Clinical Study

Survival of patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era

Abstract

Background

Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy.

Methods

Two hundred and eighty-one dMMR mCRC patients (n = 54 from three prospective Phase 3 CAIRO trials; n = 227 from the Netherlands Cancer Registry). Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors. As comparison for OS 2746 MMR proficient mCRC patients were identified.

Results

Of 281 dMMR patients, 62% received first-line and 26% second-line treatment. Median OS was 16.0 months (13.8–19.6) with antitumour therapy and 2.5 months (1.8–3.5) in untreated patients. OS1 was 12.8 months (10.7–15.2) and OS2 6.2 months (5.4–8.9) in treated dMMR patients. Treated dMMR patients had a 7.6-month shorter median OS than pMMR patients.

Conclusion

Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients.

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Fig. 1: Flow diagram of Netherlands Cancer Registry (NCR) patients.
Fig. 2: OS, OS1 and OS2 in mCRC patients with dMMR.

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Acknowledgements

Part of the results were included in an abstract which was accepted for an oral presentation at the 2019 AACR Annual Meeting.28 The following oncologists and research nurses were involved in the study: M. Bax (Maxima Medical Center), M. Beusink (Amsterdam University Medical Center), C. Bresser-de Ruyter (Rode Kruis Hospital Beverwijk), S. Brouwer (Hospital Rijnstate), A. Cats (MD, Stichting Antoni van Leeuwenhoek Hospital), M. de Buck (Zorgsaam), H. de Graaf (MD, Medical Center Leeuwarden, Leeuwarden), M. Deelen (Diakonessenhuis Hospital Utrecht), M. Fellinger (Ziekenhuisgroep Twente), N. Golsteijn (Hospital Rivierenland), S.M. Hiddema (Groene Hart Hospital), D.F.S. Kehrer (MD, IJsselland Hospital), M. Laven (Catharina Hospital), H. Polderdijk (Haga Hospital), F. Ramakers (Zuyderland Medical Center), C.J. Rienks-Bosma (Medical Center Leeuwarden), R. Roukema (Antonius Hospital Sneek), S. Ruijgrok (IJsselland Hospital), J. Schellekens-van Bronswijk (Bravis Hospital), T. Simon (LangeLand Hospital), S. Sloof (Gelre Hospital), D.J. Storm (Spaarne Hospital), E. Valenteijn (Zaans Medical Center), S. van Broekhoven (Franciscus Gasthuis & Vlietland), A.J. van de Vendel (Hospital Gelderse Vallei), E.J.E. van Gestel-Wink (Meander Medical Center), M.-L. van Groesen (OLVG), I. van Rooij-Tieleman (VieCuri Medical Center), M. Vercoulen (Elkerliek Hospital), M.J. Weterman (Amsterdam University Medical Center, University of Amsterdam). We thank the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the collection of data for the Netherlands Cancer Registry as well as IKNL staff for scientific advice.

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Contributions

Study concepts and design were completed by G.E.W., M.A.G.E., A.M.M., P.A.H.H., C.J.A.P., G.R.V., J.M.L.R. and M.K. Data acquisition: all authors with the exception of A.M.M. and P.A.H.H. Quality control of data and algorithms, data analysis and interpretation, statistical analysis, manuscript preparation and editing were completed by G.E.W., M.A.G.E., A.M.M., C.J.A.P., G.R.V., J.M.L.R. and M.K. The manuscript was reviewed and approved by all authors.

Corresponding author

Correspondence to Miriam Koopman.

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Ethics approval and consent to participate

For trial-based patients, patient inclusion criteria, informed consent and study protocols for the trials were published previously.13,14,15 For population-based patients, pseudonymised clinical data on demographic characteristics, tumour characteristics and treatment information (type, response) were obtained from the Netherlands Cancer Registry. The privacy rights for patients were maintained. The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

not applicable.

Data availability

The datasets generated during and analyzed during the current study are not publicly available due to the regulations of the Netherlands Cancer Registry but are available from the corresponding author or Netherlands Cancer Registry on reasonable request.

Competing interests

The authors declare no conflict of interest. J.W.B.G. Institutional financial instructs (IFI): BMS, Pierre Fabre, Roche, MSD, Shire, Amgen; M.K. IFI: Amgen, Bayer, BMS, Merck-Serono, Nordic Farma, Roche, Servier, Sirtex, Sanofi-Aventis; Non-financial interests (NFI): advisory role ZON-MW, daily board member DCCG, P.I. PLCRC; CJAP IFI: Amgen, Roche; J.M.L.R. IFI: Servier, Merck, Bayer; T.v.V. NFI: Pfizer, Ipsen, Astellas, Roche, Bayer; H.V. IFI: Immunovo, Glycostem, Roche; G.R.V. IFI: Servier, Bayer, Merck, BMS, Lilly. All grants were unrelated to the study and paid to the individual’s institution.

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Wensink, G.E., Elferink, M.A.G., May, A.M. et al. Survival of patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-01076-0

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