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Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings

Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated... www.nature.com/npjbcancer ARTICLE OPEN Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings 1 2 3 3 4 3,5,6,7 Po-Hung Hsieh , Alec J. Kacew , Marie Dreyer , Anthony V. Serritella , Randall W. Knoebel , Garth W. Strohbehn and 1,3,8 Mark J. Ratain Patients with breast cancer frequently experience financial hardship, often due to the high costs of anti-cancer drugs. We sought to develop alternative trastuzumab dosing strategies, compare their pharmacokinetic effectiveness to standard dosing, and assess the expected financial implications of transitioning to them. We extracted clinical data from the records of 135 retrospectively identified patients with HER2-positive early breast cancer at a single, urban comprehensive cancer center who were treated with trastuzumab between 2017 and 2019. We performed pharmacokinetic simulations on a range of trastuzumab dose levels and frequencies, assessing efficacy by trough trastuzumab concentration (C ) and population and individual likelihoods of C exceeding trough trough trastuzumab minimum effective concentration (MEC). We performed deterministic financial modeling to estimate the treatment- associated financial savings from alternative dosing strategies. Trastuzumab maintenance doses of 4 mg/kg every 3 weeks (Q3W) and 6 mg/kg every 4 weeks (Q4W) had nearly identical probabilities of C being above MEC as standard of care 6 mg/kg every trough 3 weeks. In the primary financial analysis, both trastuzumab 4 mg/kg Q3W and 6 mg/kg Q4W were associated with significant drug- and administration-related out-of-pocket cost savings over the duration of therapy, ranging from $765 (neoadjuvant, Q4W) to $2791 (adjuvant, Q4W). In particular, Q4W trastuzumab increased savings related to lost wages and travel cost avoidance. Low-dose and reduced frequency trastuzumab in appropriately selected patients may significantly reduce total drug utilization and meaningfully reduce patient financial toxicity. Prospective clinical trials evaluating low-dose or reduced-frequency administration of therapeutic monoclonal antibodies are warranted and needed. npj Breast Cancer (2022) 8:32 ; https://doi.org/10.1038/s41523-022-00393-2 INTRODUCTION Further investigation into the extent to which trastuzumab’sdose can be safely reduced is therefore warranted. Invasive breast cancer is the second most common cancer in While HER-2-targeted therapy has proven remarkably successful women, with lifetime incidence of 12% and an estimated 270,000 in treating EBC , its associated financial toxicity is significant. new cases diagnosed in the United States in 2020 . Nearly 55,000 Estimated trastuzumab-related costs in the adjuvant setting alone of these newly diagnosed breast cancers express the human can reach $70,000 per patient, before accounting for lost wages epidermal growth factor receptor 2 (HER2), the majority of which 2 and transportation costs . Patient-experienced financial toxicity are early (i.e., non-metastatic) breast cancers (EBCs) . While the subsequently contributed to health-related quality of life losses, anti-HER2 monoclonal antibody trastuzumab is an evidence-based 14–17 medication adherence issues, and inferior outcomes . Pro- 3,4 treatment in the neoadjuvant, adjuvant, or metastatic settings , blems are particularly acute in the developing world, where, the utilized dose was originally determined in HER2-positive despite, trastuzumab being noted as an essential medicine by the 5,6 metastatic breast cancer and was never optimized for EBC . World Health Organization, limited access leads to excess cancer- Trastuzumab is conventionally administered at a loading dose related mortality . Provided efficacy could be maintained, of 8 mg/kg, followed by maintenance doses of 6 mg/kg every interventional pharmacoeconomic techniques such as lower 3 weeks (Q3W) through the end of therapy. Corresponding C min doses, reduced frequency, or shorter durations may reduce harms (trough) and C (peak) concentrations associated with the FDA- max related to monoclonal antibodies and improve their value labeled Q3W regimen are 47 µg/mL and 179 µg/mL, respectively . 19,20 proposition . However, a trastuzumab concentration of ≥10–20 µg/mL appears Pharmacokinetic modeling and simulation are increasingly used sufficient to achieve antibody-dependent cell-mediated cytotoxi- to propose new drug dosing regimens and, in some cases, obtain 21,22 city, inhibition of cell proliferation in vitro, and suppression of changes to FDA labeling . Model-derived alternative dosing 7–11 tumor growth in xenograft murine model . Moreover, in the regimens can also be used to reduce the clinical and financial metastatic setting, no differences in progression-free survival toxicities patients experience with their treatment—the intent in (PFS) or overall survival (OS) have been identified between this paper. Leveraging previously published population pharma- 23,24 patients with HER2-positive breast cancer who received weight- cokinetic models for trastuzumab , we performed in silico based trastuzumab Q3W or fixed doses every 4 weeks (Q4W) . pharmacokinetic simulations with conventional or alternative 1 2 Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA. Pritzker School of Medicine, The University of Chicago, Chicago, IL, 3 4 5 USA. Department of Medicine, The University of Chicago, Chicago, IL, USA. Department of Pharmacy, University of Chicago Medicine, Chicago, IL, USA. VA Center for Clinical 6 7 Management and Research, Ann Arbor, MI, USA. VA Ann Arbor Medical Oncology, Ann Arbor, MI, USA. Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA. email: gstrohbe@umich.edu; mjr1@uchicago.edu Published in partnership with the Breast Cancer Research Foundation 1234567890():,; P.-H. Hsieh et al. dosing regimens of trastuzumab in an institutional population of Model-predicted pharmacokinetics of trastuzumab HER2-positive EBC patients. We hypothesized that the trastuzu- Median trough values predicted by pharmacokinetic simulation are mab dosing paradigm could be modified so as to enhance summarized in Fig. 1 and Supplementary Table 2. Median trough of trastuzumab’s value proposition to HER2-positive EBC patients, the entire study population, as predicted by pharmacokinetic payers, and health systems by limiting the out-of-pocket (OOP) simulation, was 49 µg/mL (5th–95th percentiles, 23–63 µg/mL). The costs patients experience and potentially reducing drug-related simulated median trough for the neoadjuvant and adjuvant adverse events , while maintaining sufficiently high, efficacious patients were 55 and 49 µg/mL, respectively. Reference data from therapeutic trough concentrations. manufacturer applications are also included in Supplementary Table 2. Overall, our patient dataset carries similar profiles as the patient population in the manufacturer’s clinical trial. We evaluated, at the level of the individual patient, the likelihood of trough values being maintained above the minimum RESULTS effective concentration (Fig. 1). Patients in the neoadjuvant and Patient population adjuvant settings had similar trough ranges of 36–64 µg/mL and We identified 196 eligible patients with breast cancer treated with 32–62 µg/mL, respectively, corresponding to 5th–95th percentiles. trastuzumab or trastuzumab-anns over the 34-month study period (Supplementary Table 2). With conventional dosing, all EBC (Table 1). Patients received trastuzumab or biosimilar as single patients maintained a trough above minimum effective concen- HER-2 inhibiting agent (n = 60) or in combination with pertuzu- tration (10 µg/mL). We therefore derived alternative trastuzumab mab (n = 109). Concurrent chemotherapy was employed in 56% dosing strategies in pharmacokinetic simulations of EBC patients. (n = 75) of the study population’s regimens, specifically 90% (n = 67) in the neoadjuvant setting and 13% (n = 8) in the adjuvant Alternative dosing regimens for EBC patients setting. Most common concurrent chemotherapy regimens in the Development of less frequent dosing regimens. Additional pharma- neoadjuvant setting included paclitaxel/trastuzumab (54%, n = cokinetic simulations were conducted for EBC patients using the 40), carboplatin/docetaxel/trastuzumab (27%, n = 20), and doc- 8 mg/kg loading dose followed by 6 mg/kg Q4W. Under this etaxel/trastuzumab (8%, n = 6). The most common concurrent condition, the vast majority of EBC patients maintained a simulated chemotherapy regimen in the adjuvant setting was carboplatin/ trough ≥10 µg/mL (Fig. 2a, b, Supplementary Table 3). Greater than docetaxel/trastuzumab (8%, n = 5) (Table 1). two-thirds of patients receiving neoadjuvant or adjuvant 6 mg/kg Q4W maintained trough values ≥20 µg/mL (Fig. 2a, b, Supplementary Table 3). We also evaluated regimens in which the Q4W schedule was not implemented until the second or third maintenance dose for Table 1. Patient clinical and laboratory characteristics (median and EBC patients, as these scenarios would be predicted to have a lower interquartile range). risk of pharmacokinetic failure (Supplementary Table 3). Neoadjuvant Adjuvant EBC*, all n = 74 n = 61 patients Development of lower-dose regimens. Following an 8 mg/kg n = 135 loading dose, a range of alternative maintenance doses were evaluated for EBC patients administered using a Q3W schedule: 3, Therapy 3.5, 4, 4.5, 5, and 6 mg/kg. Nearly all EBC patients maintained a Trastuzumab only 753 60 trough ≥10 µg/mL at doses of 3.5–6 mg/kg (Fig. 2c–h, Supple- Chemotherapy + 67 8 75 mentary Table 4). Furthermore, the majority of patients main- Trastuzumab tained a trough ≥20 µg/mL with a maintenance dose of 4 mg/kg. TH 40 3 43 On the other hand, the maintenance dose of 3 mg/kg led to subtherapeutic drug levels in many patients. TCH 20 5 25 DH 606 Determinants of trough less than target concentration CH 101 EBC patients receiving trastuzumab using extended interval or lower- CTH 000 dose dosing regimens who had any simulated trough concentrations Eribulin- 000 <10 µg/mL were evaluated in further detail. The single greatest Trastuzumab driver in these cases was serum albumin concentration <3 g/dL Gemcitabine- 000 (Supplementary Table 5). Body weight <62 kg (23% of neoadjuvant Trastuzumab patients, 28% of adjuvant patient), albumin concentration <4 g/dL Vinorelbine- 000 (20% of neoadjuvant patients, 36% of adjuvant patients), and AST ≥ Trastuzumab 30 IU/L (8% of neoadjuvant patients, 18% of adjuvant patients) were Vinorelbine- 000 each associated with simulated trough concentration <20 µg/mL Trastuzumab- (Supplementary Fig. 2, Supplementary Table 6). Utomulumab Body weight (kg) 73.2 (63.6–87.3) 71.2 (60.9–84.8) 72.2 (61.2–86.3) Drug- and administration-related patient-experienced AST (IU/L) 19 (15–23) 22 (17–27) 20 (16–25) financial toxicity with trastuzumab Albumin (g/dL) 4.2 (4.0–4.3) 4.1 (3.9–4.2) 4.1 (3.9–4.3) Primary analysis. Estimated drug- and administration-related cost- *EBC refers to ‘early breast cancer’, marked by patients receiving sharing payments associated with 6 mg/kg trastuzumab adminis- trastuzumab in the neoadjuvant or adjuvant settings. For simplicity, tered Q3W were $3928 (neoadjuvant, n= 73) and $9379 (adjuvant, patients who received pertuzumab as part of their chemotherapy + n= 60) under non-waste- billing conditions. Drug- and trastuzumab regimen are not separated out from patients who received administration-related savings associated with 6 mg/kg Q4W as a trastuzumab as the sole HER-2-targeting agent in their regimen. percentage of total costs were 14% (neoadjuvant) and 21% TH paclitaxel+ trastuzumab, TCH docetaxel + carboplatin + trastuzumab, (adjuvant). Drug- and administration-related savings associated with DH docetaxel + trastuzumab, CH carboplatin + trastuzumab, CTH carbopla- 4 mg/kg Q3W were 15% (neoadjuvant) and 20% (adjuvant) (Table 2). tin + paclitaxel + trastuzumab. Accounting for savings due to travel cost and wage loss avoidance, npj Breast Cancer (2022) 32 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; P.-H. Hsieh et al. Fig. 1 Simulated concentration-time profiles for all HER2-positive early breast cancer patients receiving trastuzumab every 3 weeks. Simulated concentration-time profiles for patients receiving trastuzumab on a q3w schedule in the a neoadjuvant or b adjuvant. The solid red line indicates median concentration, and the red shaded region represents the 95% CI. Upper dashed line represents concentration = 20 µg/mL. Lower dashed line represents target concentration = 10 µg/mL. 6 mg/kg Q4W trastuzumab administration in the adjuvant setting sufficiently high trastuzumab concentrations were almost universally was associated with savings of 21% in the of treatment (Table 2). observed. On the basis of these data, appears to be feasible in nearly Drug- and administration-related cost savings were generally greater all patients with HER2-positive EBC, but especially those without under Q3W dosing than under Q4W dosing (Supplementary Table 7). medical comorbidities. The financial implications of trastuzumab de- intensification, especially for patients, are especially salient. Esti- Sensitivity analyses. Utilization of single-use vials alongside non- mated OOP savings with reduced frequency trastuzumab were waste billing practices was associated with greater patient- especially notable in the neoadjuvant setting, reaching nearly $1500 experienced expense and absolute savings than multi-use vials per treatment course. In the United States, associated trastuzumab- and non-waste billing practices (Supplementary Table 8). How- related savings in EBC alone are estimated to exceed $700 M USD. ever, the magnitude of this effect was absent in the 4 mg/kg Q3W Our absolute financial toxicity estimates are in line with prior condition and was small (<$200 savings over the entire course of analyses of real-world data. For individuals diagnosed with breast therapy) in the 6 mg/kg Q4W condition when compared to multi- cancer in 2008–2012, median drug-related OOP costs for use vials. Under conditions of concomitant use of single-use vials trastuzumab-containing regimens was $3381 in the first 18 months and waste billing practices, use of 4 mg/kg Q3W or 6 mg/kg Q4W of therapy . This is similar to our $3927.76 estimate that includes was associated with increased savings in the time-limited both drug- and drug administration-related costs in the neoadjuvant neoadjuvant setting and approximately equal savings in the setting (Q3W, 6 mg/kg, non-waste billing). Estimates for the OOP adjuvant setting, relative to multi-use vials alongside non-waste costs associated with the adjuvant setting are higher due to longer billing (Supplementary Table 8). Waste billing itself is associated durations of therapy and continued trastuzumab price increases. with a greater patient OOP financial liability. Estimates of total EBC trastuzumab-related expenditures in the U.S. (~$3.24B USD) are to a first approximation in line with expectations, U.S. health system cost savings given the approximate U.S. share of the global breast cancer Of the ~50,000 new cases of HER2-positive breast cancer diagnosed therapeutics market, HER2+ EBC epidemiology, and global sales in the United States each year, 85% are expected to receive figures for Herceptin® (trastuzumab), totaling ~$6B USD in 2019 . trastuzumab as part of treatment in the neoadjuvant or adjuvant Further dose reductions may be feasible with the incorporation settings for a median of 12 months total. In the base case, assuming of therapeutic drug monitoring, with dose adjustment based on conventional 8 mg/kg loading dose, 6 mg/kg every 3 weeks dosing, prior trough concentrations. Given that the manufacturer has and patient weight of 75 kg, an estimated 350,625 grams of stated the minimum target trough concentration is 10–20 µg/mL, trastuzumab are provisioned in the U.S.onanannualbasis.Resulting we suggest that therapeutic drug monitoring can provide annual expected trastuzumab expenditures total $3.24B USD. assurance that the trough concentration is acceptable, as well as Universal application of alternative dosing strategies was associated facilitating even lower doses (or longer treatment intervals) in with marked reductions in total drug unit use and associated savings. select patients. EBC patients with normal albumin and hepatic Assuming conventional 8 mg/kg loading dose, 4 mg/kg Q3W function may be the best candidates for such lower doses. maintenance dosing, and patient weight of 75 kg, an estimated Furthermore, patients with obesity have decreased clearance 242,250 grams of trastuzumab are provisioned in the U.S. on an (normalized to body weight), and thus higher exposure. annual basis, with associated expenditures totaling $2.24B USD De-intensification of trastuzumab in HER2-positive breast cancer remains an area of intense interest . Recently published rando- ($1.00B savings from base case). Substituting 6 mg/kg Q4W main- tenance dosing results in ~274,125 g of trastuzumab used annually, mized controlled trials demonstrate the non-inferiority of 6 months of adjuvant trastuzumab compared to 12 months, with the added with associated expenditures of $2.53B USD (~$707 M USD savings). benefit of lower rates of cardiotoxicity and, we surmise, lower total costs . Similarly, a new paradigm of near-equivalence is emerging, DISCUSSION aiming to increase treatment access to the greatest number of Our analyses demonstrate the potential to safely de-intensify patients and reduce financial toxicity, with minimal impact on treatment with trastuzumab and its biosimilars (relative to the efficacy . Clinical trial data will likely prove necessary to increase labeled doses), perhaps reducing total drug units used by as much uptake of low-dose trastuzumab. Recently developed multivariable as 50%. Despite reductions in either maintenance dose frequency prognostic indices may help identify patients who are at low risk from Q3W to Q4W or maintenance dose from 6 to 4 mg/kg, for de-intensification-related adverse outcomes . Using such Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 32 P.-H. Hsieh et al. Fig. 2 Simulated concentration-time profile for early HER2-positive breast cancer patients receiving interventional pharmacoeconomic dosing of trastuzumab. Less frequently every 4 weeks (Q4W) dosing schedule in the a neoadjuvant and b adjuvant settings. Every 3 weeks (Q3W) schedule in the c neoadjuvant setting with maintenance dose 4.5 mg/kg, d adjuvant setting with maintenance dose 4.5 mg/kg, e neoadjuvant setting with maintenance dose 4 mg/kg, f adjuvant setting with maintenance dose 4 mg/kg, g neoadjuvant setting with maintenance dose 3.5 mg/kg, and h adjuvant setting with maintenance dose 3.5 mg/kg. In all panels, the solid red line indicates median concentration, and the red shaded region represents 95% CI of the data. Upper dashed line represents concentration = 20 µg/mL. Lower dashed line represents target concentration = 10 µg/mL. models may lower a de-intensification clinical trial’s aggregate risk demonstrate their potential financial upside (through the and improve its palatability to patients and physicians. avoidance of non-drug-related OOP costs), patients may be While oncology awaits a political solution to the ongoing drug hesitant to adopt de-escalated dosing. Prospective clinical trial pricing crisis, interventional pharmacoeconomic dosing may be data will likely be useful in overcoming any gaps in ambiguity, a useful strategy in reducing patient-experienced financial and regardless of their presence it may be justifiable to toxicity without sacrificing efficacy . In the United States, the compensate patients for any theoretical increase in risk under approach may help offset drug cost-related risks that are an inclusive shared savings framework . otherwise transferred from insurers to providers in conventional Notcapturedin thisanalysisare thepotential benefits of reducing bundled payment arrangements . In both developed and strain on health systems with capacity limitations, whether in the developing economies, interventional pharmacoeconomic dos- developed or developing world. Delayed initiation of adjuvant ing may help overcome drug supply limitations while also trastuzumab is associated with inferior outcomes . To the extent improving a drug’s value . Interventional pharmacoeconomic that treatment delays are attributable to over-stressed systems dosing can build upon other advances that have improved administering drug more frequently than the minimum frequency convenience, drug toxicity, and financial toxicity in recent years needed to achieve maximal benefit, less frequent dosing may (e.g., biosimilar entry, subcutaneous formulation, shorter adju- improve outcomes. In resource-limited settings such as some low- 31–35 vant therapy duration) . Though the financial analyses and middle-income countries, low-dose trastuzumab and other npj Breast Cancer (2022) 32 Published in partnership with the Breast Cancer Research Foundation P.-H. Hsieh et al. Patients with incomplete records of trastuzumab administration or any Table 2. Per-patient Savings for reduced-frequency trastuzumab trastuzumab administrations at outside institutions were excluded from compared to current standard-of-care dosing (Q3W, 6 mg/kg). the study. We reviewed electronic health records for: Disease and regimen characteristics for each patient in each treatment setting (neoadjuvant or Q4W 6 mg/kg Q3W 4 mg/kg adjuvant), date of first trastuzumab dose, other drugs included in the regimen (e.g., pertuzumab, cytotoxic agents), dose frequency, as well as Neoadjuvant $765 (14%) $829 (15%) date and cycle of the last dose (if regimen had been completed) or missed Adjuvant $2791 (21%) $2611 (20%) doses. Body weight, aspartate aminotransferase (AST), cancer antigen 15–3 (CA 15–3), albumin as of the day of first trastuzumab dose were collected. All savings are presented as the discount from the standard of care In cases in which laboratory values were not available for the day of the maintenance trastuzumab 6 mg/kg every 3 weeks for a given clinical first trastuzumab dose, we used the most recent available laboratory value scenario and dose (column). Values are savings versus baseline for the prior to the first trastuzumab dose. comparable clinical setting. Estimates include drug-, administration-, and travel-related cost savings and wage loss avoidance; estimates assume no- waste billing and multi-use vials. Pharmacokinetic modeling of trastuzumab Q3W every 3 weeks, Q4W every 4 weeks. Trastuzumab data were simulated using WinNonlin and NLME with Phoenix Version 8.3 (Certara USA, Inc.). We used a published two- compartment population pharmacokinetic model with parallel linear and interventional pharmacoeconomic techniques could prove particu- nonlinear elimination that included the following covariates: body weight (in kg), AST, and albumin . An R Software package (Version 4.0, http:// larly useful in enhancing access and reducing financial toxicity, 38–40 www.r-project.org/) was used for data assembly, exploratory data analysis, similar to low-dose abiraterone in prostate cancer ,aswell as 18 model diagnosis, and simulation. potentially averting unnecessary deaths . Notably missing in our analyses are the ~7500 people newly Pharmacokinetic simulations of alternative dosing strategies diagnosed with HER2-positive metastatic breast cancer each year in EBC in the U.S. Although the number of people with metastatic disease is smaller than the number with EBC, individuals with metastatic We first simulated the standard trastuzumab regimen: 8 mg/kg loading dose followedby6mg/kgmaintenance dose Q3WinpatientswithEBC. Wethen disease can remain on HER2-targeting therapy for much longer simulated 10 alternative maintenance dosing regimens, a combination of periods of time. Longer treatment courses in the metastatic alternative frequencies (Q3W or Q4W) and doses (3, 3.5, 4, 4.5, 5, and 6 mg/ setting imply not only higher per-patient cost, but also higher per- kg). We also evaluated regimens in which the alternative dose or schedule patient burden of time and travel. The derived dosing strategies was implemented with the second (and all subsequent) or third (and all may not apply to many patients in the metastatic setting, owing to subsequent) maintenance dose. Pharmacokinetic simulations were performed increased drug clearance. to 36 weeks to capture 100% steady state. We evaluated schedules based on This study is not without limitations. First, the pharmacokinetic their achievement of steady-state concentrations of at least 10 µg/mL, in simulations undergirding the proffered dosing schedules were accordance with previously published data, as well as the higher threshold of 7,8,41 derived from patients at a single urban academic medical center; 20 µg/mL . Alternative dosing strategies that consistently demonstrated trough concentrations greater than the minimum effective concentration thus, the study population may not reflect the makeup of the were then pursued in financial modeling studies. entire population of HER2-positive EBC patients receiving trastuzumab. Second, the point estimates of expected savings in this paper may have been different had probabilistic modeling Statistical analysis techniques been utilized. Third, the point estimates of expected The mean, median, standard deviation, 95% confidence interval, and individual-level savings were derived under an assumption of percentiles of simulated trastuzumab plasma concentrations were traditional Medicare coverage; patients may have commercial calculated using Phoenix Version 8.3 (Certara USA, Inc.) and R Software insurance or supplemental co-insurance that limits their OOP package (Version 4.0, http://www.r-project.org/). liability. Given the emergence of trastuzumab biosimilars, the estimates of health systems savings are likely to be artificially Deterministic financial modeling: individual out-of-pocket and high in absolute terms, though accurate in relative terms. Fourth, nationwide cost estimates we assumed that patients receiving combination treatment We estimate OOP costs using deterministic financial modeling under could receive both trastuzumab and cytotoxic chemotherapy at varying dosing, patient, treatment setting, and billing conditions. Main- the same frequency as trastuzumab (including Q4W instead of tenance trastuzumab was administered in silico to each of the patients Q3W in some cases); the major driver of cost in these cases, identified in the above dataset using one of three dosing cases: 6 mg/kg however, is the long trastuzumab-only interval. Finally, with the Q3W (standard of care), 6 mg/kg Q4W, or 4 mg/kg Q3W. The latter two were chosen for their abilities to maintain steady-state concentrations advent of subcutaneous trastuzumab, further study will be greater than the minimum effective concentration in the previously needed to assess whether de-intensification of this method of conducted pharmacokinetic simulation studies. Patients receiving trastu- administration is possible. zumab in the neoadjuvant and adjuvant settings received the simulated Altogether, this study demonstrates a roadmap toward de- therapy. We used the actual (i.e., not theoretical or estimated) durations of intensification and waste prevention, not only of trastuzumab in therapy for the individuals in our cohort to perform our calculations; each the treatment of HER2-positive EBC but also, more generally, individual serves as her own comparator in the analyses. therapeutic monoclonal antibodies in cancer. Adaptive dose or We derived model inputs from publicly available information: We 42 43 44 45 frequency de-escalation trials or randomized, controlled dose- estimated lost wages , travel distance , mileage rates , parking costs , 46,47 optimization trials with both clinical and pharmacokinetic out- trastuzumab price, and reimbursement , and drug infusion costs 48,49 (Supplementary Table 1) . We considered the lost wages of both the comes exploring the use of maintenance low-dose trastuzumab patient and a patient caregiver. Patient travel distance, defined as the are warranted, as are further pharmacokinetic studies aimed at de- distance between the patient’s home address and the main address of intensifying monoclonal antibody dosing practices. the University of Chicago Medicine (UCM), was estimated using the first available search result on GoogleMaps (Alphabet, Inc., Mountain View, CA, USA). Tolls were excluded in mapping preferences. Point estimates of each METHODS patient’s expected OOP drug-related financial liability was estimated using Patients a Medicare Part B cost-sharing framework; supplemental co-payment We retrospectively identified all individuals who had received treatment insurances were not considered in this analysis. Two billing methods are for HER2-positive EBC with trastuzumab or biosimilars at the University of used predominantly: non-waste billing and waste billing. Under waste Chicago Medicine (UCM) between January 1, 2017 and October 31, 2019. billing provisions, wasted drug is billed to Medicare and is therefore Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 32 P.-H. Hsieh et al. 52,53 eligible for cost-sharing by the patient. Under non-waste billing, wasted average sales price (ASP) . We considered the population of individuals drug is not billed to Medicare and is therefore not eligible for cost-sharing with HER2-positive EBC and estimated median treatment duration by by the patient . Under non-waste billing in which single-use vials are setting (neoadjuvant and adjuvant), under the assumption that treatment used, the amount of drug is rounded to the nearest measurable dose and/ is discontinued at the completion of evidence-based time-limited 52,54 or package size, within 10% (e.g., 768.4 mg is rounded down to 750 mg), treatment . We used Medicare ASP data to estimate the total societal and Medicare is billed for the rounded amount of drug administered spend associated with this group of patients . (750 mg, corresponding to 75 × 10 mg billing units). In the above case, the Certain assumptions are necessary. We assumed a treatment duration in drug was able to be rounded to the nearest 150 mg vial size (within 10% of the early-stage setting of 12 months. While data from a large, well- target dose), avoiding 132 mg of wasted trastuzumab. If the medication conducted randomized, controlled trial demonstrates the non-inferiority of dose cannot be rounded within 10% to the nearest vial size (e.g., a dose of 6 months of adjuvant treatment , cancer treatment guidelines in the U.S. 530 mg), the excess drug (70 mg in the case above) is wasted; Medicare is continue to advocate for 12 months of adjuvant anti-HER2 treatment .As not billed for the waste . For the purposes of generating cost estimates commonly administered, this corresponds to 1 cycle of 8 mg/kg and a subsequent 16 cycles of 6 mg/kg every 3 weeks. Total spend under these associated with low-dose trastuzumab under the no-waste billing/single- conditions represents the baseline scenario. Under alternative dosing use vial condition, the 10% tolerance allowed for the FDA-labeled dose was regiments, the total number of drug units utilized is decreased, though not applied. Multi-use vials can be utilized alongside no-waste billing. In the number of cycles may not be. Using 4 mg/kg every 3 weeks this case, the dose is rounded to the nearest 10 mg dosing unit. maintenance dosing, the expected numbers of maintenance cycles remain Calculations for cost estimates were as follows: the same as above (16 cycles in neoadjuvant/adjuvant setting). Using 6 mg/ Total Out-Of -Pocket Costs kg every 4 weeks maintenance dosing, the expected numbers of ¼ðÞ Drug cost sharing maintenance cycles are less (13 cycles in neoadjuvant/adjuvant setting). We used Medicare ASP data to estimate the total societal spend associated þðÞ Administration cost sharing with this group of patients . Contracted prices for our institution are not þðÞ Travel costsþðÞ Lost wages per visit made publicly available; ASP captures drug price net of the majority of rebates and discounts. No-waste billing; single-use vial Drug Cost Sharing Calculations for cost estimates were as follows: ¼ðÞ Number of doses Total Spend ´ ðNumber of milligrams of trastuzumab per dose per visit; ¼ ½½ðÞ Number of Newly Diagnosed Breast Cancer Cases if possible rounded to nearest whole number of vials within 10%Þ ´ðÞ % of Cases HER2-Positive ´ðÞ % of HER2-Positive Cases Early-Stage ´ðÞ 1 billing unit=10 milligrams trastuzumab ´ðÞ 8mg=kg  weight þ Maintenance dose  weight  number of treatments= ðÞ 10 mg per dosing unit ´ðÞ Medicare reimbursement per billing unit ´ðÞ Average Sales Price per 10 mg Dosing Unit ´ðÞ Medicare patient cost sharing% Savings ¼ Baseline scenario expenditures Standard billing; single-use vial Drug Cost Sharing Alternative dosing scenario expenditures ¼ðÞ Number of doses ´ðÞ Rounded number of vials per dose per visit ´ðÞ Medicare reimbursement per vial ´ðÞ Medicare patient cost sharing% Reporting summary Multi-use vial Drug Cost Sharing Further information on research design is available in the Nature Research Reporting Summary linked to this article. ¼ðÞ Number of doses ´ ðNumber of milligrams of trastuzumab per dose per visit; rounded to nearest unitÞ DATA AVAILABILITY ´ðÞ 1 billing unit=10 milligrams trastuzumab The datasets generated and analyzed during the current study are not publicly available due to their containing individually identifiable information. A redacted ´ðÞ Medicare reimbursement per billing unit dataset is available from the corresponding author on reasonable request. ´ðÞ Medicare patient cost sharing % Administration Cost Sharing CODE AVAILABILITY ¼ðÞ Medicare patient cost sharing % Relevant code and spreadsheet formulae for population pharmacokinetic and ´ðÞ Time for infusion appointment financial analyses are available from the authors. ´ðÞ Medicare reimbursement per unit time Received: 30 March 2021; Accepted: 2 February 2022; Travel Costs ¼ðNumber of visitsÞ ´ ½Parking cost per visit þðRound-trip miles traveledÞ ´ ðIRS reimbursement per mile for medical purposesÞ Lost Wages ¼ðNumber of visitsÞ ´ ðLost wages per visitÞ ´ 2 REFERENCES 1. 2020 American Cancer Society. Breast cancer facts. https://www.cancer.org/ In the primary analysis, we estimated OOP costs assuming that research/cancer-facts-statistics/breast-cancer-facts-figures.html (2020). trastuzumab would be administered to a patient who works outside the 2. 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JAMA 321, 288–300 mother. Pharm. 77,77–88 (2016). (2019). 24. Quartino, A. L. et al. Population pharmacokinetic and covariate analyses of intrave- 53. Services, C. f. M. a. M. Medicare Part B Drug Spending Dashboard, https://www.cms. nous trastuzumab (Herceptin((R))), a HER2-targeted monoclonal antibody, in patients gov/research-statistics-data-and-systems/statistics-trends-and-reports/ with a variety of solid tumors. Cancer Chemother. Pharm. 83,329–340 (2019). information-on-prescription-drugs/medicarepartb (2020). 25. Earl, H. M. et al. 6 versus 12 months of adjuvant trastuzumab for HER2-positive 54. Pondé, N., Gelber, R. D. & Piccart, M. PERSEPHONE: are we ready to de-escalate early breast cancer (PERSEPHONE): 4-year disease-free survival results of a ran- adjuvant trastuzumab for HER2-positive breast cancer? NPJ Breast Cancer 5, 1 (2019). domised phase 3 non-inferiority trial. Lancet 393, 2599–2612 (2019). 55. Network, N. C. C. Breast Cancer (Version 3.2019), https://www.nccn.org/ 26. Giordano, S. H. et al. Estimating regimen-specific costs of chemotherapy for professionals/physician_gls/pdf/breast.pdf (2019). breast. Cancer. 122, 3447–3455 (2016). 27. Wilcock, P. & Webster, R. M. The breast cancer drug market. Nat. Rev. Drug Disco. 20, 339–340 (2021). ACKNOWLEDGEMENTS 28. Tannock, I. F. et al. Near-equivalence: generating evidence to support alternative The authors thank Dr. Ling Wang for programming assistance and Ana Henry for cost-effective treatments. J. Clin. Oncol. JCO2002768, https://doi.org/10.1200/ Phoenix software assistance and Dr. Rita Nanda of the University of Chicago Medicine JCO.20.02768 (2021). for helpful discussion. 29. Prat, A. et al. A multivariable prognostic score to guide systemic therapy in early- stage HER2-positive breast cancer: a retrospective study with an external eva- luation. Lancet Oncol. 21, 1455–1464 (2020). AUTHOR CONTRIBUTIONS 30. Polite, B. et al. A pathway through the bundle jungle. J. Oncol. Pr. 12,504–509 (2016). Concept and design: P.H., A.J.K., G.W.S., and M.J.R. Acquisition, analysis, or 31. Farolfi, A. et al. Resource utilization and cost saving analysis of subcutaneous interpretation of data: All authors. Drafting of the manuscript: P.H., A.J.K., G.W.S., versus intravenous trastuzumab in early breast cancer patients. Oncotarget 8, and M.J.R. Critical revision of the manuscript for important intellectual content: All 81343–81349 (2017). authors. Statistical analysis: P.H., A.J.K., G.W.S., and M.J.R. Supervision: G.W.S. and M.J.R. 32. O’Brien, G. L. et al. Cost minimization analysis of intravenous or subcutaneous trastuzumab treatment in patients with HER2-positive breast cancer in Ireland. Clin. Breast Cancer 19, e440–e451 (2019). COMPETING INTERESTS 33. Rojas, L. et al. Cost-minimization analysis of subcutaneous versus intravenous trastuzumab administration in Chilean patients with HER2-positive early breast This work was funded by Clinical Therapeutics Training Grant (T32GM007019) (P.H.) cancer. PLoS ONE 15, e0227961 (2020). and Richard and Debra Gonzalez Fellowship (G.W.S.). G.W.S. is an employee of the Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 32 P.-H. Hsieh et al. United States Federal Government; the views expressed in this article are those of the Reprints and permission information is available at http://www.nature.com/ authors alone and do not necessarily represent those of the United States Federal reprints Government. G.W.S. and M.J.R. serve in uncompensated Director roles for the Optimal Cancer Care Alliance. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings

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www.nature.com/npjbcancer ARTICLE OPEN Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings 1 2 3 3 4 3,5,6,7 Po-Hung Hsieh , Alec J. Kacew , Marie Dreyer , Anthony V. Serritella , Randall W. Knoebel , Garth W. Strohbehn and 1,3,8 Mark J. Ratain Patients with breast cancer frequently experience financial hardship, often due to the high costs of anti-cancer drugs. We sought to develop alternative trastuzumab dosing strategies, compare their pharmacokinetic effectiveness to standard dosing, and assess the expected financial implications of transitioning to them. We extracted clinical data from the records of 135 retrospectively identified patients with HER2-positive early breast cancer at a single, urban comprehensive cancer center who were treated with trastuzumab between 2017 and 2019. We performed pharmacokinetic simulations on a range of trastuzumab dose levels and frequencies, assessing efficacy by trough trastuzumab concentration (C ) and population and individual likelihoods of C exceeding trough trough trastuzumab minimum effective concentration (MEC). We performed deterministic financial modeling to estimate the treatment- associated financial savings from alternative dosing strategies. Trastuzumab maintenance doses of 4 mg/kg every 3 weeks (Q3W) and 6 mg/kg every 4 weeks (Q4W) had nearly identical probabilities of C being above MEC as standard of care 6 mg/kg every trough 3 weeks. In the primary financial analysis, both trastuzumab 4 mg/kg Q3W and 6 mg/kg Q4W were associated with significant drug- and administration-related out-of-pocket cost savings over the duration of therapy, ranging from $765 (neoadjuvant, Q4W) to $2791 (adjuvant, Q4W). In particular, Q4W trastuzumab increased savings related to lost wages and travel cost avoidance. Low-dose and reduced frequency trastuzumab in appropriately selected patients may significantly reduce total drug utilization and meaningfully reduce patient financial toxicity. Prospective clinical trials evaluating low-dose or reduced-frequency administration of therapeutic monoclonal antibodies are warranted and needed. npj Breast Cancer (2022) 8:32 ; https://doi.org/10.1038/s41523-022-00393-2 INTRODUCTION Further investigation into the extent to which trastuzumab’sdose can be safely reduced is therefore warranted. Invasive breast cancer is the second most common cancer in While HER-2-targeted therapy has proven remarkably successful women, with lifetime incidence of 12% and an estimated 270,000 in treating EBC , its associated financial toxicity is significant. new cases diagnosed in the United States in 2020 . Nearly 55,000 Estimated trastuzumab-related costs in the adjuvant setting alone of these newly diagnosed breast cancers express the human can reach $70,000 per patient, before accounting for lost wages epidermal growth factor receptor 2 (HER2), the majority of which 2 and transportation costs . Patient-experienced financial toxicity are early (i.e., non-metastatic) breast cancers (EBCs) . While the subsequently contributed to health-related quality of life losses, anti-HER2 monoclonal antibody trastuzumab is an evidence-based 14–17 medication adherence issues, and inferior outcomes . Pro- 3,4 treatment in the neoadjuvant, adjuvant, or metastatic settings , blems are particularly acute in the developing world, where, the utilized dose was originally determined in HER2-positive despite, trastuzumab being noted as an essential medicine by the 5,6 metastatic breast cancer and was never optimized for EBC . World Health Organization, limited access leads to excess cancer- Trastuzumab is conventionally administered at a loading dose related mortality . Provided efficacy could be maintained, of 8 mg/kg, followed by maintenance doses of 6 mg/kg every interventional pharmacoeconomic techniques such as lower 3 weeks (Q3W) through the end of therapy. Corresponding C min doses, reduced frequency, or shorter durations may reduce harms (trough) and C (peak) concentrations associated with the FDA- max related to monoclonal antibodies and improve their value labeled Q3W regimen are 47 µg/mL and 179 µg/mL, respectively . 19,20 proposition . However, a trastuzumab concentration of ≥10–20 µg/mL appears Pharmacokinetic modeling and simulation are increasingly used sufficient to achieve antibody-dependent cell-mediated cytotoxi- to propose new drug dosing regimens and, in some cases, obtain 21,22 city, inhibition of cell proliferation in vitro, and suppression of changes to FDA labeling . Model-derived alternative dosing 7–11 tumor growth in xenograft murine model . Moreover, in the regimens can also be used to reduce the clinical and financial metastatic setting, no differences in progression-free survival toxicities patients experience with their treatment—the intent in (PFS) or overall survival (OS) have been identified between this paper. Leveraging previously published population pharma- 23,24 patients with HER2-positive breast cancer who received weight- cokinetic models for trastuzumab , we performed in silico based trastuzumab Q3W or fixed doses every 4 weeks (Q4W) . pharmacokinetic simulations with conventional or alternative 1 2 Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA. Pritzker School of Medicine, The University of Chicago, Chicago, IL, 3 4 5 USA. Department of Medicine, The University of Chicago, Chicago, IL, USA. Department of Pharmacy, University of Chicago Medicine, Chicago, IL, USA. VA Center for Clinical 6 7 Management and Research, Ann Arbor, MI, USA. VA Ann Arbor Medical Oncology, Ann Arbor, MI, USA. Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA. email: gstrohbe@umich.edu; mjr1@uchicago.edu Published in partnership with the Breast Cancer Research Foundation 1234567890():,; P.-H. Hsieh et al. dosing regimens of trastuzumab in an institutional population of Model-predicted pharmacokinetics of trastuzumab HER2-positive EBC patients. We hypothesized that the trastuzu- Median trough values predicted by pharmacokinetic simulation are mab dosing paradigm could be modified so as to enhance summarized in Fig. 1 and Supplementary Table 2. Median trough of trastuzumab’s value proposition to HER2-positive EBC patients, the entire study population, as predicted by pharmacokinetic payers, and health systems by limiting the out-of-pocket (OOP) simulation, was 49 µg/mL (5th–95th percentiles, 23–63 µg/mL). The costs patients experience and potentially reducing drug-related simulated median trough for the neoadjuvant and adjuvant adverse events , while maintaining sufficiently high, efficacious patients were 55 and 49 µg/mL, respectively. Reference data from therapeutic trough concentrations. manufacturer applications are also included in Supplementary Table 2. Overall, our patient dataset carries similar profiles as the patient population in the manufacturer’s clinical trial. We evaluated, at the level of the individual patient, the likelihood of trough values being maintained above the minimum RESULTS effective concentration (Fig. 1). Patients in the neoadjuvant and Patient population adjuvant settings had similar trough ranges of 36–64 µg/mL and We identified 196 eligible patients with breast cancer treated with 32–62 µg/mL, respectively, corresponding to 5th–95th percentiles. trastuzumab or trastuzumab-anns over the 34-month study period (Supplementary Table 2). With conventional dosing, all EBC (Table 1). Patients received trastuzumab or biosimilar as single patients maintained a trough above minimum effective concen- HER-2 inhibiting agent (n = 60) or in combination with pertuzu- tration (10 µg/mL). We therefore derived alternative trastuzumab mab (n = 109). Concurrent chemotherapy was employed in 56% dosing strategies in pharmacokinetic simulations of EBC patients. (n = 75) of the study population’s regimens, specifically 90% (n = 67) in the neoadjuvant setting and 13% (n = 8) in the adjuvant Alternative dosing regimens for EBC patients setting. Most common concurrent chemotherapy regimens in the Development of less frequent dosing regimens. Additional pharma- neoadjuvant setting included paclitaxel/trastuzumab (54%, n = cokinetic simulations were conducted for EBC patients using the 40), carboplatin/docetaxel/trastuzumab (27%, n = 20), and doc- 8 mg/kg loading dose followed by 6 mg/kg Q4W. Under this etaxel/trastuzumab (8%, n = 6). The most common concurrent condition, the vast majority of EBC patients maintained a simulated chemotherapy regimen in the adjuvant setting was carboplatin/ trough ≥10 µg/mL (Fig. 2a, b, Supplementary Table 3). Greater than docetaxel/trastuzumab (8%, n = 5) (Table 1). two-thirds of patients receiving neoadjuvant or adjuvant 6 mg/kg Q4W maintained trough values ≥20 µg/mL (Fig. 2a, b, Supplementary Table 3). We also evaluated regimens in which the Q4W schedule was not implemented until the second or third maintenance dose for Table 1. Patient clinical and laboratory characteristics (median and EBC patients, as these scenarios would be predicted to have a lower interquartile range). risk of pharmacokinetic failure (Supplementary Table 3). Neoadjuvant Adjuvant EBC*, all n = 74 n = 61 patients Development of lower-dose regimens. Following an 8 mg/kg n = 135 loading dose, a range of alternative maintenance doses were evaluated for EBC patients administered using a Q3W schedule: 3, Therapy 3.5, 4, 4.5, 5, and 6 mg/kg. Nearly all EBC patients maintained a Trastuzumab only 753 60 trough ≥10 µg/mL at doses of 3.5–6 mg/kg (Fig. 2c–h, Supple- Chemotherapy + 67 8 75 mentary Table 4). Furthermore, the majority of patients main- Trastuzumab tained a trough ≥20 µg/mL with a maintenance dose of 4 mg/kg. TH 40 3 43 On the other hand, the maintenance dose of 3 mg/kg led to subtherapeutic drug levels in many patients. TCH 20 5 25 DH 606 Determinants of trough less than target concentration CH 101 EBC patients receiving trastuzumab using extended interval or lower- CTH 000 dose dosing regimens who had any simulated trough concentrations Eribulin- 000 <10 µg/mL were evaluated in further detail. The single greatest Trastuzumab driver in these cases was serum albumin concentration <3 g/dL Gemcitabine- 000 (Supplementary Table 5). Body weight <62 kg (23% of neoadjuvant Trastuzumab patients, 28% of adjuvant patient), albumin concentration <4 g/dL Vinorelbine- 000 (20% of neoadjuvant patients, 36% of adjuvant patients), and AST ≥ Trastuzumab 30 IU/L (8% of neoadjuvant patients, 18% of adjuvant patients) were Vinorelbine- 000 each associated with simulated trough concentration <20 µg/mL Trastuzumab- (Supplementary Fig. 2, Supplementary Table 6). Utomulumab Body weight (kg) 73.2 (63.6–87.3) 71.2 (60.9–84.8) 72.2 (61.2–86.3) Drug- and administration-related patient-experienced AST (IU/L) 19 (15–23) 22 (17–27) 20 (16–25) financial toxicity with trastuzumab Albumin (g/dL) 4.2 (4.0–4.3) 4.1 (3.9–4.2) 4.1 (3.9–4.3) Primary analysis. Estimated drug- and administration-related cost- *EBC refers to ‘early breast cancer’, marked by patients receiving sharing payments associated with 6 mg/kg trastuzumab adminis- trastuzumab in the neoadjuvant or adjuvant settings. For simplicity, tered Q3W were $3928 (neoadjuvant, n= 73) and $9379 (adjuvant, patients who received pertuzumab as part of their chemotherapy + n= 60) under non-waste- billing conditions. Drug- and trastuzumab regimen are not separated out from patients who received administration-related savings associated with 6 mg/kg Q4W as a trastuzumab as the sole HER-2-targeting agent in their regimen. percentage of total costs were 14% (neoadjuvant) and 21% TH paclitaxel+ trastuzumab, TCH docetaxel + carboplatin + trastuzumab, (adjuvant). Drug- and administration-related savings associated with DH docetaxel + trastuzumab, CH carboplatin + trastuzumab, CTH carbopla- 4 mg/kg Q3W were 15% (neoadjuvant) and 20% (adjuvant) (Table 2). tin + paclitaxel + trastuzumab. Accounting for savings due to travel cost and wage loss avoidance, npj Breast Cancer (2022) 32 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; P.-H. Hsieh et al. Fig. 1 Simulated concentration-time profiles for all HER2-positive early breast cancer patients receiving trastuzumab every 3 weeks. Simulated concentration-time profiles for patients receiving trastuzumab on a q3w schedule in the a neoadjuvant or b adjuvant. The solid red line indicates median concentration, and the red shaded region represents the 95% CI. Upper dashed line represents concentration = 20 µg/mL. Lower dashed line represents target concentration = 10 µg/mL. 6 mg/kg Q4W trastuzumab administration in the adjuvant setting sufficiently high trastuzumab concentrations were almost universally was associated with savings of 21% in the of treatment (Table 2). observed. On the basis of these data, appears to be feasible in nearly Drug- and administration-related cost savings were generally greater all patients with HER2-positive EBC, but especially those without under Q3W dosing than under Q4W dosing (Supplementary Table 7). medical comorbidities. The financial implications of trastuzumab de- intensification, especially for patients, are especially salient. Esti- Sensitivity analyses. Utilization of single-use vials alongside non- mated OOP savings with reduced frequency trastuzumab were waste billing practices was associated with greater patient- especially notable in the neoadjuvant setting, reaching nearly $1500 experienced expense and absolute savings than multi-use vials per treatment course. In the United States, associated trastuzumab- and non-waste billing practices (Supplementary Table 8). How- related savings in EBC alone are estimated to exceed $700 M USD. ever, the magnitude of this effect was absent in the 4 mg/kg Q3W Our absolute financial toxicity estimates are in line with prior condition and was small (<$200 savings over the entire course of analyses of real-world data. For individuals diagnosed with breast therapy) in the 6 mg/kg Q4W condition when compared to multi- cancer in 2008–2012, median drug-related OOP costs for use vials. Under conditions of concomitant use of single-use vials trastuzumab-containing regimens was $3381 in the first 18 months and waste billing practices, use of 4 mg/kg Q3W or 6 mg/kg Q4W of therapy . This is similar to our $3927.76 estimate that includes was associated with increased savings in the time-limited both drug- and drug administration-related costs in the neoadjuvant neoadjuvant setting and approximately equal savings in the setting (Q3W, 6 mg/kg, non-waste billing). Estimates for the OOP adjuvant setting, relative to multi-use vials alongside non-waste costs associated with the adjuvant setting are higher due to longer billing (Supplementary Table 8). Waste billing itself is associated durations of therapy and continued trastuzumab price increases. with a greater patient OOP financial liability. Estimates of total EBC trastuzumab-related expenditures in the U.S. (~$3.24B USD) are to a first approximation in line with expectations, U.S. health system cost savings given the approximate U.S. share of the global breast cancer Of the ~50,000 new cases of HER2-positive breast cancer diagnosed therapeutics market, HER2+ EBC epidemiology, and global sales in the United States each year, 85% are expected to receive figures for Herceptin® (trastuzumab), totaling ~$6B USD in 2019 . trastuzumab as part of treatment in the neoadjuvant or adjuvant Further dose reductions may be feasible with the incorporation settings for a median of 12 months total. In the base case, assuming of therapeutic drug monitoring, with dose adjustment based on conventional 8 mg/kg loading dose, 6 mg/kg every 3 weeks dosing, prior trough concentrations. Given that the manufacturer has and patient weight of 75 kg, an estimated 350,625 grams of stated the minimum target trough concentration is 10–20 µg/mL, trastuzumab are provisioned in the U.S.onanannualbasis.Resulting we suggest that therapeutic drug monitoring can provide annual expected trastuzumab expenditures total $3.24B USD. assurance that the trough concentration is acceptable, as well as Universal application of alternative dosing strategies was associated facilitating even lower doses (or longer treatment intervals) in with marked reductions in total drug unit use and associated savings. select patients. EBC patients with normal albumin and hepatic Assuming conventional 8 mg/kg loading dose, 4 mg/kg Q3W function may be the best candidates for such lower doses. maintenance dosing, and patient weight of 75 kg, an estimated Furthermore, patients with obesity have decreased clearance 242,250 grams of trastuzumab are provisioned in the U.S. on an (normalized to body weight), and thus higher exposure. annual basis, with associated expenditures totaling $2.24B USD De-intensification of trastuzumab in HER2-positive breast cancer remains an area of intense interest . Recently published rando- ($1.00B savings from base case). Substituting 6 mg/kg Q4W main- tenance dosing results in ~274,125 g of trastuzumab used annually, mized controlled trials demonstrate the non-inferiority of 6 months of adjuvant trastuzumab compared to 12 months, with the added with associated expenditures of $2.53B USD (~$707 M USD savings). benefit of lower rates of cardiotoxicity and, we surmise, lower total costs . Similarly, a new paradigm of near-equivalence is emerging, DISCUSSION aiming to increase treatment access to the greatest number of Our analyses demonstrate the potential to safely de-intensify patients and reduce financial toxicity, with minimal impact on treatment with trastuzumab and its biosimilars (relative to the efficacy . Clinical trial data will likely prove necessary to increase labeled doses), perhaps reducing total drug units used by as much uptake of low-dose trastuzumab. Recently developed multivariable as 50%. Despite reductions in either maintenance dose frequency prognostic indices may help identify patients who are at low risk from Q3W to Q4W or maintenance dose from 6 to 4 mg/kg, for de-intensification-related adverse outcomes . Using such Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 32 P.-H. Hsieh et al. Fig. 2 Simulated concentration-time profile for early HER2-positive breast cancer patients receiving interventional pharmacoeconomic dosing of trastuzumab. Less frequently every 4 weeks (Q4W) dosing schedule in the a neoadjuvant and b adjuvant settings. Every 3 weeks (Q3W) schedule in the c neoadjuvant setting with maintenance dose 4.5 mg/kg, d adjuvant setting with maintenance dose 4.5 mg/kg, e neoadjuvant setting with maintenance dose 4 mg/kg, f adjuvant setting with maintenance dose 4 mg/kg, g neoadjuvant setting with maintenance dose 3.5 mg/kg, and h adjuvant setting with maintenance dose 3.5 mg/kg. In all panels, the solid red line indicates median concentration, and the red shaded region represents 95% CI of the data. Upper dashed line represents concentration = 20 µg/mL. Lower dashed line represents target concentration = 10 µg/mL. models may lower a de-intensification clinical trial’s aggregate risk demonstrate their potential financial upside (through the and improve its palatability to patients and physicians. avoidance of non-drug-related OOP costs), patients may be While oncology awaits a political solution to the ongoing drug hesitant to adopt de-escalated dosing. Prospective clinical trial pricing crisis, interventional pharmacoeconomic dosing may be data will likely be useful in overcoming any gaps in ambiguity, a useful strategy in reducing patient-experienced financial and regardless of their presence it may be justifiable to toxicity without sacrificing efficacy . In the United States, the compensate patients for any theoretical increase in risk under approach may help offset drug cost-related risks that are an inclusive shared savings framework . otherwise transferred from insurers to providers in conventional Notcapturedin thisanalysisare thepotential benefits of reducing bundled payment arrangements . In both developed and strain on health systems with capacity limitations, whether in the developing economies, interventional pharmacoeconomic dos- developed or developing world. Delayed initiation of adjuvant ing may help overcome drug supply limitations while also trastuzumab is associated with inferior outcomes . To the extent improving a drug’s value . Interventional pharmacoeconomic that treatment delays are attributable to over-stressed systems dosing can build upon other advances that have improved administering drug more frequently than the minimum frequency convenience, drug toxicity, and financial toxicity in recent years needed to achieve maximal benefit, less frequent dosing may (e.g., biosimilar entry, subcutaneous formulation, shorter adju- improve outcomes. In resource-limited settings such as some low- 31–35 vant therapy duration) . Though the financial analyses and middle-income countries, low-dose trastuzumab and other npj Breast Cancer (2022) 32 Published in partnership with the Breast Cancer Research Foundation P.-H. Hsieh et al. Patients with incomplete records of trastuzumab administration or any Table 2. Per-patient Savings for reduced-frequency trastuzumab trastuzumab administrations at outside institutions were excluded from compared to current standard-of-care dosing (Q3W, 6 mg/kg). the study. We reviewed electronic health records for: Disease and regimen characteristics for each patient in each treatment setting (neoadjuvant or Q4W 6 mg/kg Q3W 4 mg/kg adjuvant), date of first trastuzumab dose, other drugs included in the regimen (e.g., pertuzumab, cytotoxic agents), dose frequency, as well as Neoadjuvant $765 (14%) $829 (15%) date and cycle of the last dose (if regimen had been completed) or missed Adjuvant $2791 (21%) $2611 (20%) doses. Body weight, aspartate aminotransferase (AST), cancer antigen 15–3 (CA 15–3), albumin as of the day of first trastuzumab dose were collected. All savings are presented as the discount from the standard of care In cases in which laboratory values were not available for the day of the maintenance trastuzumab 6 mg/kg every 3 weeks for a given clinical first trastuzumab dose, we used the most recent available laboratory value scenario and dose (column). Values are savings versus baseline for the prior to the first trastuzumab dose. comparable clinical setting. Estimates include drug-, administration-, and travel-related cost savings and wage loss avoidance; estimates assume no- waste billing and multi-use vials. Pharmacokinetic modeling of trastuzumab Q3W every 3 weeks, Q4W every 4 weeks. Trastuzumab data were simulated using WinNonlin and NLME with Phoenix Version 8.3 (Certara USA, Inc.). We used a published two- compartment population pharmacokinetic model with parallel linear and interventional pharmacoeconomic techniques could prove particu- nonlinear elimination that included the following covariates: body weight (in kg), AST, and albumin . An R Software package (Version 4.0, http:// larly useful in enhancing access and reducing financial toxicity, 38–40 www.r-project.org/) was used for data assembly, exploratory data analysis, similar to low-dose abiraterone in prostate cancer ,aswell as 18 model diagnosis, and simulation. potentially averting unnecessary deaths . Notably missing in our analyses are the ~7500 people newly Pharmacokinetic simulations of alternative dosing strategies diagnosed with HER2-positive metastatic breast cancer each year in EBC in the U.S. Although the number of people with metastatic disease is smaller than the number with EBC, individuals with metastatic We first simulated the standard trastuzumab regimen: 8 mg/kg loading dose followedby6mg/kgmaintenance dose Q3WinpatientswithEBC. Wethen disease can remain on HER2-targeting therapy for much longer simulated 10 alternative maintenance dosing regimens, a combination of periods of time. Longer treatment courses in the metastatic alternative frequencies (Q3W or Q4W) and doses (3, 3.5, 4, 4.5, 5, and 6 mg/ setting imply not only higher per-patient cost, but also higher per- kg). We also evaluated regimens in which the alternative dose or schedule patient burden of time and travel. The derived dosing strategies was implemented with the second (and all subsequent) or third (and all may not apply to many patients in the metastatic setting, owing to subsequent) maintenance dose. Pharmacokinetic simulations were performed increased drug clearance. to 36 weeks to capture 100% steady state. We evaluated schedules based on This study is not without limitations. First, the pharmacokinetic their achievement of steady-state concentrations of at least 10 µg/mL, in simulations undergirding the proffered dosing schedules were accordance with previously published data, as well as the higher threshold of 7,8,41 derived from patients at a single urban academic medical center; 20 µg/mL . Alternative dosing strategies that consistently demonstrated trough concentrations greater than the minimum effective concentration thus, the study population may not reflect the makeup of the were then pursued in financial modeling studies. entire population of HER2-positive EBC patients receiving trastuzumab. Second, the point estimates of expected savings in this paper may have been different had probabilistic modeling Statistical analysis techniques been utilized. Third, the point estimates of expected The mean, median, standard deviation, 95% confidence interval, and individual-level savings were derived under an assumption of percentiles of simulated trastuzumab plasma concentrations were traditional Medicare coverage; patients may have commercial calculated using Phoenix Version 8.3 (Certara USA, Inc.) and R Software insurance or supplemental co-insurance that limits their OOP package (Version 4.0, http://www.r-project.org/). liability. Given the emergence of trastuzumab biosimilars, the estimates of health systems savings are likely to be artificially Deterministic financial modeling: individual out-of-pocket and high in absolute terms, though accurate in relative terms. Fourth, nationwide cost estimates we assumed that patients receiving combination treatment We estimate OOP costs using deterministic financial modeling under could receive both trastuzumab and cytotoxic chemotherapy at varying dosing, patient, treatment setting, and billing conditions. Main- the same frequency as trastuzumab (including Q4W instead of tenance trastuzumab was administered in silico to each of the patients Q3W in some cases); the major driver of cost in these cases, identified in the above dataset using one of three dosing cases: 6 mg/kg however, is the long trastuzumab-only interval. Finally, with the Q3W (standard of care), 6 mg/kg Q4W, or 4 mg/kg Q3W. The latter two were chosen for their abilities to maintain steady-state concentrations advent of subcutaneous trastuzumab, further study will be greater than the minimum effective concentration in the previously needed to assess whether de-intensification of this method of conducted pharmacokinetic simulation studies. Patients receiving trastu- administration is possible. zumab in the neoadjuvant and adjuvant settings received the simulated Altogether, this study demonstrates a roadmap toward de- therapy. We used the actual (i.e., not theoretical or estimated) durations of intensification and waste prevention, not only of trastuzumab in therapy for the individuals in our cohort to perform our calculations; each the treatment of HER2-positive EBC but also, more generally, individual serves as her own comparator in the analyses. therapeutic monoclonal antibodies in cancer. Adaptive dose or We derived model inputs from publicly available information: We 42 43 44 45 frequency de-escalation trials or randomized, controlled dose- estimated lost wages , travel distance , mileage rates , parking costs , 46,47 optimization trials with both clinical and pharmacokinetic out- trastuzumab price, and reimbursement , and drug infusion costs 48,49 (Supplementary Table 1) . We considered the lost wages of both the comes exploring the use of maintenance low-dose trastuzumab patient and a patient caregiver. Patient travel distance, defined as the are warranted, as are further pharmacokinetic studies aimed at de- distance between the patient’s home address and the main address of intensifying monoclonal antibody dosing practices. the University of Chicago Medicine (UCM), was estimated using the first available search result on GoogleMaps (Alphabet, Inc., Mountain View, CA, USA). Tolls were excluded in mapping preferences. Point estimates of each METHODS patient’s expected OOP drug-related financial liability was estimated using Patients a Medicare Part B cost-sharing framework; supplemental co-payment We retrospectively identified all individuals who had received treatment insurances were not considered in this analysis. Two billing methods are for HER2-positive EBC with trastuzumab or biosimilars at the University of used predominantly: non-waste billing and waste billing. Under waste Chicago Medicine (UCM) between January 1, 2017 and October 31, 2019. billing provisions, wasted drug is billed to Medicare and is therefore Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 32 P.-H. Hsieh et al. 52,53 eligible for cost-sharing by the patient. Under non-waste billing, wasted average sales price (ASP) . We considered the population of individuals drug is not billed to Medicare and is therefore not eligible for cost-sharing with HER2-positive EBC and estimated median treatment duration by by the patient . Under non-waste billing in which single-use vials are setting (neoadjuvant and adjuvant), under the assumption that treatment used, the amount of drug is rounded to the nearest measurable dose and/ is discontinued at the completion of evidence-based time-limited 52,54 or package size, within 10% (e.g., 768.4 mg is rounded down to 750 mg), treatment . We used Medicare ASP data to estimate the total societal and Medicare is billed for the rounded amount of drug administered spend associated with this group of patients . (750 mg, corresponding to 75 × 10 mg billing units). In the above case, the Certain assumptions are necessary. We assumed a treatment duration in drug was able to be rounded to the nearest 150 mg vial size (within 10% of the early-stage setting of 12 months. While data from a large, well- target dose), avoiding 132 mg of wasted trastuzumab. If the medication conducted randomized, controlled trial demonstrates the non-inferiority of dose cannot be rounded within 10% to the nearest vial size (e.g., a dose of 6 months of adjuvant treatment , cancer treatment guidelines in the U.S. 530 mg), the excess drug (70 mg in the case above) is wasted; Medicare is continue to advocate for 12 months of adjuvant anti-HER2 treatment .As not billed for the waste . For the purposes of generating cost estimates commonly administered, this corresponds to 1 cycle of 8 mg/kg and a subsequent 16 cycles of 6 mg/kg every 3 weeks. Total spend under these associated with low-dose trastuzumab under the no-waste billing/single- conditions represents the baseline scenario. Under alternative dosing use vial condition, the 10% tolerance allowed for the FDA-labeled dose was regiments, the total number of drug units utilized is decreased, though not applied. Multi-use vials can be utilized alongside no-waste billing. In the number of cycles may not be. Using 4 mg/kg every 3 weeks this case, the dose is rounded to the nearest 10 mg dosing unit. maintenance dosing, the expected numbers of maintenance cycles remain Calculations for cost estimates were as follows: the same as above (16 cycles in neoadjuvant/adjuvant setting). Using 6 mg/ Total Out-Of -Pocket Costs kg every 4 weeks maintenance dosing, the expected numbers of ¼ðÞ Drug cost sharing maintenance cycles are less (13 cycles in neoadjuvant/adjuvant setting). We used Medicare ASP data to estimate the total societal spend associated þðÞ Administration cost sharing with this group of patients . Contracted prices for our institution are not þðÞ Travel costsþðÞ Lost wages per visit made publicly available; ASP captures drug price net of the majority of rebates and discounts. No-waste billing; single-use vial Drug Cost Sharing Calculations for cost estimates were as follows: ¼ðÞ Number of doses Total Spend ´ ðNumber of milligrams of trastuzumab per dose per visit; ¼ ½½ðÞ Number of Newly Diagnosed Breast Cancer Cases if possible rounded to nearest whole number of vials within 10%Þ ´ðÞ % of Cases HER2-Positive ´ðÞ % of HER2-Positive Cases Early-Stage ´ðÞ 1 billing unit=10 milligrams trastuzumab ´ðÞ 8mg=kg  weight þ Maintenance dose  weight  number of treatments= ðÞ 10 mg per dosing unit ´ðÞ Medicare reimbursement per billing unit ´ðÞ Average Sales Price per 10 mg Dosing Unit ´ðÞ Medicare patient cost sharing% Savings ¼ Baseline scenario expenditures Standard billing; single-use vial Drug Cost Sharing Alternative dosing scenario expenditures ¼ðÞ Number of doses ´ðÞ Rounded number of vials per dose per visit ´ðÞ Medicare reimbursement per vial ´ðÞ Medicare patient cost sharing% Reporting summary Multi-use vial Drug Cost Sharing Further information on research design is available in the Nature Research Reporting Summary linked to this article. ¼ðÞ Number of doses ´ ðNumber of milligrams of trastuzumab per dose per visit; rounded to nearest unitÞ DATA AVAILABILITY ´ðÞ 1 billing unit=10 milligrams trastuzumab The datasets generated and analyzed during the current study are not publicly available due to their containing individually identifiable information. 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A pathway through the bundle jungle. J. Oncol. Pr. 12,504–509 (2016). Concept and design: P.H., A.J.K., G.W.S., and M.J.R. Acquisition, analysis, or 31. Farolfi, A. et al. Resource utilization and cost saving analysis of subcutaneous interpretation of data: All authors. Drafting of the manuscript: P.H., A.J.K., G.W.S., versus intravenous trastuzumab in early breast cancer patients. Oncotarget 8, and M.J.R. Critical revision of the manuscript for important intellectual content: All 81343–81349 (2017). authors. Statistical analysis: P.H., A.J.K., G.W.S., and M.J.R. Supervision: G.W.S. and M.J.R. 32. O’Brien, G. L. et al. Cost minimization analysis of intravenous or subcutaneous trastuzumab treatment in patients with HER2-positive breast cancer in Ireland. Clin. Breast Cancer 19, e440–e451 (2019). COMPETING INTERESTS 33. Rojas, L. et al. Cost-minimization analysis of subcutaneous versus intravenous trastuzumab administration in Chilean patients with HER2-positive early breast This work was funded by Clinical Therapeutics Training Grant (T32GM007019) (P.H.) cancer. PLoS ONE 15, e0227961 (2020). and Richard and Debra Gonzalez Fellowship (G.W.S.). G.W.S. is an employee of the Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 32 P.-H. Hsieh et al. United States Federal Government; the views expressed in this article are those of the Reprints and permission information is available at http://www.nature.com/ authors alone and do not necessarily represent those of the United States Federal reprints Government. G.W.S. and M.J.R. serve in uncompensated Director roles for the Optimal Cancer Care Alliance. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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