Immunotherapy may become new first line treatment in some metastatic colorectal cancers

Munich, Germany, 22 October 2018 - Immunotherapy with nivolumab and low-dose ipilimumab could become a new first line treatment in patients with some metastatic colorectal cancers following late-breaking results from the CheckMate-142 trial reported at the ESMO 2018 Congress in Munich. (1) The drug combination shrank tumours and had beneficial effects on survival in patients with microsatellite instabiliy (MSI)-high metastatic colorectal cancer.

Around 4% of metastatic colorectal cancers are MSI-high, also called mismatch repair deficient. This means that tumour cells have mutations in the genes that usually repair DNA. Patients with MSI-high tumours have shorter survival (~14-19 months) than those with non-MSI-high tumours (~17-25 months), when treated with chemotherapy in a first-line setting. (2,3)

The phase II CheckMate-142 trial previously showed that in patients with MSI-high metastatic colorectal cancer that is resistant to chemotherapy, immunotherapy with nivolumab and low-dose ipilimumab provided durable clinical benefit and manageable side effects, leading to approval by the US Food and Drug Administration (FDA).

Today researchers report for the first time the CheckMate-142 results in patients who have received no prior treatment for MSI-high metastatic colorectal cancer. The study enrolled 45 patients. The median age was 66 years and 51% were male. Patients were followed-up for a median of 13.8 months for the primary endpoint of objective response rate.

The objective response rate was 60% and 7% of patients had a complete response. Some 84% of patients had tumour shrinkage. It took a median of 2.6 months to respond to treatment. The median duration of response, median progression-free survival, and median overall survival have not yet been reached. The 12-month progression-free survival and overall survival rates were 77% and 83%, respectively.

Other trials have tested high-dose ipilimumab combined with nivolumab, but CheckMate-142 used low-dose ipilimumab with nivolumab, which resulted in less toxicity. Treatment-related grade 3 and 4 toxicities were reported in 16% of patients and 7% discontinued therapy due to treatment-related adverse events.

Study author Prof. Heinz-Josef Lenz, Co-Leader, Gastrointestinal Cancers Program, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, US, said: "The combination of low-dose ipilimumab and nivolumab has a durable clinical response and is well tolerated as first line treatment in patients with MSI-high metastatic colorectal cancer. The data suggest that nivolumab and ipilimumab may be a first line treatment option for these patients."

Commenting on the results for ESMO, Prof. Thierry Andre, Head of Medical Oncology, Hopital Saint-Antoine, Assistance Publique - Hopitaux de Paris, France, said: "Nivolumab plus low-dose ipilimumab is effective in most patients with MSI-high metastatic colorectal cancer. Patients improve dramatically and some return to work. It means healthcare systems can be confident that resources are being targeted effectively. This is in contrast to other metastatic cancers (melanoma, lung or kidney) where it is more difficult to select patients who benefit from immunotherapy."

Andre noted that these phase II results could lead the manufacturer to ask the FDA to approve this immunotherapy combination for the first line treatment of MSI-high metastatic colorectal cancer, but the European Medicines Agency (EMA) will probably require a randomised phase III trial. The ongoing phase III KEYNOTE-177 study in MSI-high metastatic colorectal cancer is comparing first line treatment with pembrolizumab versus chemotherapy with or without targeted therapy and the first results are expected in 2019. Andre; said: "Another question is whether the combination of nivolumab and ipilimumab is superior to nivolumab alone for the first line treatment of patients with MSI-high metastatic colorectal cancer. Previous results from CheckMate-142 suggest, with indirect comparisons, improved efficacy with nivolumab plus low-dose ipilimumab relative to nivolumab alone in previously treated patients with MSI-high metastatic colorectal cancer." (4)

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References

1. Abstract LBA18_PR 'Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC)' will be presented by Heinz-Josef Lenz during Proffered Paper Session on Monday 22 October, 09:15 to 10.50 (CEST) in Hall A2 - Room 18. Annals of Oncology, Volume 29 Supplement 8 October 2018
2. Heinemann V, et al. Somatic DNA mutations, tumor mutational burden (TMB), and MSI Status: Association with efficacy in patients (pts) with metastatic colorectal cancer (mCRC) of FIRE-3 (AIO KRK-0306). J Clin Oncol. 2018;36:3591-3591. doi: 10.1200/JCO.2018.36.15_suppl.3591
3. Venderbosch S, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014;20:5322-5330. doi: 10.1158/1078-0432.CCR-14-0332.
4. Overman MJ, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018;36:773-779. doi: 10.1200/JCO.2017.76.9901.

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LBA18_PR - Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC)

H-J.J. Lenz1, E. Van Cutsem2, M.L. Limon3, K.Y. Wong4, A. Hendlisz5, M. Aglietta6, P. Garcia-Alfonso7, B. Neyns8, G. Luppi9, D. Cardin10, T. Dragovich11, U. Shah12, A. Atasoy13, R. Postema14, Z. Boyd15, J-M. Ledeine16, M. Overman17, S. Lonardi18

1Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 2Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium, 3Medical Oncology, Hospital Universitario Virgen del Rocio, Seville, Spain, 4Medical Oncology, Westmead Hospital, Sydney, Australia, 5Internal Medicine, Institut Jules Bordet, Brussels, Belgium, 6Medical Oncology, Candiolo Cancer Institute and University of Torino Medical School, Candiolo, Italy, 7Medical Oncology, Hospital Gral Universitario Gregorio Maranon, Madrid, Spain, 8Medical Oncology, University Hospital Brussels, Brussels, Belgium, 9Oncology and Hematology, University Hospital of Modena, Modena, Italy, 10Department of Medicine, Vanderbilt - Ingram Cancer Center, Nashville, TN, USA, 11Medical Oncology and Hematology, Banner MD Anderson, Gilbert, AZ, USA, 12Hematology-Medical Onoclogy, Lehigh Valley Hospital, Allentown, PA, USA, 13R&D Oncology Clinical Development, Bristol-Myers Squibb Company, Princeton, NJ, USA, 14HEOR, Bristol-Myers Squibb Company, London, UK, 15Oncology Translational Medicine, Bristol-Myers Squibb Company, Princeton, NJ, USA, 16Biostatistics, Bristol-Myers Squibb Company, Princeton, NJ, USA, 17Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 18Medical Oncology, Istituto Oncologico Vento IOV-IRCSS, Padua, Italy

Background: In previously chemotherapy-treated patients with MSI-H/dMMR mCRC from the phase II CheckMate-142 trial, NIVO + low-dose IPI (1 mg/kg) provided durable clinical benefit (investigator-assessed [INV] objective response rate [ORR] 55%, median duration of response [DOR] not reached, 12-month overall survival [OS] rate 85%) and manageable safety. Here we report the first results of the efficacy and safety of NIVO + low-dose IPI as a first-line (1L) therapy for patients with MSI-H/dMMR mCRC from CheckMate-142.

Methods: Patients with no prior treatment for MSI-H/dMMR mCRC were treated with NIVO 3 mg/kg every 2 weeks (Q2W) + low-dose IPI every 6 weeks (Q6W) until disease progression. The primary endpoint was ORR (INV; RECIST v1.1).

Results: Of 45 patients, 51% were male and median age was 66 years. Median follow-up (time from first dose to data cut-off) was 13.8 months (range 9-19). The ORR and disease control rate (DCR) were 60% and 84%, respectively, with a 7% complete response rate (Table). Median DOR was not reached. At 12 months, progression-free survival (PFS) and OS rates were 77% and 83%, respectively. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 16% of patients and 7% of patients had any grade TRAEs leading to discontinuation. Any grade select immune-mediated TRAEs affecting the hepatic (13%), gastrointestinal (11%), pulmonary (2%), and renal (2%) systems resolved in 100% of patients, while those affecting the skin (33%) and endocrine (24%) systems resolved in 45% and 60% of patients, respectively.

Conclusions: NIVO (Q2W) + low-dose IPI (Q6W) demonstrated robust and durable clinical benefit and was well-tolerated as a 1L treatment for MSI-H/dMMR mCRC. These results suggest that NIVO + low-dose IPI may represent a new treatment option for these patients.

Clinical trial identification: NCT02060188

Editorial Acknowledgement: Professional medical writing assistance and editorial assistance was provided by Tanmayi Mankame, PhD, and Christine Craig of Parexel International, funded by Bristol-Myers Squibb

Legal entity responsible for the study: Bristol-Myers Squibb

Funding: Bristol-Myers Squibb

Disclosure: H-J.J. Lenz: Honoraria: Bayer, Boehringer Ingelheim, Merck Serono, Roche; Consulting or Advisory Role: Bayer, Merck Serono, Pfizer, Roche; Travel, Accommodations, Expenses: Bayer, Merck Serono, Roche. E. Van Cutsem: Grants: Amgen, Bayer, BMS, Boehringer, Celgene, Ipsen, Lilly, Merck, MSD, Novartis, Roche, Servier; Honoraria: Bayer, BMS, Celgene, Lilly, Novartis, Servier. K.Y. Wong: Consultant/advisory role: Baxalta; Honoraria: Baxalta; Travel, accommodations, expenses: Roche. M. Aglietta: Honoraria: Bristol-Myers Squibb; Consulting or Advisory Role: Bristol-Myers Squibb; Travel, Accommodations, Expenses: Bristol-Myers Squibb. B. Neyns: Honoraria: BMS, Merck, Novartis, Roche; Consultant/Advisory: BMS, Merck, Novartis, Roche; Speakers' Bureau: Novartis; Research (Inst): Merck KGaA, Novartis, Pfizer; Travel: Amgen, BMS, Merck, Novartis, Roche. D. Cardin: Consulting or Advisory Role: Merrimack, Raphael Pharmaceuticals; Research Funding (Inst.): Celgene, EMD Serono, Hoffman-LaRoche, Incyte, Oncolytics, Synta, BMS, Advaxis (Inst). A. Atasoy: Employment: BMS. R. Postema: BMS employee and shareholder. Z. Boyd: Employment: Bristol Meyers Squibb; Stock and other ownership interests: Roche/Genentech, Bristol Meyers Squibb. J-M. Ledeine: Employment: Bristol-Myers Squibb; Stock and other ownership interests: Bristol-Myers Squibb. M. Overman: Consulting or Advisory Role: Bristol-Myers Squibb, Merrimack, Roche/Genentech; Research Funding: Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, Roche. S. Lonardi: Consulting or Advisory Role: Amgen, Bayer, Merck, Lilly; Speakers' Bureau: Lilly, Roche, BMS; Research Funding: Amgen. All other authors have declared no conflicts of interest.

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