Anticipated Cost Savings with Alternate Dosing Schema of Nivolumab/Ipilimumab for the Treatment of Metastatic Melanoma

Dual blockade of programmed death-1 and cytotoxic T lymphocyte antigen-4 with nivolumab and ipilimumab is a standard therapeutic regimen for advanced melanoma.  The dosing regimen of nivolumab 1 mg/kg and ipilimumab 3 mg/kg (NIVO1+IPI3) was established in a phase I dose–escalation study, which reported higher rates of objective response rates of 53% with NIVO1+IPI3 compared to 43% with NIVO3+IPI1, although the study was very small limiting strong conclusions about comparative efficacy.¹ NIVO1+IPI3 was then utilized in the phase 3 CHECKMATE-067 trial, which demonstrated superior clinical efficacy of the dual blockade compared to ipilimumab alone in advanced melanoma patients. The current US Food and Drug Administration (FDA) approved combination regimen for treatment of metastatic melanoma is NIVO1+IPI3.Notably, the combination of NIVO1+IPI3 is known to result in a high rate of adverse events (AEs), with clinically significant immune-mediated AEs estimated as high as 91% in routine clinical practice.^2-4 Subsequently, the CHECKMATE-511 trial, a phase 3b/4 study, demonstrated statistically significantly fewer grade 3-5 AEs among patients with NIVO3+IPI1 (34%) compared to those treated with NIVO1+IPI3 (48%). Additionally, this study found no statistically significant differences in secondary end points of objective response rates or median progression-free survival, although the study was not powered to show noninferiority for these end points.⁵ As such, while NIVO3 + IPI1 is an alternative regimen for advanced melanoma with less associated toxicity, it remains an off-label dosing regimen. 

While nivolumab and ipilimumab has been established as standard therapeutic regimen for advanced melanoma, a drawback of these agents is the financial cost.  Dose-banding is a method of delivering intravenous anticancer treatments in a way that is standardized, optimized, and with reduced cost.⁶  The concept of dose banding was developed in the United Kingdom in the late 1990s and is now established in clinical practice. With dose banding, doses are now within a defined range, usually ±5% of the calculated dose, are rounded to an agreed standard midpoint dose. Dose banding has been proven to be a safe practice with comparable clinical outcomes compared to those of conventional chemotherapy dosing via body surface area.⁶ We performed a modeling study to examine the potential pharmacoeconomic impact of transitioning metastatic melanoma patients at our center from NIVO1+IPI3 to NIVO3+IPI1 dosing using our current institutional dose banding practices.

We analyzed patients with advanced or unresectable melanoma who were seen at the Seattle Cancer Care Alliance between April 2019 to July 2019 and were treated with combination nivolumab and ipilimumab.  Patients who were treated with nivolumab maintenance therapy during the study window following combination therapy prior to the study window were excluded.

Procedures and Outcomes

This was a retrospective analysis approved by the University of Washington Medicine Institutional Review Board. The weight of the patients on the original date of administration of therapy was used to calculate the anticipated dose of the NIVO3+IPI1 and NIVO1+IPI3 regimens.  A dose banding strategy was applied to all doses, which involved rounding the doses down by as much as 10% to minimize next nearest vial size given our institution’s current rounding policy (Table 1). If rounded down, the banded dose would be the dose billed and the dose received by the patient.  This could include rounding down to a dose using a combination of different vial sizes. If the dose could not be rounded down within 10%, it was then rounded up to the next nearest vial size combination as shown in Table 1. This would be the dose billed, as our institution bills for unused medication remaining in vials, but the patient would still receive the ordered dose. Ipilimumab is currently available in 50 mg and 200 mg vials, whereas nivolumab is available in 40 mg, 100 mg, and 240 mg vials.  The doses were multiplied by the average wholesale cost per milligram per Medi-Span ($32.42 per mg of NIVO and $180.03 per mg of IPI).⁷ We then calculated the cost difference of the two different dosing regimens of ipilimumab and nivolumab.  

Statistical Analysis

Descriptive statistics were utilized to analyze the anticipated cost difference and difference in antibody utilization between the two dosing strategies. 

Twenty-one patients received a total of 59 doses of combination ipilimumab and nivolumab in our cohort. The mean weight of the patients was 91 kg and the median weight of the patients was 87 kg (range 49.7-155.5 kg). The modeled pharmaceutical usage and expenditure with universal NIVO1+IPI3 and NIVO3+IPI1 strategies are shown in Table 2. Universal implementation of NIVO1+IPI3 resulted in estimated pharmaceutical expenditure of $3,091,023.66. Universal implementation of NIVO3+IPI1 resulted in estimated expenditure of $1,631,559.42, a savings of $1,459,473 (>$69,000 per patient) or 47.2% compared with NIVO1+IPI3 over the study period.  The average cost per patient in NIVO1+IPI3 group was $52,390 versus $27,653 in the NIVO3+IPI1 group. If a patient were to receive four cycles of either dosing regimen, the average cost per patient in the NIVO1+IPI3 group would be $209,560 versus $110,612 in the NIVO3+IPI1 group.

Our study shows that pharmaceutical expenditure of nivolumab plus ipilimumab regimens in melanoma patients would be significantly decreased with NIVO3+IPI1 compared to the current FDA-approved dosing schema (NIVO1+IPI3). This was anticipated as ipilimumab is considerably more expensive per mg than nivolumab.  The CHECKMATE-511 trial demonstrated that NIVO3+IPI1 has an improved safety profile (lower rates of severe AEs) without a major observed difference in efficacy thus far.⁵ Our study demonstrates that NIVO3+IPI1 also is expected to reduce pharmaceutical costs significantly.  

Limitations

There are a few limitations to our study and this assessment overall. Our study encompassed a relatively small number of patients treated at a single cancer center.  The average weight of our patients is greater than that in other studies examining checkpoint inhibitor dosing strategies for patients with metastatic cancer, which may result in an increase in the anticipated savings than in other patient populations.⁸ Additionally, our dosing strategy took into account health system savings accounting for our institutional practices, which utilizes dose banding.  In the CHECKMATE-511 study, the overall 3-year survival rates were similar between the two dosing regimens. However, this study was not designed to formally demonstrate noninferiority of NIVO3+IPI1 to NIVO1+IPI3 for efficacy end points, so we cannot conclude that these two regimens have similar efficacy.⁵ Of note, in CHECKMATE-511, fewer patients treated with NIVO1 + IPI3 completed the four cycles of combination therapy as compared to NIVO3 +IPI1 due to toxicity.  Early discontinuation of NIVO1+IPI3 could reduce pharmaceutical expenditure compared to a more tolerable regimen. Our study also does not account for other sources of health care spending including medications and hospitalizations, which may be higher in the NIVO1 + IPI3 regimen due to inpatient costs associated with severe adverse events. High rates of hospitalizations were seen in a cohort of 64 patients with melanoma who received NIVO1 +IPI3, in which over one-third of patients were hospitalized for an immune-related AE.⁹ 

Considerations of optimal dosing strategy for nivolumab and ipilimumab are increasingly important as the combination has continued to gain new therapeutic indications over the last decade, including recent approvals for hepatocellular carcinoma (NIVO1+IPI3) and nonsmall cell lung cancer (NIVO 3mg/kg every 3 weeks + IPI 1mg/kg every 6 weeks). There are nearly 300 clinical studies worldwide reported by the US National Library of Medicine that are investigating a combination of ipilimumab and nivolumab, which reinforces the vital importance of understanding the economic implications of various dosing strategies.

Authors: Allison Kupsh, PharmD¹; Laura Alwan, PharmD^1,2; Eve Segal, PharmD^1,2; Kate Trieselmann, PharmD^1,2; Evan Hall, MD^3,4

Affiliations: ¹Department of Pharmacy, University of Washington, Seattle, WA
²Department of Pharmacy, Seattle Cancer Care Alliance, Seattle, WA
³Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
⁴Division of Oncology, Department of Medicine, University of Washington, Seattle, WA

Correspondence: Allison Kupsh, PharmD
Email: akupsh@uw.edu