Frontline Nivolumab Plus Ipilimumab Reduces Symptomatic Burden in MSI-H/dMMR mCRC

The frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of health-related quality of life (HRQOL) deterioration and provided symptom relief compared with chemotherapy in patients with microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC), according to findings from the phase 3 CheckMate 8HW trial (NCT04008030) that were presented at the 2024 ESMO Gastrointestinal Cancers Congress.

Regarding changes in the mixed model for repeated measures (MMRM) from baseline, there was a favorable trend in global health status score improvements with nivolumab/ipilimumab beginning at week 13. In the chemotherapy arm, global health status scores either demonstrated stability or decreased from baseline.

Additionally, differences in global health status score improvements in 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 of (95% CI, 3.6-15.9). Investigators also reported clinically meaningful improvements in global health status with nivolumab/ipilimumab at week 21 (P <.001).

The nivolumab combination conferred improvements in various functions according to the EORTC QLQ-C30 assessment. Least squares mean differences between the nivolumab/ipilimumab and chemotherapy arms included 10.6 for global health status, 7.3 for physical functioning, 12.0 for role functioning, and 9.6 for social functioning. Treatment with nivolumab plus ipilimumab also reduced the severity of symptoms vs chemotherapy based on EORTC QLQ-CR29 assessments, which included least squares means differences of –16.8 for fatigue, –4.3 for nausea and vomiting, and –7.8 for pain.

Overall, the rate of global health status improvements increased with nivolumab plus ipilimumab compared with chemotherapy. Those who received the nivolumab combination had deterioration in global health status less frequently than patients who were treated with chemotherapy.

“In summary, these [HRQOL] results provide further support for the use of first-line nivolumab and ipilimumab in MSI-H/dMMR metastatic CRC,” lead study author Sara Lonardi, MD, from Veneto Institute of Oncology IOV-IRCCS in Padua, Italy, said in the presentation.

In the multicenter, open-label CheckMate 8HW trial, patients were randomly assigned 2:2:1 to one of 3 treatment arms. In the first arm, patients received nivolumab alone at 240 mg every 2 weeks for 6 doses followed by 480 mg every 4 weeks. In the combination arm, 202 patients 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. In the chemotherapy arm, investigators administered 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) to 101 patients.

The trial’s dual primary end points were progression-free survival (PFS) in the nivolumab/ipilimumab arm vs chemotherapy arm across the frontline setting and PFS in the nivolumab/ipilimumab arm vs nivolumab monotherapy arm across all treatment lines. Other secondary end points included safety, overall survival, overall response rate, and HRQOL.

Analyses for HRQOL in the trial were based on patient responses to the EORTC QLQ-C30, EORTC QLQ-CR29, and EQ-5D-3L instruments. The primary period of interest was week 21, with prespecified minimally important changes from baseline and MID between treatment arms. An additional outcome in the HRQOL analysis was time to confirmed deterioration (TTCD), which investigators identified as the time between treatment randomization and the point when worsening changes in scores from baseline matched or surpassed responses.

Patients with histologically confirmed unresectable or metastatic MSI-H/dMMR CRC were eligible for enrollment on the trial. Having an ECOG performance status of 0 or 1 was another requirement for study entry.

Findings from the prespecified interim analysis, which investigators presented at the 2024 Gastrointestinal Cancers Symposium, showed that the median PFS was not reached (95% CI, 38.4 months to not evaluable) with the nivolumab combination vs 5.9 months (95% CI, 4.4-7.8) with chemotherapy (HR, 0.21; 97.91% CI, 0.13-0.35; P <.0001).2 The PFS rates in each respective arm were 79% vs 21% at 12 months and 72% vs 14% at 24 months.

Treatment with nivolumab/ipilimumab reduced the risk of global health status deterioration, although Lonardi noted that the number of events was low in each arm (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).

References

1. Lonardi S, Andre T, Arnold D, et al. Health-related quality of life with first-line nivolumab plus ipilimumab vs chemotherapy in patients with microsatellite instability-high colorectal cancer: CheckMate 8HW. Presented at the 2024 ESMO Gastrointestinal Cancers Annual Congress; June 26-29, 2024; Munich, Germany. Abstract 312.
2. Andre T, Elez E, Van Cutsem E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): first results of the CheckMate 8HW study. J Clin Oncol. 2024;42(suppl 3):LBA768. doi:10.1200/JCO.2024.42.3_suppl.LBA768