - Advanced Prostate Cancer Meeting, London UK 30/11/2018: Astellas; Honoraria (self), Advisory / Consultancy, Translational Clinical Oncology Advisory Board, London, 24/07/2018; FIH Precision Oncology SAB, Frankfurt, 10-11/11/2015: Novartis; Advisory / Consultancy, Clinical Advisory Board, London, 19/03/2018 and 12/02/2015: Karus Therapeutics; Advisory / Consultancy, GI Advisory Board, London, 2/12/2017: Phoenix ACT;

v430 | Gynaecological Cancers

Honoraria (self), European Digestive Oncology Research Forum, London, 27-28/11/2017: Eli Lilly; Honoraria (self), KOL ERK Workshop, New Orleans, 17/04/2016; HSP90 Workshop, Washington DC,8/03/2014: Astex; Honoraria (self), AUY922 meeting, New Jersey, USA,12/02/2015: Vernalis; Research grant / Funding (institution), ONX-0801:Funding for investigator-initiated Phase I trial: Onyx Pharmaceuticals; Research grant / Funding (institution), ONX-0801:top-up funding for investigator-initiated phase I trial: BTG International; Research grant / Funding (institution), RAF/MEK: funding for investigator-initiated phase I trial: Chugai; Research grant / Funding (institution), TAXTORC: funding for investigator-initiated phase I trial: AstraZeneca; Research grant / Funding (institution), FRAME: funding for investigator-initiated phase I trial: Verastem. A. Minchom: Travel / Accommodation / Expenses: Loxo; Advisory / Consultancy: Janssen; Honoraria (self): Faron; Speaker Bureau / Expert testimony: Bayer Media Event. J. Lopez: Advisory / Consultancy: Genmab; Advisory / Consultancy: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Research grant / Funding (institution), Travel / Accommodation / Expenses: Basilea. All other authors have declared no conflicts of interest.

1056P

Comparative proteomic profiles of cervical cancer and paried paracancerous tissue and the potential effects of DUSP7 overexpression through inhibiting RAS pathway on the biological characteristics of human cervical cancer cell line SIHA

X. Jiang, H. Bai, Z. Zhang Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China Background: The present study aimed to compare the protein profiles between paired samples of cervical cancer and paracancerous tissue and to identify a series of differentially expressed proteins (DEPs) through quantitative proteomics. Methods: The DEPs were identified through proteomic profiles of three paired samples of cervical cancer (CC) and paracancerous tissue and through IHC examination in the CC tissue arrays. The lentiviral particles containing DUSP7 gene were transfected into SIHA cells (DUSP7-SIHA). CCK8 assay, colony formation assay, wound healing assay and transwell migration assay were used to evaluate the ability of cell proliferation, cell clone formation, cell migration and invasion. Immunofluorescence assay was used to detect the expression of E-cadherin and Vimentin in the target cells. Results: The decreased expression of DUSP7 (P ¼ 0.045 and 0.044, respectively) and increased expression of PLD1 (P ¼ 0.046 and 0.028, respectively) were significantly associated with a tumor size >2cm and parametrial infiltration. The decreased expression of DUSP7, and increased expression of PLD1 were adversely related to patients’ relapse (P ¼ 0.003, 0.040, and 0.001, respectively) and survival (P ¼ 0.034, 0.001, and 0.006, respectively). The DUSP7-SIHA cells proliferated slower than NC-SIHA cells, based on a clear delay in the doubling time (47.7261.14 h vs. 23.9960.47 h, P ¼ 0.0001). Cell cycle analysis indicated that the DUSP7-SIHA cells displayed a concomitant decrease in the percentage of cells in S phase (37.7160.53% vs. 46.9660.59%, P < 0.0001) and a significant increase in the percentage of cells in G0/G1 phase (52.5063.49% vs. 44.0460.71%, P ¼ 0.0473) suggesting that inhibited proliferation of DUSP7-SIHA cells might be due to the inactivation of DNA synthesis. E-cadherin increased but Vimentin was reduced in DUSP7-SIHA cells, which demonstrated that overexpression of DUSP7 had a potential role in inhibiting EMT of SIHA cells. Conclusions: The biological function of DUSP7 was possibly achieved through dephosphorylation of the ERK1/2 and inactivation of the RAS pathway. Legal entity responsible for the study: Beijing Chaoyang Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

1057P

Molecular profiling reveals novel targetable biomarkers in neuroendocrine carcinoma of the uterine cervix

S. Vranic1, D. Arguello2, E. Contreras2, A. Cimic3, Z. Gatalica4 College of Medicine, Qatar University, Doha, Qatar, 2Pathology, Caris Life Sciences, Phoenix, AZ, USA, 3Pathology, Maimonides Medical Center, New York, NY, USA, 4 Pathology, Caris Life Sciences, New York, NY, USA

1

Background: Neuroendocrine carcinoma of the uterine cervix (NEC) is a rare cervical malignancy, accounting for 0.9% of all cervical carcinomas. Cervical NEC is a highgrade cancer with an aggressive clinical course and poor outcome. Given that no target therapy has been approved yet for NEC, we explored novel targetable biomarkers in a large cohort of NEC of the cervix. Methods: Sixty-two NEC of the cervix were profiled for biomarkers of targeted therapy including antibody-drug conjugates (DLL3, TROP-2, and FOLR1), tropomyosin receptor kinases (NTRK1/2/3 gene fusions), and immune checkpoint inhibitors (PDL1, TMB, and MSI) using immunohistochemistry and DNA/RNA next-generation sequencing assays. Results: The study included 36 primary and 26 metastatic cervical NEC. The mean patient’s age was 43.6 years (range, 24-82 years). DLL3 expression was observed in 81% of the cases with 49% of cases expressing diffusely (50% of positive cancer cells) DLL3 protein. DLL3 expression was inversely correlated with commonly observed mutations: PIK3CA (7/47) (p ¼ 0.018) and PTEN mutations (5/40) (p ¼ 0.006). Other frequently seen mutations (TP53 17%, KRAS 11% and CTTNB1 5%) were not associated with DLL3 expression. PD-L1 expression, high TMB and MSI-H were seen in single cases. Although NTRK protein expression was observed in 21% of the cases, none of these

Volume 30 | Supplement 5 | October 2019

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Results: Seven studies with 783 patients were included in this meta-analysis. The combined HR and 95%CI of OS was 2.52 (1.09-5.83), p ¼ 0.031. The pooled results for PFS were HR ¼ 2.07, 95%CI¼0.52-8.23, p ¼ 0.302. The results of subgroup analysis showed that PD-L1 was a significant prognostic factor of poor OS in Asian patients (HR ¼ 4.77, 95%CI¼3.02-7.54, p < 0.001) and of poor PFS in Asian patients (HR ¼ 4.78, 95%CI¼1.77-12.91, p ¼ 0.002). However, the pooled results suggested that PD-L1 was not significantly correlated with lymph node metastasis, tumour size, FIGO stage, depth of invasion, lymph-vascular invasion, or age. Conclusions: The results of this meta-analysis suggest that PD-L1 overexpression is related to poor OS in patients with cervical cancer and poor PFS in Asian patients with cervical cancer. This study also suggests that PD-L1 is a promising prognostic indicator for cervical cancer. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.