The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a first-line treatment has shown to reduce the risk of health-related quality of life (HRQOL) deterioration and provide symptom relief compared to chemotherapy in patients with microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC). These findings were presented at the 2024 ESMO Gastrointestinal Cancers Congress from the phase 3 CheckMate 8HW trial (NCT04008030).
Improvements in Global Health Status
According to the mixed model for repeated measures (MMRM) analysis, the nivolumab/ipilimumab arm showed a favorable trend in global health status score improvements starting at week 13. In contrast, the chemotherapy arm's global health status scores either remained stable or decreased from baseline. The nivolumab arm surpassed the trial’s prespecified minimally important difference (MID) threshold of 5.0 at week 13, with a least squares mean difference of 9.7 (95% CI, 3.6-15.9). Clinically meaningful improvements in global health status were also reported at week 21 (P < .001).
Enhanced Functioning and Reduced Symptoms
The EORTC QLQ-C30 assessment revealed that the nivolumab combination led to improvements in various functions. The least squares mean differences between the nivolumab/ipilimumab and chemotherapy arms were 10.6 for global health status, 7.3 for physical functioning, 12.0 for role functioning, and 9.6 for social functioning. Furthermore, treatment with nivolumab plus ipilimumab reduced the severity of symptoms compared to chemotherapy, as indicated by EORTC QLQ-CR29 assessments, with least squares means differences of –16.8 for fatigue, –4.3 for nausea and vomiting, and –7.8 for pain.
Reduced Risk of Deterioration
Overall, the rate of global health status improvements increased with nivolumab plus ipilimumab compared to chemotherapy. Patients treated with the nivolumab combination experienced deterioration in global health status less frequently than those treated with chemotherapy (HR, 0.32; 95% CI, 0.18-0.57). The nivolumab combination also lowered the likelihood of deterioration in measures including physical functioning (HR, 0.49; 95% CI, 0.26-0.94), role functioning (HR, 0.50; 95% CI, 0.29-0.87), social functioning (HR, 0.54; 95% CI, 0.28-1.04), and fatigue (HR, 0.50; 95% CI, 0.31-0.80).
Study Design and Patient Population
The CheckMate 8HW trial was a multicenter, open-label study where patients were randomly assigned 2:2:1 to one of three treatment arms. The first arm received nivolumab alone at 240 mg every 2 weeks for 6 doses, followed by 480 mg every 4 weeks. The combination arm included 202 patients who received nivolumab at 240 mg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks. The chemotherapy arm consisted of 101 patients who received modified 5-fluorouracil plus leucovorin and oxaliplatin (mFOLFOX6) or leucovorin calcium plus fluorouracil and irinotecan hydrochloride (FOLFIRI) with or without bevacizumab (Avastin) or cetuximab (Erbitux).
The dual primary end points of the trial were progression-free survival (PFS) in the nivolumab/ipilimumab arm vs the chemotherapy arm and PFS in the nivolumab/ipilimumab arm vs the nivolumab monotherapy arm. Secondary end points included safety, overall survival, overall response rate, and HRQOL. HRQOL analyses were based on patient responses to the EORTC QLQ-C30, EORTC QLQ-CR29, and EQ-5D-3L instruments, with a primary focus on week 21 and prespecified minimally important changes from baseline and MID between treatment arms.
Patients eligible for enrollment had histologically confirmed unresectable or metastatic MSI-H/dMMR CRC and an ECOG performance status of 0 or 1.
Prior Findings
Previous findings from a prespecified interim analysis, presented at the 2024 Gastrointestinal Cancers Symposium, demonstrated that the median PFS was not reached (95% CI, 38.4 months to not evaluable) with the nivolumab combination compared to 5.9 months (95% CI, 4.4-7.8) with chemotherapy (HR, 0.21; 97.91% CI, 0.13-0.35; P < .0001). The PFS rates in each respective arm were 79% vs 21% at 12 months and 72% vs 14% at 24 months.
Dr. Sara Lonardi from Veneto Institute of Oncology IOV-IRCCS in Padua, Italy, the lead study author, summarized that these HRQOL results further support the use of first-line nivolumab and ipilimumab in MSI-H/dMMR metastatic CRC.
