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Aims: Patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are eligible for first‐line immune checkpoint inhibition if their tumour is positive for programmed death ligand 1 (PD‐L1) determined by the combined positive score (CPS). This nationwide study, using real‐world data, investigated the developing PD‐L1 testing landscape in the first 3 years after introduction of the test in HNSCC and examined interlaboratory variation in PD‐L1 positivity rates. Methods: Pathology reports of HNSCC patients mentioning PD‐L1 were extracted from the Dutch Pathology Registry (Palga). Tumour and PD‐L1 testing characteristics were analysed per year and interlaboratory variation in PD‐L1 positivity rates was assessed using funnel plots with 95% confidence limits around the overall mean. Results: A total of 817 PD‐L1 tests were reported in 702 patients among 19 laboratories; 85.2% of the tests on histological material were stated to be positive. The national PD‐L1 positivity rate differed significantly per year during the study period (79.7–89.9%). The use of the recommended 22C3 antibody increased from 59.9 to 74.3%. A total of 673 PD‐L1 tests on histological material from 12 laboratories were analysed to investigate interlaboratory variation. Four (33%) deviated significantly from the national mean of PD‐L1‐positive cases using CPS ≥ 1 cut‐off, while two (17%) deviated significantly for CPS ≥ 20 cut‐off. Conclusion: In the first 3 years of PD‐L1 assessment in HNSCC, the testing landscape became more uniform. However, interlaboratory variation in PD‐L1 positivity rates between Dutch laboratories was substantial. This implies that there is a need for further test standardisation to reduce this variation. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICI) have dramatically changed the landscape of metastatic urothelial carcinoma (UC). However, optimal duration of treatment with ICI in the metastatic setting remains unclear. On the basis of real-world data from the Netherlands of patients treated with pembrolizumab for metastatic UC, we point out that early discontinuation of ICI seems to be reasonable in a subgroup of patients, especially in patients with responding disease (partial or complete response). It is important to draw attention to this topic and to pursue further efforts to evaluate shorter treatment duration for optimizing patient care and outcomes, but also for keeping healthcare affordable. Background: Since there is no clear consensus on optimal treatment duration of PD-(L)1 targeting checkpoint inhibitors in the setting of urothelial cancer (UC) patients, even patients with durable responses are often treated up to 2 years. It is questionable whether this is necessary and whether quality of life improves when treatment is discontinued earlier and restarted when necessary. Methods: We collected available data from locally advanced or metastatic UC patients within the Netherlands between September 2017 and December 2019 treated with first or second-line pembrolizumab, to evaluate treatment duration, reasons for discontinuation, subsequent treatments and survival outcomes. Results: Data were available from 74 patients: 85% (63/74) of patients had a treatment duration of 12 months or shorter, and in seven out of them, treatment was discontinued for another reason than progressive disease. Two patients (3%) had a treatment duration between 12 and 24 months, and eight patients (11%) completed 24 months of treatment. Survival at data cut-off (1 July 2020) with a median follow-up of 35 months was 100% in patients with partial or complete response (6/7 patients) and treatment duration ≤ 12 months, and 100% in patients treated for 24 months. In total, three patients were re-treated with pembrolizumab upon progressive disease during follow-up. Conclusions: In patients who reach partial or complete response during treatment with a PD-(L)1 targeting checkpoint inhibitor, early discontinuation of treatment with pembrolizumab and restart if necessary seems to be reasonable with preserved favorable outcomes. This article should drive further efforts to optimize the treatment duration for patients who respond to treatment with pembrolizumab. [ABSTRACT FROM AUTHOR]

Background: The phase 3 clinical trial KEYNOTE-426 suggested a higher efficacy regarding overall survival (OS) and progression-free survival (PFS) of pembrolizumab+axitinib compared to sunitinib as a first-line treatment for patients with advanced renal cell carcinoma. In this analysis, the potential cost-effectiveness of this combination treatment versus sunitinib for patients with advanced clear-cell renal cell carcinoma (accRCC) was examined from the societal perspective in the Netherlands. Methods: For this analysis, a partitioned survival model was constructed. Clinical data were obtained from the published KEYNOTE-426 trial reports; data on costs and (dis-)utilities were derived from published literature. Costs outside of the healthcare sector included treatment-related travel, informal care and productivity loss. Next to a probabilistic scenario analysis, various scenario analyses were performed that aimed at survival extrapolation, different utility values, treatment duration and drug pricing, as well as restricting the cohort to patients with an intermediate or poor prognosis. Further, a budget impact analysis over three years was conducted, in which a sensitivity analysis concerning ranges in costs and the number of patients was applied. Moreover, a scenario concerning increasing market penetration of pembrolizumab+axitinib up to a market share of 80% in the third year was analyzed. Results: The incremental cost-effectiveness ratio (ICER) of pembrolizumab +axitinib was estimated at €368,396/quality-adjusted life year (QALY) gained, with an incremental QALY gain of 0.55 over sunitinib. The probability of costeffectiveness at a willingness-to-pay threshold of €80,000/QALY was estimated at 0%, a 50% probability was estimated at €340,000/QALY. Cost-effectiveness was not achieved in any of the applied scenarios. The budget impact over three years amounted to €417.3 million upon instantaneous and full replacement of sunitinib, and to €214.9 million with increasing market penetration. Conclusion: Pembrolizumab+axitinib was not estimated to be cost-effective compared to sunitinib as a first-line treatment for patients with accRCC in the Netherlands from a societal perspective. In none of the analyzed scenarios, costeffectiveness was achieved. However, price reductions and shorter treatment durations might lead to a more favorable ICER. [ABSTRACT FROM AUTHOR]

Background: High and increasing expenses on pembrolizumab ask for more cost-effective and sustainable treatment strategies to improve affordability of healthcare. Therefore, a part of the Dutch hospitals implemented an alternative, partially lower, weight-based dosing protocol for pembrolizumab. This provided the unique opportunity to compare the overall survival (OS) of the alternative pembrolizumab dosing protocol to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients., Methods: This is a retrospective cohort study with a non-inferiority primary objective. Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1966 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1st 2021, and Mar 31st, 2023. Alternative weight-based pembrolizumab dosing (100/150/200 mg Q3W or 200/300/400 mg Q6W) was administered to 604 patients, and 1362 patients received standard pembrolizumab dosing (200 mg Q3W or 400 mg Q6W). A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing protocols. The non-inferiority margin was set at a hazard ratio (HR) of 1.2 for OS. Non-inferiority is established by showing that the upper limit of the 95 % confidence interval (CI) of the HR of OS is smaller or equal to 1.2., Results: Distribution of age (66.7 years +/-9.4), sex (45 % female) and treatment combinations were similar for both groups, comorbidity score was higher in the standard group. Median daily dose in the alternative dosing group was 22 % lower compared to the standard dosing group, 7.14 mg/day (interquartile range (IQR):5.48-8.04 mg/day) vs. 9.15 mg/day (IQR:8.33-9.52 mg/day), respectively. Alternative dosing was non-inferior to standard dosing regarding overall survival (adjusted HR 0.83, 95 %CI:0.69-1.003)., Conclusion: This large, retrospective real-world analysis supports the hypothesis that the alternative, partially lower pembrolizumab dosing protocol in NSCLC maintains treatment effectiveness while reducing treatment costs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Ruben Malmberg has received payment for lectures from BMS. Roelof van Leeuwen has received grants from BMS and Pfizer, consulting fees from BMS, MDS, Pfizer, Pierre Fabre, AstraZeneca, and Roche, and payment for presentations and attending meetings from AstraZeneca. Hans Smit is a member on the advisory board of BMS and MSD and is a member representative of the Dutch scientific committee for pulmonary disease (no payments involved). Juliëtte Zwaveling has received a grant from AstraZeneca. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Managed entry agreements and especially financial-based agreements are commonly used in European countries for innovative cancer pharmaceuticals. These agreements facilitate access to innovative treatments while mitigating financial risks for payers. This study focuses on the confidential price agreement made by the Dutch government for the reimbursement of pembrolizumab, the implications of broadening indications on cost-effectiveness, and the viability or desirability of said agreement., Methods: We selected 5 indications in which pembrolizumab was deemed effective and developed portioned survival models for each indication. Survival and progression-free survival data from the published trials were utilized to recreate individual patient data, and we extrapolated-using parametric models-to a time horizon of 30 years. Inputs for both quality of life and costs were derived from the available literature and were indexed., Results: The incremental cost-effectiveness ratios ranged between €35 313 and €322 349 per quality-adjusted life-year, depending on the indication. Only 1 indication fell under the €80 000 (or €100 000) cost-effectiveness threshold. When applying the average reported discount on intramural pharmaceuticals in The Netherlands, incremental cost-effectiveness ratios ranged between €20 881 and €252 934 per quality-adjusted life-year gained, and the €80 000 (or €100 000) threshold was met in 3 indications out of 5., Conclusions: Our results show that pembrolizumab could be cost-effective in some indications, depending on the confidential price agreement established. However, the possibility of reimbursing not cost-effective care when the price is anchored in 1 indication remains possible. Indication-based pricing could help align value and price for innovative pharmaceuticals that are subject to indication broadening., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

This study aims to assess how clinical outcomes of immunotherapy in real-world (effectiveness) correspond to outcomes in clinical trials (efficacy) and to look into factors that might explain an efficacy-effectiveness (EE) gap. All patients diagnosed with stage IV non-small cell lung cancer (NSCLC) in 2015–2018 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. Progression-free survival (PFS) and overall survival (OS) from first-line (1L) pembrolizumab and second-line (2L) nivolumab were compared with clinical trial data by calculating hazard ratios (HRs). From 1950 diagnosed patients, 1005 (52%) started with any 1L treatment, of which 83 received pembrolizumab. Nivolumab was started as 2L treatment in 141 patients. For both settings, PFS times were comparable between real-world and trials (HR 1.08 (95% CI 0.75–1.55), and HR 0.91 (95% CI 0.74–1.14), respectively). OS was significantly shorter in real-world for 1L pembrolizumab (HR 1.55; 95% CI 1.07–2.25). Receiving subsequent lines of treatment was less frequent in real-world compared to trials. There is no EE gap for PFS from immunotherapy in patients with stage IV NSCLC. However, there is a gap in OS for 1L pembrolizumab. Fewer patients proceeding to a subsequent line of treatment in real-world could partly explain this. [ABSTRACT FROM AUTHOR]

Background Similar to the earlier anti-cancer therapies, monoclonal antibodies were introduced in bodysize-based schedules, despite the fact that body size only modestly effects the distribution, elimination and efficacy of monoclonal antibodies. Fixed-dosing of nivolumab and pembrolizumab has recently been approved by the European Medicines Agency. Objective To investigate the implementation of fixed-dosing of nivolumab, pembrolizumab and other monoclonal antibodies in the treatment of cancer. Method An online questionnaire was distributed among Dutch hospitals in January 2019. Results The majority of the hospitals (> 60%) responded, with a good representation of the characteristics of the hospitals in the Netherlands. Most hospitals which prescribe nivolumab and/or pembrolizumab have introduced fixed-dose-based schedules. However, the dosing of the other monoclonal antibodies was still based on body size. Conclusion Fixed-dosebased schedules of nivolumab and pembrolizumab have been rapidly implemented in most Dutch hospitals after approval of the European Medicines Agency. Despite emerging evidence which supports fixed-dose-based schedules for almost all the other monoclonal antibodies, its implementation stays behind. To increase the acceptance of fixed-dose-based schedules of monoclonal antibodies in the guidelines, additional studies may be needed, which focus on evaluating exposure, activity and cost effectiveness with the attempt to uncover the exact savings in costs for patient care. [ABSTRACT FROM AUTHOR]

Age-related immune dysfunction (ARID) describes age-associated changes in immunity that may affect the efficacy of immunotherapy with checkpoint inhibitors. We evaluated the efficacy of treatment with ipilimumab (530 patients) or pembrolizumab (562 patients) in a Danish national cohort of metastatic melanoma patients. We confirmed known prognostic biomarkers related to treatment with ipilimumab and found no impact of age on survival or progression-free survival. In patients treated with pembrolizumab, we also confirmed known prognostic biomarkers. Overall survival (OS) and progression-free survival was significantly higher in patients aged between 70 and 80 years compared with younger patients. In multivariate analysis with OS as end-point, age was shown to be an independent good prognostic biomarker in these patients. Survival in patients aged above 80 years was not better than in younger patients, probably because of increase in significant comorbidity. Our analyses have revealed a higher survival rate when using drugs targeting PD1 in metastatic melanoma patients between the age of 70 and 80 years. ARID does not seem to negatively impact the efficacy of treatment with checkpoint inhibitors in metastatic melanoma patients. Despite these encouraging data for elderly patients, clinicians still need to carefully consider the higher risk of more serious outcomes of the immune-related adverse events in the elderly patient population, before deciding to treat old patients with checkpoint inhibitors. • Large national cohort of metastatic melanoma patients treated with anti-CTLA4 or anti-PD1. • Age between 70 and 80 predicts better survival after treatment with anti-PD1 compared with younger patients. • Survival is not affected by age using anti-CTLA4 as checkpoint inhibitor in metastatic melanoma patients. [ABSTRACT FROM AUTHOR]

Background: Little is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR, a population-based registry to monitor the quality and safety of melanoma care in the Netherlands. This study aims to describe treatment patterns, relapse, and toxicity rates of adjuvant-treated melanoma patients beyond the clinical trial setting., Methods: Analyses were performed on adjuvant-treated melanoma patients included in the DMTR. Descriptive statistics were used to analyse patient-, and treatment characteristics. A baseline registration completeness analysis was performed, and an analysis on trial eligibility in clinical practice patients. Recurrence-free survival (RFS) at 12-months was estimated with the Kaplan-Meier method., Results: A total of 641 patients were treated with adjuvant anti-PD-1 therapy. RFS at 12-months was 70.6% (95% CI, 66.9-74.6) with a median follow-up of 12.8 months. Sex, stage of disease and Breslow thickness were associated with a higher hazard for RFS. Eighteen per cent of the anti-PD-1-treated patients developed grade ≥3 toxicity. Sixty-one per cent of patients prematurely discontinued anti-PD-1 therapy., Conclusion: Adjuvant anti-PD-1 treatment of resected stage III/IV melanoma in daily practice showed slightly higher toxicity rates and more frequent premature discontinuation but similar RFS rates compared to trials., Competing Interests: Conflict of interest statement AvdE has advisory relationships with Amgen, Bristol Myers Squibb, Roche, Novartis, MSD, Pierre Fabre, Sanofi, Pfizer, Ipsen, Merck and has received research study grants not related to this paper from Sanofi, Roche, Bristol Myers Squibb, Idera and TEVA and has received travel expenses from MSD Oncology, Roche, Pfizer and Sanofi and has received speaker honoraria from BMS and Novartis. MBS has consultancy/advisory relationships with Pierre Fabre, MSD and Novartis. JdG has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, Novartis. GH consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Pierre Fabre and has received research grants not related to this paper from Bristol Myers Squibb, Seerave. EK has consultancy/advisory relationships with BristolMyers Squibb, Novartis, Merck, Pierre Fabre, and received research grants not related to this paper from Bristol Myers Squibb. KS has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, Abbvie and received honoraria from Novartis, MSD and Roche. AvdV has consultancy relationships with Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, Eisai, Merck. JH has advisory relationships with Achilles Therapeutics, Bristol Myers Squibb, BioNTech, Immunocore, Ipsen, MSD, Merck Serono, Molecular Partners, Novartis, Neogene Therapeutics, PokeAcel, Pfizer, Roche/Genentech, Sanofi, T-Knife, Third Rock Ventures, and has received research grants not related to this paper from Amgen, Bristol Myers Squibb, MSD, BioNTech, Neogene Therapeutics and Novartis. All grants were paid to the institutions. The funders had no role in the writing of this article or decision to submit it for publication. AvA has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC. Research grants from Amgen, Merck-Pfizer. All outside of current work and all paid to institute. MA has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer. Research grants Merck-Pfizer. Not related to current work and paid to institute. HMW has received travel expenses from Ipsen and Astellas and has received honoraria from Roche and Astellas. RvR has received expert meeting fees from Roche and advisory board fees from Pfizer. EE has received speaker honoraria from BMS, Pierre Fabre, Kyowa Kirin, and travel/conference expenses from MSD. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)