Microsatellite instability and immunogenicity in colorectal cancer: Do resident memory Tcells (Trm) play a role in colorectal cancer?

abstracts

Annals of Oncology

(institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): CASI Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Genentech/ Roche; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Adaptimmune. A. Spreafico: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Symphogen AstraZeneca / Medimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen Oncology/ Johnson & Johnson. A.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Genentech/ Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Medimmune. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/ MedImmune; Advisory / Consultancy: Morphosys; Advisory / Consultancy: Roche; Advisory / Consultancy: GeneSeeq; Advisory / Consultancy: Loxo; Advisory / Consultancy: Oncorus; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AbbVie. P. Bedard: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): SERVIER; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly. All other authors have declared no conflicts of interest.

616P

Microsatellite instability and immunogenicity in colorectal cancer: Do resident memory Tcells (Trm) play a role in colorectal cancer?

W.T. Toh1, J. Toh2, A. Ferguson3, K. Spring4, H. Mehajan5, M. Palendira3 Colorectal, Westmead Hospital, Westmead, Australia, 2Colorectal, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia, 3Medical Oncology, Centenary Institute, Sydney, Australia, 4Medical Oncology, Ingham Institute, Liverpool, Australia, 5ICPMR, Westmead Hospital, Westmead, Australia

1

Background: Colorectal cancers with microsatellite instability (MSI) are associated with abundance of tumour infiltrating lymphocytes (TILs). Recent studies have shown that a proportion of TILs may actually be resident memory T cells, not just a continuous circulation of T cells. Methods: Patients with known MSI and BRAF status were eligible for inclusion in this study. Histopathology slides prepared with haematoxylin and eosin were reviewed using an Olympus BX53 microscope to examine the tumour invading edge and core. These slides were then scanned electronically and reexamined with both the investigator and a pathologist. Blocks from these representative slides were recut using a microtome in preparation for quantitative multiplex immunofluorescence staining. All immunofluorescence staining was carried out on 4-mm-thick sections using an Autostainer Plus (Dako – Agilent Technologies) with appropriate positive and negative controls. Opal Multiplex IHC Assay kit (PerkinElmer) was used. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15. Results: 72 patients with known MSI and BRAF status were eligible for inclusion in this study. 36 of these patients were successfully underwent quantitative multiplex immunofluorescence staining. Overall, there was a statistically significant increase in T cells in the MSI BRAF mutant and wild type group over the MSS group. There was a statistically significant difference in Trm between MSI-H BRAF mutant vs. MSS (mean/mm2:

Volume 30 | Supplement 5 | October 2019

2.922 (2.4239-3.4201) vs. 0.9854 (0.8162-1.1546) p ¼ 0.0002). There was also a statistically significant difference between MSI-H BRAF wt vs. MSS (mean/ mm2: 2.119 (1.7603-2.4777) vs. 0.9854 (0.8162-1.1546) p ¼ 0.0002). The difference between MSI-H BRAF mutant and wild type was not statistically significant. Conclusions: This study has shown that resident memory T cells are in greater abundance in MSI-H colorectal cancers compared to their MSS counterpart. Trms may play a role in the immunogenicity of MSI-H colorectal cancers, and may be a target for immune-related therapy. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

617P

Early response evaluation and CEA response in patients treated in a Danish randomized study comparing trifluridine/tipiracil (TAS-102) with or without bevazicumab in patients with chemorefractory metastatic colorectal cancer (mCRC)

C. Qvortrup1, M. Yilmaz2, S. Mo¨ller3, D. Zitnjak4, L. Maltha1, M. Krogh5, L. Noergaard Petersen1, F. Hejlesen2, S.B. Winther5, K.G. Thomsen5, P. Pfeiffer5 1 Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, 2Department of Oncology, Aalborg University Hospital, Aalborg, Denmark, 3 Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark, 4Department of Oncology, Hospital of Southern Jutland, Soenderborg, Denmark, 5Department of Oncology, Odense University Hospital, Odense, Denmark Background: Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) prolongs OS in patients with chemorefractory mCRC. Inspired by the results of C-TASK FORCE (Kuboki 2017), we designed an investigator-initiated randomized trial in the last setting in mCRC patients demonstrating improved PFS and OS in patients receiving bevazicumab combined with TAS-102 as compared to patients treated with TAS-102 alone (Pfeiffer WCGI 2019). In the last line setting half of patients will not benefit from therapy as they have PD at the first evaluation performed after 2 months of therapy. In the present study we included an early response evaluation after 1 month of therapy aiming to identify patients not having any effect of therapy. In addition, we evaluated plasma CEA as a marker of response. Methods: The main inclusion criteria were: histologically confirmed and chemorefractory mCRC; PD during or after therapy with FU, irinotecan, oxaliplatin, and EGFR-inhibitor (RASwt); prior treatment with bevacizumab was allowed; PS 0-1. In arm A: FTD/TPI 35 mg/m2/dose bid from days 1-5 and 8-12; in arm B the same dose of FTD/TPI with bevacizumab (5 mg/kg), days 1 and 15 of a 28-day cycle. Response evaluation performed during treatment at 4 weeks, 8 weeks, and every 8 weeks thereafter. CEA was tested at baseline and at every 2. cycle. Results: 93 patients with chemo-refractory mCRC were randomized from Sep. 2017 to Oct. 2018. The median PFS was significantly improved from 2.6 months (arm A) to 4.6 months (arm B) with a HR 0.45 (95% CI, 0.29-0.72; P ¼ 0.001). Median OS was significantly prolonged from 6.7 months (arm A) to 9.4 months (arm B) with HR 0.55 (95% CI, 0.32-0.94; P ¼ 0.03) (Pfeiffer WCGI 2019). Sub-group analyses including predictive markers for early progression will presented. Conclusions: FTD/TPI in combination with bevacizumab prolong PFS and OS and is a new option in patients with chemo-refractory mCRC. Predictive markers for early progression are ongoing and will be presented. Clinical trial identification: 2016-005241-23. Legal entity responsible for the study: Per Pfeiffer. Funding: Servier. Disclosure: C. Qvortrup: Research grant / Funding (institution): Servier. P. Pfeiffer: Research grant / Funding (institution): Servier; Research grant / Funding (institution): Merck. All other authors have declared no conflicts of interest.

618P

Updated survival analysis of the randomized phase III trial comparing S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer (SALTO) by the Dutch colorectal cancer group

J.J. Kwakman1, E. Van Werkhoven2, L.H. Simkens3, J.M. van Rooijen4, A. van de Wouw5, A.J. Ten Tije6, G-J. Creemers7, M.P. Hendriks8, M. Los9, R. van Alphen10, M.B. Polee11, E.W. Muller12, A. Van der Velden13, T. Van Voorthuizen14, M. Koopman15, L. Mol16, C.J.A. Punt1 1 Medical Oncology, Amsterdam University Medical Center, location AMC, Amsterdam, Netherlands, 2Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, Netherlands, 3Medical Oncology, Maxima Medical Center, Eindhoven, Netherlands, 4 Medical Oncology, Martini Hospital, Groningen, Netherlands, 5Medical Oncology, VieCuri MC, Venlo, Netherlands, 6Medical Oncology, Amphia Ziekenhuis, Breda, Noord Brabant, Netherlands, 7Medical Oncology, Catharina Hospital, Eindhoven, Netherlands, 8 Medical Oncology, NorthWest Clinics, Alkmaar, Netherlands, 9Medical Oncology, Sint Antonius Hospital, Nieuwegein, Netherlands, 10Medical Oncology, ElisabethTweeSteden Hospital, Tilburg, Netherlands, 11Medical Oncology, Medical Center Leeuwarden, Leeuwarden, Netherlands, 12Medical Oncology, Slingeland Hospital, Doetinchem, Netherlands, 13Medical Oncology, Tergooi Hospital, Hilversum, Netherlands, 14Medical Oncology, Rijnstate Hospital, Arnhem, Netherlands, 15Medical

doi:10.1093/annonc/mdz246 | v233

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demonstrated polyclonal KRAS, NRAS, and BRAF mutations at C5 before radiographic progression at C9. Conclusions: The addition of T to Pmab leads to a high rate of tumor shrinkage in RAS/RAF wt mCRC. Median PFS is similar to Pmab alone in the ASPECCT trial, which may be due to a high incidence of skin toxicity with the combination that leads to dose interruption and/or reduction. Additional results from cfDNA and tumor biopsies will be presented. Clinical trial identification: NCT02399943. Legal entity responsible for the study: Philippe Bedard. Funding: Conquer cancer foundation of ASCO career development (Dr P. Bedard), Canadian Cancer Research Society Institute innovation grant (Dr P. Bedard), and drug supply from GlaxoSmithKline and Novartis. Disclosure: A.R.R. Albiruni: Honoraria (self), Advisory / Consultancy, Research grant / Funding