Real-World Study of Flip-Dose Ipi/Nivo in Melanoma Shows Survival Benefit

Reversing the standard approved dose levels of nivolumab (Opdivo) and ipilimumab (Yervoy) in metastatic melanoma led to less high-grade toxicity and superior efficacy outcomes, according to a real-world study published in the Journal of the National Cancer Institute.¹

The study, led by researchers at the Karolinska University Hospital and Sahlgrenska University Hospital in Sweden, evaluated the outcomes of nearly 400 patients treated in clinical practice. The NIVO3+IPI1 regimen (3 mg/kg nivolumab plus 1 mg/kg ipilimumab) markedly outperformed the FDA-approved NIVO1+IPI3 regimen (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) across all major clinical end points, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

The Toxicity Challenge in Combination Therapy

Since its approval in 2015, the combination of NIVO1+IPI3 every 3 weeks has been a cornerstone of treatment for advanced melanoma. The combination comes with 62% of patients experiencing grade 3 or 4 immune-related adverse events (irAEs) and 34% discontinuing treatment due to irAEs, particularly during the first 4 cycles, when both ipilimumab and nivolumab are given.²

The randomized phase 3/4 CheckMate 511 trial (NCT02714218) previously investigated NIVO3+IPI1 as an alternative dosing schedule, and investigators found it resulted in significantly fewer grade 3 or higher AEs.³ It also showed similar outcomes between the 2 schedules in terms of efficacy in descriptive analyses, but the study was not designed to measure the noninferiority of the flipped dose. Sweden’s national treatment guidelines approved the use of NIVO3+IPI1 in advanced melanoma in 2019.¹ In the US, it is listed as an alternative dose by the NCCN guidelines when there is concern about the tolerability of 3 mg/kg ipilimumab.⁴ 

Study Design and Findings

The researchers used real-world data to compare 209 patients treated with the NIVO3+IPI1 regimen and 190 patients treated with the standard NIVO1+IPI3 regimen.¹ The patient population included patients at the treatment centers with advanced nonuveal melanoma who started treatment between 2015 to 2023, with the study period ending in February 2025. There were no significant differences in most baseline characteristics, but there was a median age of 63 in the flipped-dose group vs 60 in the standard-dose group. Disease stage also varied, with the flipped-dose group including more patients with early-stage disease as well as with brain metastases.

The ORR was 48.8% for the flipped-dose group vs 36.9% for the standard-dose group (P =.016). Disease control rate was 60.3% vs 45.8%, respectively (P =.004), and complete responses were achieved in 23.0% vs 15.3%, respectively.

The median PFS was 8.9 months for the flipped-dose group vs 2.7 months for the standard-dose group, and the median OS was 42.4 months vs 14.5 months, respectively. After adjusting for baseline age, tumor stage, performance status, number of metastatic sites, and lactate dehydrogenase levels, the flipped regimen maintained superior survival outcomes, with an adjusted HR for progression or death of 0.67 (95% CI, 0.53-0.87; P =.002) and an adjusted HR for death of 0.59 (95% CI; 0.44-0.79; P <.001).

The efficacy benefit was consistent across most subgroups, although the 2 dose groups showed the least difference in PFS and OS in those with stage III, M1a, and M1b disease and those with low central nervous system burden.

Safety as a Driver of Efficacy

The study confirmed that the flipped dose is substantially safer. Grade 3 to 5 irAEs occurred in 30.6% of the NIVO3+IPI1 group compared with 51.1% in the NIVO1+IPI3 group. Discontinuation due to irAEs was needed in 32.1% in the NIVO3+IPI1 group and 36.8% in the NIVO3+IPI1 group, but only 16.7% were due to grade 3 or higher irAEs vs 27.3% in the respective groups. Discontinuation occurred after a median of 3 doses in patients receiving 1 mg/kg ipilimumab vs 2 in those receiving 3 mg/kg.

Notably, 57.4% of patients were able to complete 4 doses of ipilimumab in the NIVO3+IPI1 group vs 33.7% in the NIVO1+IPI3 group, and 45.5% were able to receive at least 3 doses of maintenance nivolumab vs only 27.4% in these respective groups. At least 12 doses of maintenance nivolumab were given in 20.6% vs 13.2%, respectively.

Subsequent therapy was given in 39.2% in the NIVO3+IPI1 group vs 47.4% in the NIVO1+IPI3 group. Treatments included BRAF/MEK inhibitors, rechallenge with immune checkpoint inhibitors, and chemotherapy.

The researchers suggested that the improved efficacy of the lower-dose ipilimumab is a direct result of its improved safety profile allowing patients to stay on treatment longer and receive more doses of nivolumab, which may ultimately drive the superior durability of the regimen.

Implications for Clinical Practice

The findings support the use of the flipped dosage, which is also used as the standard dose in combination in renal cell carcinoma and non–small cell lung cancer, and has been used in several studies of neoadjuvant melanoma. However, the study is limited by its real-world population and the retrospective nature.

“The efficacy differences of the 2 regimes could theoretically have been due to increased clinical experience with [immune checkpoint inhibitors] over time among the healthcare personnel, including improved management of irAEs, potentially leading to better outcomes with the NIVO3+IPI1 that was implemented later,” the investigators acknowledged in their report. They also noted that a real-world population may have worse overall tolerance for serious irAEs and that physicians could choose the standard dose for patients with more aggressive disease.

Although the retrospective methodology is limited, the findings support the signal for improved tolerability already shown in CheckMate 511, and the significant difference in median PFS and OS indicates this dosing schedule can yield long-term durability.

REFERENCES

1. Björkström K, Liu C, Fager A, Liu LL, Ny L, Helgadottir H. Evaluation of the flipped dose NIVO3+IPI1 in patients with advanced unresectable melanoma. J Natl Cancer Inst. Published online December 8, 2025. doi:10.1093/jnci/djaf327

2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836

3. Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: Results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol. 2019;37(11):867-875. doi:10.1200/JCO.18.01998

4. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: cutaneous, version 2.2025. Accessed January 8, 2025. https://tinyurl.com/mu6z9urf