A phase 3 study of nivolumab, nivolumab + ipilimumab, or chemotherapy for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: CheckMate 8HW

¹Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris and Sorbonne Université, Paris, France; ²University Hospitals Gasthuisberg and University of Leuven (KU Leuven), Leuven, Belgium; ³Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; ⁴Hopital Foch, Suresnes, France; ⁵Centre Léon Bérard, Lyon Cedex, France; ⁶National Cancer Center Hospital (NCCH) East, Kashiwa, Japan; ⁷University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark; ⁸Fundación Favaloro, Buenos Aires, Argentina; ⁹Shanghai East Hospital, Shanghai, China; ¹⁰Hematology-Oncology Practice Eppendorf (HOPE) and University Cancer Center Hamburg (UCCH), Hamburg, Germany; ¹¹Bristol Myers Squibb, Princeton, NJ, USA; ¹²Veneto Institute of Oncology IOV-IRCCS, Padua, Italy

Background

• Patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) treated with chemotherapy have poorer outcomes than patients with microsatellite stable/mismatch repair-proficient mCRC¹
• The ESMO 2019 guidelines suggest patients with advanced dMMR tumors may benefit from anti–programmed death (PD)-1 therapy.² The NCCN 2022 guidelines include nivolumab (NIVO) ± ipilimumab (IPI) or pembrolizumab as initial treatments for MSI-H/dMMR mCRC ³
• Pembrolizumab monotherapy is approved in multiple countries as first-line therapy for patients with MSI-H/dMMR mCRC ^4,5; however, despite observed clinical benefit vs chemotherapy, the 24-month progression-free survival (PFS) rate was 48%⁶
• NIVO (anti–PD-1) and IPI (anti–cytotoxic T lymphocyte antigen-4 [CTLA-4]) are immune checkpoint inhibitors with distinct but complementary mechanisms⁷
• NIVO and/or NIVO + IPI are approved in previously treated patients with MSI-H/dMMR mCRC in the United States, European Union, and Japan, based on findings from the phase 2, non-randomized, multicohort CheckMate 142 study^8-10
• Indirect comparisons suggest that NIVO (3 mg/kg) + IPI (1 mg/kg) combination therapy provides improved clinical benefit vs NIVO monotherapy with a favorable benefit-risk profile for previously treated patients with MSI-H/dMMR mCRC ^11,12
  • Investigator-assessed (INV) objective response rate (ORR): 55% vs 31%, respectively; 12-month INV PFS rate: 71% vs 50%; 12-month overall survival (OS) rate: 85% vs 73%
  • Grade 3/4 treatment-related adverse events (TRAEs): 32% vs 20%, respectively; discontinuation due to any-grade TRAEs: 13% vs 7%
• NIVO + IPI also demonstrated robust and durable clinical benefit and was well tolerated for the first-line treatment of MSI-H/dMMR mCRC ¹³
  • INV ORR: 69%; 24-month INV PFS rate: 74%; 24-month OS rate: 79%
  • Grade 3/4 TRAEs: 22%; discontinuation due to any-grade TRAEs: 13%

Polling question 1

Study rationale

• To date, no prospective phase 3 studies have reported results for anti–PD-1 plus anti–CTLA-4 combination therapy vs anti–PD-1/PD-ligand 1 monotherapy or chemotherapy in patients with MSI-H/dMMR mCRC
• Moreover, there are limited data on the comparative efficacy of immunotherapies vs chemotherapy in patients with MSI-H/dMMR mCRC who have not received prior systemic therapy or have received at least 1 prior line of systemic therapy⁶
• CheckMate 8HW (NCT04008030) is a phase 3 study of NIVO + IPI combination therapy vs NIVO monotherapy or chemotherapy in patients with MSI-H/dMMR mCRC

Study objectives

• To compare the efficacy and safety of NIVO + IPI combination therapy vs NIVO monotherapy or chemotherapy in patients with centrally confirmed MSI-H/dMMR mCRC

Study design

• CheckMate 8HW is a randomized, international, multicenter, open-label, phase 3 study in patients with recurrent or metastatic MSI-H/dMMR CRC not amenable to surgery
• Patients across all lines of therapy were eligible; recruitment of patients in the first-line setting is ongoing
• An estimated 831 patients will be randomized to receive NIVO + IPI, NIVO, or investigator’s choice chemotherapy (Figure 1)

Figure 1. Study design

^aPatients with ≥ 2 prior lines are randomized only to the NIVO or NIVO + IPI arms;
^bPatients receiving investigator’s choice chemotherapy are eligible to receive
NIVO + IPI upon progression.
R, randomization.

Enrollment criteria

• Key eligibility criteria are shown in Table 1

Table 1. Key inclusion and exclusion criteria

AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.

Study endpoints

• Study endpoints are shown in Table 2

Table 2. Study endpoints^a

^aAll response and progression events will be evaluated using RECIST, version 1.1;
^bIn patients with centrally confirmed MSI-H/dMMR mCRC.
BICR, blinded independent central review.

Polling question 2

Study sites

• Patients will be enrolled in 23 countries (Figure 2)

Figure 2. Countries with study sites^a

^aStudy sites as of May 23, 2022, per ClinicalTrials.gov.

Study dates

• Estimated primary completion date: August 5, 2025

Acknowledgments

• The patients and families who are making the study possible
• The investigators and clinical study teams
• The senior global trial manager for this study is Janice Kaps-Trotter
• Elvis Cela for study enrollment support
• Robert Neely for diagnostic sciences support
• Bristol Myers Squibb (Princeton, NJ) and Ono Pharmaceutical Company, Ltd. (Osaka, Japan)
• The study is supported by Bristol Myers Squibb
• All authors contributed to and approved the presentation; writing and editorial assistance were provided by Andrew Scott, PharmD, of Parexel, funded by Bristol Myers Squibb

Disclosures

Presented at: ESMO World Congress on Gastrointestinal Cancer (ESMO-GI) 2022, June 29–July 2, Barcelona, Spain.

Contact: http://www.globalbmsmedinfo.com

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The safety and efficacy of investigational agents and/or investigational uses or combinations of agents approved for other indications have not been established and there is no guarantee of health authority approval for the uses being investigated.