LBA24 - Neoadjuvant immunotherapy in locally advanced MMR-deficient colon cancer: 3-year disease-free survival from NICHE-2

Background

Patients with MMR-deficient (dMMR) colon cancer have limited benefit from standard-of-care chemotherapy, with recurrence rates of up to 40% in stage 3 disease. In NICHE-2, we previously showed a 99% pathologic response rate, including 95% major pathologic responses (MPR) and 68% pathologic complete responses (pCR). Here we present the previously unreported primary endpoint of 3-year disease-free survival (DFS).

Methods

Patients with locally advanced dMMR colon cancer received ipilimumab on Day 1 and nivolumab on Day 1+15, followed by surgery within 6 weeks. The study had two independent primary endpoints: safety and 3-year DFS. As reported previously, the safety endpoint was met. For DFS, a 3-year DFS rate of 93% would be deemed successful, at a power of 80% and a 2-sided alpha of 2.5%, assuming an 82% 3-year DFS in historical controls. Circulating tumor DNA (ctDNA) was analyzed using the Signatera^TM tumor-informed assay on plasma samples from baseline, Day 15, pre-surgery and 3 weeks post-surgery (minimal residual disease (MRD)) timepoints.

Results

Of the 111 patients in the efficacy analysis, 64% had cT4 tumors. With a median follow-up after surgery of 36.5 months (range 7.8 – 83.4), all patients were alive and there were no disease recurrences, resulting in a 3-year DFS of 100%. In 108 patients with available plasma samples, baseline ctDNA was detected in 92%. On Day 15, 45% of these patients had cleared ctDNA. While not different at baseline, ctDNA levels on Day 15 and pre-surgery were significantly lower in pCR vs MPR groups. Pre-surgery ctDNA clearance was observed in 94% of patients with a pCR and 70% with an MPR. 16 patients remained ctDNA+ pre-surgery, albeit with significant reductions in ctDNA levels, and included 2 of 3 partial responders and 1 of 1 non-responder. All patients were ctDNA negative at the MRD timepoint.

Conclusions

Here we show a 100% 3-year DFS in patients with dMMR colon cancer treated with one dose of ipilimumab and two doses of nivolumab prior to surgery. The survival data are also supported by negative ctDNA at the MRD timepoint in all patients, while on-treatment ctDNA dynamics provide an additional monitoring instrument for future trials on organ preservation.

Clinical trial identification

NCT03026140.

Editorial acknowledgement

Legal entity responsible for the study

NKI - Netherlands Cancer Institute.

Funding

Bristol Myers Squibb.

Disclosure

M. Chalabi: Financial Interests, Institutional, Research Grant: BMS, BMS, Roche Genentech, Roche Genentech, MSD, Agenus; Non-Financial Interests, Advisory Role, Advisory Board: BMS, BMS, MSD; Non-Financial Interests, Advisory Role: Kineta. P.G.M. de Gooyer: Non-Financial Interests, Personal, Other, Partner works at pharmaceutical company: MSD. E.E. Voest: Financial Interests, Personal, Advisory Board, Hourly rate: Biogeneration Ventures; Financial Interests, Personal, Member of Board of Directors, independent, non-executive director and share holder: Sanofi; Financial Interests, Personal, Other, Founder, strategic adviser and share holder: Mosaic Therapeutics; Financial Interests, Personal, Ownership Interest, Mandatory shares as part of board membership: Sanofi; Financial Interests, Personal, Ownership Interest, Start up company with shares: Mosaic Therapeutics; Financial Interests, Institutional, Coordinating PI, DRUP trial: Amgen, AstraZeneca, BMS, Eisai, Ipsen, MSD, Novartis, Pfizer, GSK, Seattle Genetics; Financial Interests, Institutional, Coordinating PI, DRUP trialDRUG Access Protocol: Bayer, Roche; Financial Interests, Institutional, Coordinating PI, DRUG Access Protocol: Sanofi; Non-Financial Interests, Other, Supervisory Board: HMF – Hartwig Medical Foundation; Non-Financial Interests, Principal Investigator, Senior group leader: Oncode Institute; Non-Financial Interests, Advisory Role, Editorial Board: JAMA Oncology. T.N. Schumacher: Non-Financial Interests, Personal, Advisory Role, Venture Parner: Third Rock Ventures; Financial Interests, Personal, Stocks/Shares, Advisor and Stockholder: Allogene Therapeutics, Merus, Scenic Biotech; Financial Interests, Personal, Stocks or ownership, Founder, Advisor and Stockholder: Asher Bio, Cell Control, Neogene Therapeutics. J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squipp, Achilles Therapeutics, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Iovance Biotherapeutics, AstraZeneca; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Immunocore, Gadeta, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics, Scenic; Financial Interests, Personal, Advisory Board: Third Rock Venture, CureVac, Imcyse; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio, Sastra Cell Therapy; Non-Financial Interests, Member: ASCO, AACR, SITC; Other, Editor-in-Chief IOTECH: ESMO; Other, Editorial Board ESMO Open: ESMO; Other, Editorial Board: Kidney Cancer. All other authors have declared no conflicts of interest.