Progression-free Research Articles

Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial

Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8–99.8%] with a 2-year PFS of 75% [95% CI: 56.5–99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of FOXP3+ T cells to proliferating CD11c+ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4+ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.

Cost-Effectiveness Analyses of First Line Ibrutinib Versus Acalabrutinib Versus Zanubrutinib Followed By Second Line Venetoclax Plus Rituximab in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients

Background. Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKI) has significantly improved progression-free (PFS) and overall survival (OS) outcomes when compared with chemoimmunotherapy in the front line setting of CLL. Following the approval of the first generation of BTKI (ibrutinib, IBR) in 2016 as first line (1L) treatment of CLL, second generation BTKIs with more favorable safety profiles were approved/recommended in 2020 (acalabrutinib, ACA) and 2021 (zanubrutinib, ZAN). We performed a network meta-analysis (NMA) of these three BTKIs in terms of PFS in support of cost-effectiveness analyses from US payer perspective. Methods. We conducted a NMA of 5 trials (Woyach 2018, Burger 2015, Sharman 2020, Tam 2021, Goede 2014) on the PFS hazard ratios (HR) of the 3 BTKIs and any other CLL interventions that connected in the network. We specified a 5-state Markov model to capture the disease and clinical pathway for CLL patients over a 10 years' time horizon: progression free (PF) on 1L treatment [PF1]; progression before initiating second line (2L) treatment [P1]; PF on 2L treatment [PF2]; progression after 2L treatment [P2]; and death. Patients started PF on 1L treatment with a BTKI and moved to other states based on extracted transition probabilities from lognormal parametric distributions fitted to Kaplan-Meier PFS curves of phase III trials of IBR, ACA and ZAN. Venetoclax plus rituximab (VR) was considered the 2L treatment with PF2, P2 and death in 2L extracted from Seymour 2018. The transition probabilities of PF on 1L treatment and progression after 1L were adjusted based on the NMA results. OS and time to next treatment (TTNT) after first progression were considered the same for the three BTKIs. Costs of regimens (wholesale acquisition cost), adverse event (AE) management, and disease progression were incorporated into the appropriate health states. Utilities of PF1 (0.799), P1 (0.66), PF2 (0.55) and P2 (0.42) were obtained from literature. Annual discount rate of 3.0% was applied. Life years (LY), quality adjusted LY (QALY), and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated. Probabilistic sensitivity analyses (PSA; 10,000 iterations) were performed to obtain cost-effectiveness acceptability curves (CEAC). Results. Compared with IBR, ACA (HR=0.54; 95%CI=0.41-0.72) but not ZAN (HR=1.03; 95%CI=0.80-1.34) was associated with a statistically significant lower HR of progression or death. At 10 years, 77% of ACA patients were in PF1 and 9% in PF2, compared to 49% and 28% of ZAN patients, and 50% and 27% of IBR patients. As shown in the table, in base case analyses, total costs of IBR treatment were higher by $104,331 over ACA and by $350,340 over ZAN; with ACA being higher by $246,009 over ZAN. Survival was estimated to be 6.83 LYs for IBR, 7.02 LYs for ACA (+0.19) and 6.82 LYs for ZAN (-0.01). QALYs were estimated to be 5.00 for IBR, 5.46 for ACA (+0.46) and 5.09 for ZAN (+0.09). This yielded negative (cost saving) ICER of $-549,110/LYg and ICUR of $-226,806/QALYg for ACA over IBR. The statistically non-significant survival benefit, the 0.01 LY lost but 0.09 QALY gained, and the lower cost of ZAN over IBR yielded an ICER of $35,034,000/LYg and a negative (cost saving) ICUR of $3,892,666/QALYg. Compared to ZAN, treatment with ACA was associated with incremental costs of $246,009, 0.20 LY and 0.37 QALY differentials, yielding ICER of $1,230,045/LYg yet ICUR of $664,889/QALYg. All estimates were confirmed with negligible differences in PSAs. In a scenario analysis for the PF1 state only, QALY gains were 5.25 for ACA, 4.40 for ZAN and 4.34 for IBR. Considering cost differentials of $-69,138 for ACA and $-352,297 for ZAN relative to IBR, the corresponding ICURs were $-75,975/QALYg and $-5,871,617/QALYg, resp. Conclusion. Clinically over the course of 1L treatment with a BTKI followed by 2L treatment with VR, ACA in 1L is associated with greater reductions in the risk of progression or death compared to IBR and ZAN over 10 years. This benefit comes at lower cost than IBR, which resulted in cost-saving ICUR and ICER estimates; but at higher cost than ZAN, which resulted in an ICUR of ~$665,000 per QALY gained. Proportionately, QALY results came out more favorably than LY results. This rather unusual result is attributable to the better safety profiles and lower AE costs of ACA and ZAN, coupled with lower pricing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cost-Effectiveness of Axicabtagene Ciloleucel for Adult Patients with Relapsed or Refractory Follicular Lymphoma in the United States

INTRODUCTION: Axicabtagene ciloleucel (axi-cel) was granted accelerated US Food and Drug Administration (FDA) approval in early 2021 for the treatment of adults with relapsed/refractory (r/r) follicular lymphoma (FL) after 2 or more lines of systemic treatment. Due to limited availability of efficacious therapies in third line and beyond, FL patients are commonly re-treated with conventional therapies. FL patients in the third line of treatment face a median progression-free survival (PFS) of 11 months, demonstrating the need for treatment options that lead to long-term remission. The objective of this study was to assess the cost-effectiveness of axi-cel under a range of model assumptions compared to standard of care (SOC) treatments in r/r FL patients who have had at least two lines of prior therapy from a US third-party payer perspective. METHODS: A cost-effectiveness model was developed in Microsoft Excel using a partitioned-survival approach with three mutually exclusive health states: progression-free (PF) disease, progressed disease (PD), and death. Patient-level analyses of the 36-month ZUMA-5 (axi-cel) and SCHOLAR-5 (SOC) studies were used to extrapolate PFS and overall survival (OS) over a lifetime horizon. The base case analysis assumed 25% of the population alive at 5 years experienced long-term remission (i.e., functional cure); this assumption was informed by clinical opinion and was varied in scenario analyses. The remaining 75% of patients were modeled according to the best-fitting parametric survival curves identified by Akaike information criterion and the Bayesian information criterion, which were exponential models for both PFS and OS. Unit costs were obtained from published list prices and peer-reviewed literature. Healthcare resource utilization and quality of life data were obtained from published literature. Adverse event rates were obtained from clinical trial data and product prescribing information. The primary model outcome was the incremental cost-effectiveness ratio (ICER) measured as incremental cost per quality-adjusted life year (QALY) gained. In one-way sensitivity analysis (OWSA), key model parameters were varied by 20% of their base case values, or reported standard errors if available, to test their impact on the ICER. In probabilistic sensitivity analysis (PSA), all inputs for the model base case were varied by 10% or according to their reported standard errors to evaluate the impact of simultaneous uncertainty of model parameters on the ICER. Following US cost-effectiveness standard practice, costs and outcomes were discounted at 3% per year. RESULTS: In the base case analysis (25% of patients alive at 5 years deemed to be functionally cured), axi-cel led to an increase of 3.92 life-years (LYs) and 3.22 QALYs relative to SOC. Axi-cel resulted in a total cost increase of $288,979 relative to SOC, driven primarily by increased PF treatment costs of $297,270. Axi-cel was also associated with reduced costs in the PD state (-$18,999) due to less time spent in PD relative to SOC. The base case ICER for axi-cel versus SOC was $89,784 per QALY gained. In scenario analyses with cure fractions ranging from 0% to 40%, the ICER varied from $115,971 to $74,063 per QALY gained. Across all parameters varied in the OWSA, the ICER varied between $122,892 and $78,628; the ICER was most sensitive to the PF health state utility, mean patient age, physician visit costs, and the length of hospitalization for axi-cel infusion. In the PSA, axi-cel had a 96% probability of being cost-effective across 1,000 iterations using a $150,000 willingness-to-pay threshold (WTP) threshold. CONCLUSIONS: Under a range of cure assumptions, including cure fractions varying from 0% to 40%, axi-cel for treatment in r/r FL patients who have had a least two lines of prior systemic therapy would be considered cost-effective compared to SOC using the commonly cited $150,000 US WTP threshold. Results were robust across a range of sensitivity analyses accounting for parameter uncertainty. Long-term follow-up is necessary to reduce uncertainties about the proportion of patients receiving axi-cel who experience long-term remission. Additionally, given there are several new effective FL therapies in trials and pending FDA approval that were not incorporated into SCHOLAR-5, future studies should evaluate the cost-effectiveness of axi-cel against a comparator arm that includes these new treatments. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 2328: Metabolomics pathways and biomarkers in predicting breast cancer prognosis

Abstract Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in Americans. With more than 3 million breast cancer survivors in the US, a number that is projected to increase, it is important to identify targets for precision intervention to improve breast cancer prognosis. With the rapid advancement of technology for metabolomics, the results from several recent studies have shown that metabolomics may have applications in breast cancer diagnosis and subtype analysis, characterization of heterogeneity of breast cancer, and prognosis. In the current study, we performed a global urinary metabolomic analysis of 120 breast cancer patients: 60 progression-free (PF) cases as the reference group and 60 with progressive disease (PD: recurrence, second primary, metastasis, or death). The urine samples were collected immediately after radiotherapy. Using UPLC-MS/MS and GC-MS, Metabolon Inc. identified a robust set of 1,742 biochemicals (1,258 known and 484 unknown structure). The most notable differences between PF and PD patients involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., glucose, sedoheptulose, and N6-carboxymethyllysine), branch-chain amino acid metabolism (e.g., alpha-hydroxyisocaproate and beta-hydroxyisovalerylglycine), phosphatidylcholine metabolism (e.g., 1-palmitoyl-2-oleoyl-GPC (16:0/18:1) and 1-palmitoyl-2-linoleoyl-GPC (16:0/18:2)), arginine metabolism (e.g., dimethylarginine, N-acetylcitrulline, and homocitrulline), oxidative stress-related metabolites (e.g., cysteine-glutathione disulfide, gamma-glutamylisoleucine, and gamma-glutamylthreonine), androgenic steroids (Dehydroepiandrosterone sulfate (DHEA-S) and 16a-hydroxy DHEA 3-sulfate), and nucleotide metabolism. Some of these identified metabolomic differences may serve as potential predictive biomarkers of breast cancer prognosis. In summary, with increasing interest in targeting tumor metabolism in precision medicine and our pilot data suggesting multiple metabolic pathways in predicting breast cancer prognosis, future research is warranted to validate our findings and identify metabolomic targets for precision interventions. Citation Format: Jennifer J. Hu, Cristiane Takita, Isildinha M. Reis, George Yang, Wei Zhao, Eunkyung Lee. Metabolomics pathways and biomarkers in predicting breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2328.

Cost-effectiveness analysis of nivolumab plus ipilimumab versus platinum-doublet chemotherapy for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States

Aim We evaluated the cost-effectiveness of nivolumab in combination with ipilimumab (NIVO + IPI) versus platinum-doublet chemotherapy (PDC) for the first-line treatment of stage IV or recurrent non-small cell lung cancer (NSCLC) from a third-party payer perspective in the United States (US). Methods A partitioned survival model was developed using efficacy, safety, and utility inputs derived from Part 1 of the phase 3 CheckMate 227 trial (NCT02477826) with 37.7-month minimum follow-up for overall survival (OS). OS and progression-free (PF) survival were extrapolated over a 20-year time-horizon using parametric spline-based models selected based on goodness of fit and validated with data from external sources. Duration of treatment Kaplan–Meier curves were used for treatment cost calculations. US-specific costs (2021 dollars) for drug acquisition, administration, and monitoring; disease management (PF and progressed disease health states); end-of-life care; adverse events; and subsequent treatments were derived from publicly available sources. Time-to-death utilities were applied in the base case, whereas treatment-specific progression-based utilities were tested in a scenario analysis. Main outcomes included incremental cost per life-year gained (LYG) and quality-adjusted life-year (QALY). Model uncertainty was assessed through deterministic and probabilistic sensitivity analyses. Results NIVO + IPI resulted in 1.53 additional life-years, 1.33 additional QALYs, and $142 088 in additional costs compared with PDC. The incremental cost per LYG was $92 651, whereas incremental cost per QALY gained was $106 553. The application of treatment-specific progression-based utilities yielded an incremental cost per QALY gained of $117 076. Probabilistic sensitivity analysis revealed a 98% probability that NIVO + IPI was cost-effective versus PDC at a willingness-to-pay threshold of $150 000 per QALY. Conclusions NIVO + IPI was estimated to be cost-effective as a first-line treatment for stage IV or recurrent NSCLC in the US, with increased survival and higher cost compared with PDC.

Productivity losses under various second-line recurrent or metastatic cervical cancer treatment scenarios in the United States.

e17520 Background: Recent data showed that a substantial proportion of second-line (2L)-eligible recurrent or metastatic cervical cancer (r/mCC) patients do not receive therapy. Additionally, although higher direct medical costs has been demonstrated with increasing r/mCC disease severity, there is no data on the impact of 2L treatment choices on societal costs. This study aims to estimate productivity loss due to untreated r/mCC and reduction in productivity losses associated with various 2L therapy options in the United States. Methods: We simulated the natural history of r/mCC by developing a Markov model with three stages: progression-free (PF), progressive (P), and death (D) for the course of r/mCC patients (average age: 50 years) during 2L treatment. We considered four treatment scenarios for patients who progressed on 1L systemic therapy: no 2L therapy, chemotherapy, overall 2L treatments (including option of cytotoxic monotherapy, immunotherapy, or other combination therapies), and tisotumab vedotin (TV). The model was parameterized and calibrated to match the overall survival and progression-free survival reported in recent clinical studies. Productivity loss associated with each disease stage was estimated by time spent at each stage, activity performance rate, and annual market and non-market productivity. Model outcomes included cumulative time spent in each stage and per patient 1-year and 5-year productivity losses. Results: Within a 1-year period, patients spend an estimated 6.1 months in the P stage under the no 2L treatment scenario; 4.4 months in PF and 4.3 months in P under 2L chemotherapy; 4.4 months in PF and 4.8 months P under overall 2L treatments scenario; and 5.7 months in PF and 4.3 months in P under TV scenario. Per person 1-year productivity under no 2L therapy was between $11.7K-$16.8K. As compared with no 2L therapy, 1-year per-person productivity improved by $5K-$14.6K under chemotherapy, by $5.8K-$15.6K under overall 2L treatments, and by $7.3-$19.9K under TV. When extending to a 5-year horizon, the projected cumulative per patient productivity improvement relative to that of patients with no 2L therapy ranged by $9.2K-$20.7K under chemotherapy, by $12.9K-$25.3K under overall 2L treatments, and by $19K-$36.9K under TV. Conclusions: Societal costs of 2L r/mCC in terms of lost productivity is substantially less in patients receiving 2L treatment vs. no treatment, within a 1-year period of becoming eligible for 2L therapy. Among patients receiving treatment (chemotherapy only or overall 2L treatment), we projected that society still incurs potentially meaningful lost productivity, relative to being treated with TV. TV’s 2021 approval in 2L r/mCC offers additional treatment option for patients, and continued efforts should be directed toward providing more treatment options in this setting.

P-171: Multistate models provide complementary insights into outcomes for patients treated in the UK NCRI Myeloma XI randomised trial

P-171: Multistate models provide complementary insights into outcomes for patients treated in the UK NCRI Myeloma XI randomised trial

PCN81 Economic Evaluation of First-LINE Atezolizumab for Extensive-STAGE SMALL-Cell LUNG Cancer: The Difference between the Standard Parametric MODEL and the Mixture Cure MODEL

This study evaluated the cost-effectiveness of atezolizumab + chemotherapy versus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (SCLC) in the US. The 3 health states partitioned survival (PS) model was used over the lifetime. Effectiveness and safety data were derived from the IMpower133 trial. The parametric survival model and mixture cure model were used for the atezolizumab + chemotherapy group, and the parametric survival model was used for the chemotherapy group. Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from previous studies. Sensitivity analysis were performed to observe model stability. In model 1, compared with chemotherapy alone, atezolizumab + chemotherapy yielded an additional 0.11 quality-adjusted life-years (QALYs), with an incremental cost of US$84,257. The incremental cost-utility ratio (ICUR) was US$785,848/QALY. In model 2, atezolizumab + chemotherapy yielded an additional 0.10 QALYs, with an incremental cost of US$84,257; the ICUR was US$827,610/QALY. In the one-way sensitivity analysis, progression-free (PF) and postprogression (PP) utilities were the main drivers. In the scenario analysis (PF utility=0.673, PP utility =0.473), the results obtained with model 1 and model 2 showed that the ICUR was US$910,557/QALY and US$965,607/QALY, respectively. In the PSA on model 1 and model 2, the probabilities that atezolizumab + chemotherapy would not be cost-effective were 100% if the willingness-to-pay threshold was US$100,000/QALY. The findings of the present analysis suggest that atezolizumab + chemotherapy is not cost-effective in patients receiving first-line treatment for extensive-stage SCLC in the US.

Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase IIIb OPINION primary analysis.

5545 Background: In the Phase II Study 19 trial (NCT00753545; Ledermann et al Lancet Oncol 2014), maintenance olaparib improved progression-free survival (PFS) vs placebo in PSR OC pts, including non-BRCAm pts. A significant PFS benefit was also seen with maintenance olaparib vs placebo in gBRCAm PSR OC pts in the Phase III SOLO2 trial (NCT01874353; Pujade-Lauraine et al Lancet Oncol 2017). To investigate olaparib maintenance monotherapy in non-gBRCAm PSR OC pts who had received ≥2 prior lines of platinum-based chemotherapy (PBC), we performed the Phase IIIb, single-arm, OPINION study (NCT03402841). Methods: Pts had high-grade serous or endometrioid OC and were in complete response (CR) or partial response (PR) to PBC. Pts received maintenance olaparib (tablets; 300 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS (modified RECIST v1.1). Secondary endpoints included PFS by homologous recombination deficiency (HRD) and somatic BRCA mutation (sBRCAm) status determined by central Myriad tumor and germline testing; and time to first subsequent treatment (TFST). The primary analysis was planned for 18 months (mo) after the last patient was enrolled. Results: 279 pts were enrolled from 17 countries (mean age: 64 years); 253 pts (90.7%) were confirmed non-gBRCAm. At data cut-off (Oct 2, 2020), median PFS was 9.2 mo (95% CI 7.6–10.9), with 210 PFS events (75.3% maturity). 65.3%, 38.5% and 24.3% of pts were progression-free (PF) at 6, 12 and 18 mo, respectively. The Table shows PFS in key subgroups. Median TFST was 13.9 mo (95% CI 11.5–16.4). Median exposure to olaparib was 9.4 mo (range 0.0–31.9). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 29.0% of pts and serious TEAEs in 19.7% of pts. TEAEs led to dose interruption, dose reduction and treatment discontinuation in 47.0%, 22.6% and 7.5% of pts, respectively. Conclusions: Our findings support the use of olaparib maintenance therapy in non-gBRCAm PSR OC pts, consistent with our interim analysis and previous trials in this setting. Clinical trial information: NCT03402841. [Table: see text]

Economic Evaluation of First-Line Atezolizumab for Extensive-Stage Small-Cell Lung Cancer in the US

Introduction: This study evaluated the cost-effectiveness of atezolizumab + chemotherapy vs. chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (SCLC) in the United States (US).Methods: The three health states partitioned survival (PS) model was used over the lifetime. Effectiveness and safety data were derived from the IMpower133 trial. The parametric survival model and mixture cure model were used for the atezolizumab + chemotherapy group to explore the long-term uncertainty of the effect of immunotherapy, and the parametric survival model was used for the chemotherapy group. Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from previous studies. Sensitivity analyses were performed to observe model stability.Results: If the mixture cure model was considered for the intervention group, compared with chemotherapy alone, atezolizumab + chemotherapy yielded an additional 0.11 quality-adjusted life-years (QALYs), with an incremental cost of US$84,257. The incremental cost-utility ratio (ICUR) was US$785,848/QALY. If the parametric survival model was considered for the intervention group, atezolizumab + chemotherapy yielded an additional 0.10 QALYs, with an incremental cost of US$84,257; the ICUR was US$827,610/QALY. In the one-way sensitivity analysis, progression-free (PF) and postprogression (PP) utilities were the main drivers. In the scenario analysis (PF utility = 0.673, PP utility = 0.473), the results showed that the ICUR was US$910,557/QALY and US$965,607/QALY when the mixture cure model and parametric survival model was considered for the intervention group, respectively. In the PSA, the probabilities that atezolizumab + chemotherapy would not be cost-effective were 100% if the willingness-to-pay threshold was US$100,000/QALY.Conclusions: The findings of the present analysis suggest that atezolizumab + chemotherapy is not cost-effective in patients receiving first-line treatment for extensive-stage SCLC in the US.

PCN106 A Study to Assess the Impact of Incorporating the ‘Probability of Being in Response Function’ into an Economic Model for Nivolumab in Advanced Renal-Cell Carcinoma

Response to treatment is a clinically meaningful outcome for patients with cancer. Economic models that capture the dynamics between treatment response and disease evolution can be well suited for immuno-oncologic (I-O) therapy. The probability of being in response function (PBRF) is a composite endpoint that combines time to response, response rate and duration of response. This study investigated the impact of incorporating the PBRF into a partitioned survival model (PSM) of nivolumab versus everolimus in previously treated advanced renal cell carcinoma. A 4-state PSM was developed by further partitioning the progression-free (PF) state of a standard 3-state PSM into two separate states: “PF with response” and “PF without response” using the PBRF concept. Patient-level data from CheckMate 025 was used for the utility and survival analyses. Aggregated health-state utility values (HSUV) were estimated from EQ-5D-3L trial data using a Canadian-based tariff. Best fitting parametric survival models were used to extrapolate outcomes beyond the 5-year trial follow-up. Quality-adjusted life-years (QALYs) over a 10-year time horizon were estimated using the 4-state PSM with PBRF and the 3-state PSM. Mean HSUV for PF “with response” and PF “without response” were 0.91 and 0.84, respectively. Over a 10-year horizon, the 4-state PBRF model generated 0.84 QALYs in the PF state for nivolumab (0.54 [64%] with response; 0.30 [36%] without response) versus 0.54 for everolimus (0.08 [14%] with response; 0.46 [86%] without response). The incremental QALYs comparing nivolumab with everolimus in the PF state were 10% higher in the 4-state PBRF model versus the 3-state PSM. The PSM augmented with PBRF provided a more detailed assessment of QALYs gained in the PF state for nivolumab and everolimus than the 3-state PSM. Model developers should consider this approach when there are marked differences in the response profiles of competing interventions.

Outcome By Primary Treatment Type and Timing of Progression Among Follicular Lymphoma Patients: A Large, Population-Based Study in Sweden

Purpose: Follicular lymphoma (FL) is generally regarded as an indolent malignancy, yet the clinical outcome is highly variable. In recent years, POD24 (progression of disease within 24 months) has emerged as a potential prognostic marker for overall survival (OS) in FL and other non-Hodgkin lymphomas. The association with survival, however, has mostly been studied in selected clinical trial cohorts and among patients treated with R-CHOP. We aimed to investigate OS by timing of progression and type of primary treatment in a population-based setting in Sweden. Methods: We identified all patients diagnosed with FL in stages II-IV and grade 1-3a between 2007 and 2014, using the population-based Swedish lymphoma register. Data were complemented with information on progression, transformation and second-line treatment through medical charts review up to December 31st, 2017. The analysis covered 4 out of 6 health care regions (75% of all patients diagnosed nationally). The patients were categorized according to type of first-line treatment: R-chemo of any type, R-Benda, R-CHOP (including R-CHOEP), or other (including immunotherapy only). Among patients where it was decided to start first-line treatment within 6 months of diagnosis (and where treatment was started within nine months), POD was defined as either lack of response to first-line therapy (stable [SD] or progressive disease [PD]), or initial response and subsequent relapse/progression/transformation as indication for second-line therapy. To quantify the impact of timing of POD on survival, the five-year OS conditional on either being progression-free (PF) or having experienced POD at different time points during follow-up, was estimated using a flexible parametric illness-death model. Results: Among a total of 970 FL patients, median age at diagnosis was 66 years and patients were followed for a median of 6.4 years (range 0-12 years). The 5-year OS was 75% and progression-free survival was 59%. Six hundred (62%) patients had a first-line treatment within nine months of diagnosis and were hence analyzed further, whereas the remaining 370 (38%) patients were classified as wait-and-watch and were not analyzed further. Among the 600 treated patients, 337 (56%) had R-chemo (R-CHOP or alike (n=210), R-Benda (n=97), other (n=30)), and 263 (44%) received non-R-chemo treatment (mainly R-monotherapy, radiotherapy only, or R-lenalidomide). Patients who received R-Benda were on average older than the other groups. Among patients treated with R-chemo, those who stayed progression-free had a 5-year conditional OS above 75% regardless of PF time point. For patients who progressed, the 5-year conditional OS improved as time point of POD was prolonged (Fig 1a, left panel). Early POD (within 12-24 months) was associated with a particularly poor prognosis (5-year conditional OS below 55%). The OS improvement over time of POD was especially pronounced among R-Benda treated patients (Fig 1b, right panel). Among patients receiving non-R-chemo treatments, early POD was associated with a slightly worse 5-year OS but differences between POD and PF patients were less marked (Fig 1a, right panel). Conclusion: This population-based study of Swedish stage II-IV FL patients shows that among immunochemotherapy-treated patients, progression of disease was always associated with worse survival in comparison to progression-free patients regardless of timing of progression. This reduction in survival was more pronounced the earlier the progression (as described by others). Interestingly, among patients selected for milder non-immunochemotherapy-based treatments, progression of disease did not have a strong effect on survival. Disclosures Weibull: Janssen Cilag: Research Funding. Wahlin:Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Smedby:Takeda: Research Funding; Janssen: Research Funding; Celgene: Consultancy.

Cost-effectiveness analysis of the SP142 versus 22C3 PD-L1 assays in the treatment of atezolizumab plus nab-paclitaxel for patients with advanced triple negative breast cancer in the Brazilian private healthcare system

Objective The aim of the study was to demonstrate the clinical and economic impact of two PD-L1 IHC assays, SP142 versus 22C3, to identify the eligibility of the patients with advanced triple negative breast cancer (aTNBC) to the treatment with atezolizumab plus nab-paclitaxel in the Brazilian private healthcare system (BPHS). Methods The study performed a cost-effectiveness analysis based on a partitioned-survival model with three mutually exclusive health states: progression-free (PF), progression, and death. Data of progression-free survival and overall survival were extracted from a retrospective exploratory analysis of IMpassion130, an analytical harmonization of PD-L1 IHC assays. The analyses included only direct costs (drug acquisition and management of adverse events) that were based on CBHPM (Classificação Brasileira Hierarquizada de Procedimentos Médicos) and CMED PF18% (Câmara de Regulação do Mercado de Medicamentos) tables. A probabilistic sensitivity analysis was performed as a second-order Monte Carlo Simulation in order to evaluate the uncertainties of the model. Results The SP142 assay has the potential to improve PFS and generate savings to the BPHS. The incremental cost-effectiveness ratio (ICER) was –USD 4,119.43 per month of progression-free survival. Conclusions The SP142 assay demonstrated to be a dominant alternative compared to 22C3 to guide the treatment with atezolizumab plus nab-paclitaxel in patients with aTNBC.

Cost utility analysis of tisagenlecleucel vs salvage chemotherapy in the treatment of relapsed/refractory diffuse large B-cell lymphoma from Singapore’s healthcare system perspective

Background Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) have limited treatment options and poor prognoses. Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy has shown early promise in improving survival outcomes, but at a high upfront cost. This study evaluated the cost-effectiveness of tisagenlecleucel versus salvage chemotherapy for treating patients with r/r DLBCL who have failed at least 2 lines of systemic therapies. Methods A hybrid decision tree and three-state partitioned survival model (progression-free (PF), progressive disease and death) was developed from the Singapore healthcare payer perspective. Survival curves from JULIET trial and CORAL-1 extension study were extrapolated beyond trial period over a 15-year time horizon to estimate the underlying progression-free survival and overall survival parametric distributions for both arms. Health state utilities were retrieved from the literature, and direct costs were sourced from public healthcare institutions in Singapore. One-way probabilistic sensitivity analyses and scenario analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results. Results Compared with salvage chemotherapy, tisagenlecleucel was associated with a base-case incremental cost-effectiveness ratio (ICER) US$508,530 (S$686,516) per quality adjusted life year (QALY) gained and US$320,200 (S$432,269) per life year (LY) gained. One-way sensitivity analysis showed the ICER was most sensitive to time horizon, PF utility and cost of tisagenlecleucel. Scenario analyses confirmed that the ICERs remained high under favorable assumptions and substantial price reduction was required to reduce the ICER. Conclusions Our analysis showed tisagenlecleucel use in r/r DLBCL patients who failed at least 2 prior lines of systemic therapies was associated with exceedingly high ICER, which is unlikely to represent good use of healthcare resources. Comparative clinical evidence from the ongoing trials might provide more insight into future evaluations.

PCN87 COST-EFFECTIVENESS OF RIBOCILIB PLUS NONSTEROIDAL AROMATASE INHIBITOR (NSAI) IN HORMONE RECEPTOR–POSITIVE, HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2–NEGATIVE (HR+/HER2-) ADVANCED BREAST CANCER (ABC): A CANADIAN HEALTHCARE PERSPECTIVE

The MONALEESA-7 trial demonstrated the efficacy and safety of ribociclib plus NSAI (R+NSAI) vs. placebo plus NSAI for pre-/peri-menopausal women with HR+/HER2- ABC who had received no prior endocrine therapy (ET) for advanced disease. This analysis evaluated the cost-effectiveness of R+NSAI vs. NSAI in this population from a Canadian healthcare payer perspective. The incremental cost-effectiveness ratio (ICER) expressed as incremental costs per quality-adjusted life-year (QALY) gained for R+NSAI versus NSAI, was estimated using a semi-Markov cohort model developed in Microsoft Excel with states for progression-free (PF), post-progression (PP), and dead. A 15-year time horizon was used. Survival distributions for PFS, PPS and time to discontinuation (TTD) were based on parametric survival distribution fit to data from MONALEESA-7. Health-state utilities were estimated using EQ-5D index values collected in MONALEESA-7. Direct costs of ABC treatment (medication and administration costs, follow-up and monitoring, adverse events, subsequent treatments) were based on Canadian specific values from published sources. Costs ($ CAN) and QALYs were discounted at 1.5% annually. In the base case, R+NSAI was estimated to result in gains of 1.44 life years and 1.19 QALYs vs. NSAI, at an incremental cost of $210,767. The ICER of R+NSAI vs. NSAI was $177,245 per QALY gained based on deterministic analyses and $178,872 based on the mean of probabilistic analyses. Results were sensitive to parametric distributions used for projecting long-term TTD, PFS, and PPS. For pre-/peri-menopausal women with HR+/HER2- ABC who had received no prior ET for advanced disease, R+NSAI is projected to result in substantial gains in QALYs compared with NSAI. At its current list price, ribociclib used in combination with an NSAI is cost-effective in this population at an ICER threshold of approximately $177,245. These results may be useful in deliberations regarding reimbursement and access to this treatment.

Cost-Effectiveness of Alectinib for Patients with Untreated ALK-Positive Non-Small Cell Lung Cancer in China

To assess the cost-effectiveness of alectinib versus crizotinib as first-line treatments for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients from the perspective of China's healthcare system. A Markov model was developed to assess the clinical outcomes and costs of alectinib and crizotinib, which included five health states: progression-free (PF) without central nervous system (CNS) progression, PF with CNS progression, post-progression (PP) without CNS progression, PP with CNS progression, and death. Clinical data for transition probabilities were obtained from the ALEX trial at the updated data cutoff. Healthcare resource utilization and costs were derived from clinical expert opinions and published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the uncertainty of the results. Scenario analyses were conducted including using clinical data from the ALESIA trial in Asian patients, using utilities from the ALEX trial, and choosing different parametric survival models. In base case analysis, alectinib yielded an additional 1.04 quality-adjusted life years (QALYs) with incremental costs of $54,827, resulting in an incremental cost-effectiveness ratio (ICER) of $52,869/QALY. In scenario analysis, the ICER was $56,787/QALY using clinical data from the ALESIA trial. In probabilistic sensitivity analysis, the probabilities of alectinib being cost-effective were 0.4% and 43.7% when the willingness-to-pay (WTP) thresholds were $28,109/QALY and $50,000/QALY, respectively. Alectinib could prolong the mean time of PF and delay the time to CNS progression. However, because of its high drug cost, alectinib was unlikely to be cost-effective for untreated ALK-positive NSCLC patients in China.

PCN140 - Cost-Effective Study of Alectinib in Treating Crizotinib-Failed Anaplastic Lymphoma Kinase Positive (ALK+) Non-Small Cell Lung Cancer (NSCLC) Patients in Taiwan

The primary aim was to evaluate the cost-effectiveness of alectinib in treating patients with ALK+ NSCLC who failed on prior crizotinib treatment in Taiwan. We assessed the incremental cost-effective ratio (ICER) of alectinib using a partitioned semi-Markov model provided by the manufacturer of alectinib with three post-treatment health states: progression-free (PF), post-progression (PP), and death. Overall survival and progression-free survival estimates derived from clinical trials were used for an indirect comparison between alectinib and ceritinib and for calculation of the life-years (LYs) and quality adjusted life-years (QALYs) gained after treatment initiation. The analysis was carried out from payer’s perspective (Taiwan National Health Insurance, NHI) and only included direct medical costs covered by the NHI program. The costs and outcomes were both discounted 3% annually over a 5-year time horizon. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to evaluate the robustness of the ICER estimates. In the base case scenario, the incremental LYs and QALYs were 0.69 and 0.25, respectively while the incremental costs were New Taiwan Dollar (NTD) 1,226,449 (equals to USD 40,882 according an exchange rate of 1 USD to 30 NTD), yielding an ICER of NTD 4,834,193 (USD 161,140) per QALY gained. One-way sensitivity analyses revealed utility in PF state, reimbursement price of alectinib, cost of supportive care in PP state, and utility in PP state significantly influenced the ICER estimates, sequentially. The projected ICER ranged from NTD 5,818,353-2,829,273 (USD 193,945- 94,309) per QALY in the scenario analyses when time to treatment discontinuation was set to trial-observed treatment time and when utility in PP state=0.46 was used. While treatment with alectinib increased LYs, the ICERs exceeded the threshold of NTD 2,000,000 (USD 66,667) per QALY. The model estimates were highly sensitive to utility estimates associated with different health states and drug price.

Cost-Effectiveness of Nivolumab-Ipilimumab Combination Therapy Compared with Monotherapy for First-Line Treatment of Metastatic Melanoma in the United States.

The approval of new immunotherapies has dramatically changed the treatment landscape of metastatic melanoma. These survival gains come with trade-offs in side effects and costs, as well as important considerations for third-party payer systems, physicians, and patients. To develop a Markov model to determine the cost-effectiveness of nivolumab, ipilimumab, and nivolumab-ipilimumab combination as firstline therapy in metastatic melanoma, while accounting for differential effectiveness in programmed death-ligand 1 (PD-L1) positive and negative patients. A 3-state Markov model (PD-L1 positive stable disease, PD-L1 negative stable disease, and progression and/or death) was developed using a U.S. societal perspective with a lifetime time horizon of 14.5 years. Transition probabilities were calculated from progression-free (PF) survival data reported in the CheckMate-067 trial. Costs were expressed in 2015 U.S. dollars and were determined using national sources. Adverse event (AE) management was determined using immune-related AE (irAE) data from CheckMate-067, irAE management guides for nivolumab and ipilimumab, and treatment guidelines. Utilities were obtained from published literature, using melanoma-specific studies when available, and were weighted based on incidence and duration of irAEs. Base case, one-way sensitivity, and probabilistic sensitivity analyses were conducted. Nivolumab-ipilimumab combination therapy was not the cost-effective choice ($454,092 per PF quality-adjusted life-year [QALY]) compared with nivolumab monotherapy in a base case analysis at a willingness-to-pay threshold of $100,000 per PFQALY. Combination therapy and nivolumab monotherapy were cost-effective choices compared with ipilimumab monotherapy. PD-L1 positive status, utility of nivolumab and combination therapy, and medication costs contributed the most uncertainty to the model. In a population of 100% PD-L1 negative patients, nivolumab was still the optimal treatment, but combination therapy had an improved incremental cost-effectiveness ratio (ICER) of $295,903 per PFQALY. Combination therapy became dominated by nivolumab, when 68% of the sample was PD-L1 positive. In addition, the cost of ipilimumab would have to decrease to < $21,555 per dose for combination therapy to have an ICER < $100,000 per PFQALY and to < $19,151 (a 42% reduction) to be more cost-effective than nivolumab monotherapy. Nivolumab-ipilimumab combination therapy was not cost-effective compared with nivolumab monotherapy, which was the most cost-effective option. Professionals in managed care settings should consider the pharmacoeconomic implications of these new immunotherapies as they make value-based formulary decisions, and future cost-effectiveness studies are completed. No funding supported this study. Merino was a contractor with EMD Serono at the time of this study but does not have any conflicts of interest and did not receive any funding related to this study. All other authors have no financial disclosures and no conflicts of interest. All the authors contributed to the study concept and design. Tran, McDowell, and Barcelon took the lead in data collection, along with Oh, Keyvani, and Merino. All authors except Merino contributed to data interpretation. The manuscript was written by Oh, Tran, McDowell, and Wilson and revised by Oh, Tran, McDowell, Wilson, and Keyvani. This analysis was presented at Academy of Managed Care Pharmacy Managed Care & Specialty Pharmacy Annual Meeting 2016, April 19-22, 2016, in San Francisco, California, and at the International Society for Pharmacoeconomics and Outcomes Research Annual International Meeting, May 21-25, 2016, in Washington DC.

The cost-effectiveness of alectinib in anaplastic lymphoma kinase-positive (ALK+) advanced NSCLC previously treated with crizotinib

Introduction Anaplastic lymphoma kinase (ALK) targeting drugs provide an important option for advanced non-small cell lung cancer patients with this distinct tumor type; however, there is considerable uncertainty as to which drug provides the optimal value after crizotinib treatment. This study estimated the cost-utility of alectinib vs ceritinib from a US payer perspective.Methods A cost-utility model was developed using partition survival methods and three health states: progression-free (PF), post-progression (PP), and death. Survival data were derived from the key clinical trials (alectinib: NP28761 & NP28673, ceritinib: ASCEND I and II). Costs included drugs, adverse events, and supportive care. Utilities were based on trial data and the literature. One-way and probabilistic sensitivity analyses (PSA) were performed to assess parameter uncertainty.Results Treatment with alectinib vs ceritinib resulted in increases of 2.55 months in the PF state, 0.44 quality adjusted life-years (QALYs), and $13,868, yielding a mean cost/QALY of $31,180. In the PSA, alectinib had a 96% probability of being cost-effective at a willingness-to-pay of $100,000/QALY. Drivers of model results were drug costs and utilities in the PF health state. The ICER ranged from $10,600–$65,000 per QALY in scenario analyses, including a sub-group analysis limited to patients with prior chemotherapy and crizotinib treatment.Conclusions Treatment with alectinib in ALK + crizotinib-treated patients increased time progression-free and QALYs vs ceritinib. The marginal cost increase was driven by longer treatment durations with alectinib. This model demonstrates that alectinib may be considered a cost-effective treatment after progression on crizotinib.

Economic Evaluation of Carfilzomib+Dexamethasone (Kd) Vs Bortezomib+Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma (R/RMM)

Background: Carfilzomib is an innovative second generation proteasome inhibitor (PI) that binds irreversibly and selectively to the proteasome. Carfilzomib exhibits sustained inhibition of the proteasome with minimal off-target activity. Kd was approved in 2016 as a treatment (Tx) option for R/RMM patients who have received one to three prior lines of therapy.In the ENDEAVOR phase 3, open label, multicenter randomized controlled trial assessing Kd vs Vd, median progression-free survival (PFS) was 18.7 months (95% CI:15.6 - could not be estimated) in the Kd group vs 9.4 months (8.4 - 10.4) in the Vd group at an a priori, pre-specified interim analysis (hazard ratio [HR]: 0.53 [95% CI: 0.44 - 0.65]; p<0.0001). OS data at the 1st interim analysis were immature. In the current study, we assessed the cost-effectiveness (CE) of Kd vs Vd from a US payer perspective using data from ENDEAVOR and long-term overall survival (OS) data from the Surveillance, Epidemiology, and End Results Program (SEER).Methods: A partitioned-survival model with a progression-free (PF), a post-progression (PP) and a death state was built with a 30 year horizon. PFS was modelled using separately fitted log-logistic parametric curves. In order to estimate measures of efficacy for OS and to incorporate treatment effect into the model, time-dependent multiple semiparametric Cox regression analyses were implemented for OS outcomes, which controlled for baseline covariates. OS for Vd in the base case was modelled with a separately fitted Weibull parametric curve, which was fitted to the Vd data. The time-dependent multiple Cox model generated a HR for 0 to 12 months and a HR beyond 12 months for Kd vs Vd, which were applied to model the Kd OS curve. The OS curves beyond 36 months were extrapolated with SEER data. A Weibull distribution was used for the extrapolation by matching the SEER registry data to the ENDEAVOR population, which was assumed to represent the Vd survival rate. To this extrapolated survival curve beyond 36 months, the OS treatment effect was applied in order to model the Kd curve.Grade ≥ 3 adverse events (AEs) with ≥ 2% incidence in any ENDEAVOR arm were included. Utilities were derived from the literature and adjusted for the treatment specific improvement in QoL observed when patients were PF in ENDEAVOR. Costs related to drug (WAC prices), administration, monitoring, AE management, and subsequent Tx were considered. The base case utilized OS results from an updated OS dataset (March 2016) that resulted in an ad hoc OS analysis. A 3% discount rate was applied to costs and health outcomes.Results: In the base-case, results from the model showed thatKd was more effective compared to Vd, providing 1.874 PfLY, 1.854 LY, and 1.654 QALY gains over the modelled horizon. Kd incurred $227,703 in total additional costs and the ICER vs Vd was 137,660$/QALY.Conclusions: The model predicts that Kd delivers 1.85 additional life years over the the comparator Vd. Per the base case, Kd is cost-effective vs Vd at generally accepted willingness-to-pay thresholds of $150,000/QALY and $300,000/QALY in the US. Based on the ENDEAVOR data, Kd is a superior PI-based doublet compared to Vd, and should be preferred whenever doublets are appropriate for the patient, Furthermore, this CE analysis shows that Kd delivers considerable incremental value to patients with relapsed or refractory MM and to payers who must allocate budgets for the treatment of patients. [Display omitted] DisclosuresJakubowiak:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Majer:Amgen Inc: Employment, Equity Ownership. Houisse:Amgen Inc: Consultancy. Benedict:Amgen Inc: Consultancy. Campioni:Amgen: Employment, Other: Holds Amgen Stock. Panjabi:Amgen Inc: Employment, Equity Ownership. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.