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Proffered paper session - Immunotherapy of Cancer

2621 - Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer

Date

22 Oct 2018

Session

Proffered paper session - Immunotherapy of Cancer

Presenters

Myriam Chalabi

Authors

M. Chalabi1, L.F. Fanchi2, J.G. Van den Berg3, G.L. Beets4, M. Lopez-Yurda5, A.G. Aalbers4, C. Grootscholten1, P. Snaebjornsson3, M. Maas6, M. Mertz7, E. Nuijten5, M. Kuiper8, M. Kok9, M.E. Van Leerdam8, T.N. Schumacher10, E.E. Voest11, J.B. Haanen12

Author affiliations

  • 1 Gastrointestinal Oncology, Netherlands Cancer Institute, 1006 BE - Amsterdam/NL
  • 2 Molecular Oncology And Immunology, Netherlands Cancer Institute, Amsterdam/NL
  • 3 Pathology, Netherlands Cancer Institute, Amsterdam/NL
  • 4 Surgical oncology, Netherlands Cancer Institute, Amsterdam/NL
  • 5 Biometrics, Netherlands Cancer Institute, Amsterdam/NL
  • 6 Radiology, Netherlands Cancer Institute, Amsterdam/NL
  • 7 Bioimaging Facility, Netherlands Cancer Institute, Amsterdam/NL
  • 8 Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam/NL
  • 9 Medical Oncology, Netherlands Cancer Institute, 1006 BE - Amsterdam/NL
  • 10 Molecular Oncology And Immunology, Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
  • 11 Gastrointestinal Oncology, Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
  • 12 Medical Oncology, Netherlands Cancer Institute, Amsterdam/NL
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Abstract 2621

Background

Programmed death 1 (PD-1) and CTLA-4 blockade demonstrated durable clinical benefit in patients with advanced mismatch repair deficient (dMMR) colorectal cancer. This is the first neoadjuvant study to test ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD1) in early stage dMMR and MMR proficient (pMMR) colon cancers (CC).

Methods

Patients with resectable, early stage CC received ipilimumab 1mg/kg on day (D)1 and nivolumab 3mg/kg on D1+15. Surgery was planned a maximum of 6 weeks after informed consent. Primary endpoints were safety and feasibility. Secondary endpoints included: efficacy assessed by pathological response criteria, and associations between response and tumor mutational burden (TMB), interferon (IFN)ᵧ gene signatures, T-cell infiltration and T-cell receptor (TCR) clonality.

Results

So far, 14 patients with either pMMR (n=8) or dMMR (n=7) tumors were treated. Treatment was well-tolerated and all patients underwent radical resection of 15 tumors without delays in surgery. Major pathological responses (<5% viable tumor cells) were observed in 7/7 (100%) dMMR CC, with 4/7 (57%) complete responses. Four of these dMMR tumors were clinically stage IIIB/C before start of treatment. Even though no major pathological responses were seen in pMMR tumors, significant increases in T-cell infiltration, particularly CD8+ T-cells, were seen post-treatment in both pMMR and dMMR tumors, with a median fold change of 2.4 (p=0.018) and 4.8 (p=0.0009), respectively.

Strikingly, in spite of the major difference in TMB between dMMR and pMMR tumors (p=0.008), pre-treatment TCR clonality and IFNᵧ gene signatures did not differ substantially between these tumors. In contrast, post-treatment IFNᵧ signatures increased the ability to distinguish responders (dMMR) from non-responders (pMMR).

Conclusions

Short-term, neoadjuvant ipilimumab plus nivolumab resulted in major pathological responses in 100% of dMMR tumors and did not compromise surgery. While dMMR status and TMB were associated with response, pre-treatment measures of tumor inflammation may have limited predictive value. Our data suggest that neoadjuvant immunotherapy in dMMR CC warrants further research and has the potential to change the current standard of care.

Clinical trial identification

NCT03026140

Editorial Acknowledgement

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