MUNICH, Germany - Pre-operative treatment with a combination of the immune checkpoint inhibitors nivolumab and ipilimumab achieves major pathological responses in 100% of early-stage colon cancers with mismatch repair deficiencies, according to results reported at ESMO 2018 (1) from the first exploratory phase II trial to investigate this approach.
Restoring patients’ immune response against cancer cells with checkpoint inhibitors is an established treatment strategy for several tumour types. These agents are of particular interest in mismatch repair deficient (dMMR) tumours because they have high mutational load and upregulation of immune checkpoints (2).
Checkpoint inhibitors have previously shown durable responses in metastatic colorectal cancers so the new study investigated whether neoadjuvant treatment in dMMR early-stage colon cancer would achieve clinically significant response rates.
The exploratory trial treated 14 patients with early-stage colon cancer with the checkpoint inhibitors nivolumab (two doses of 3mg/kg on day 1 and 15) and ipilimumab (one dose of 1mg/kg on day 1) before surgery. The two drugs act in different ways to restore immune responses: ipilimumab blocks cytotoxic T lymphocyte associated protein 4 (CTLA-4) and nivolumab blocks programmed cell death protein 1 (PD-1).
Results reported at ESMO 2018 showed that 100% (7/7) of the patients with dMMR colon cancer had major pathological responses (defined as <5% of viable tumour cells remaining). Four of these seven patients (57%) had complete responses.
In contrast, no major pathological responses were seen in pMMR tumours, however there were significant increases in T-cell infiltration.
The immunotherapy regimen was well tolerated and all of the patients underwent radical resection of their tumours without delays in surgery.
“This is the first study with immune checkpoint inhibitors in early stage colon tumours. Our data suggest that neoadjuvant immunotherapy in dMMR colon cancer warrants further research and has the potential to change the standard of care,” said lead author Dr Myriam Chalabi, from the Netherlands Cancer Institute, Amsterdam, Netherlands. She commented: “The response we saw is much more dramatic than in metastatic disease, which we did not expect.”
“For MMR deficient tumours, the results were amazing, with 100% of patients so far having either complete or near complete responses within the short timeframe of treatment, which is usually 4 weeks,” she continued. “I think the finding will have implications for clinical practice in the future. At this stage, it’s too early to call it practice changing but it could be if similar results are seen in larger studies.”
Commenting on the study for ESMO, Dr Aurélien Marabelle, Clinical Director of the Cancer Immunotherapy Program at the Gustave Roussy Cancer Centre, Villejuif, France, said: “The study positions immunotherapy at an earlier stage of the disease history for patient with localised disease, and, interestingly, in the neo-adjuvant setting as opposed to the adjuvant setting that is now approved in melanoma and non-small-cell lung cancer.”
Marabelle cautioned that the study was small, not randomised and there was no control arm of patients not treated with immunotherapy. He said: “Limited data are available but if they show complete pathological responses in the neoadjuvant setting, this therapeutic strategy might become standard of care for dMMR colorectal cancer.” He added that dMMR tumours are more frequent in localised cancers (~15% of patients) than at the metastatic stage (~5%).
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2018 Congress
Official Congress hashtag: #ESMO18
- Abstract LBA37_PR ‘Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer’ by Myriam Chalabi during the Proffered Paper Session on Monday 22 October, 11:15 to 12:45 (CEST) in Room 18 - Hall A2. Annals of Oncology, Volume 29 Supplement 8 October 2018
- Sclafani F. PD-1 inhibition in metastatic dMMR/MSI-H colorectal cancer. Lancet Oncology 2017; 18: 1141-1142
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LBA37_PR - Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer
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. Kuiper1, M. Kok8, M.E. Van Leerdam1, T.N. Schumacher2, E.E. Voest1, J.B. Haanen8
1Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands, 2Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands, 3Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands, 4Surgical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands, 5Biometrics, Netherlands Cancer Institute, Amsterdam, Netherlands, 6Radiology, Netherlands Cancer Institute, Amsterdam, Netherlands, 7Bioimaging Facility, Netherlands Cancer Institute, Amsterdam, Netherlands, 8Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
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
Legal entity responsible for the study: Netherlands Cancer Institute
Funding: Bristol-Myers Squibb
Disclosure: All authors have declared no conflicts of interest
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