Choosing PD-1 Inhibitors in Oncology Setting, Left or Right?—Lessons From Value Assessment With ASCO-VF and ESMO-MCBS

Background: Influx of innovative therapies and dramatic rise in prices have been prompting value-driven decision-making. Both the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have independently proposed value assessment frameworks. Objectives: To comprehensively examine the value of nivolumab and pembrolizumab by two value assessment frameworks with a cohort of published randomized controlled trials and offer insight into the association between these two frameworks. Methods: Trials were identified with a cutoff date of Nov 30th, 2019. Receiver operating characteristic curves were generated to establish the predictive value of ASCO-VF score to meet ESMO-MCBS grade and discriminate the agreement of these two value assessment tools. Spearman correlation was used to assess the association between monthly cost and ASCO-VF score/ESMO-MCBS grade. Results: 19 randomized controlled trials were eligible. seven (36.8%) trials were of treatment included nivolumab while 12 (63.2%) pembrolizumab. 8 (42.1%) of the trials were of treatments for non-small-cell lung cancer, 5 (26.3%) for melanoma, 2 (10.5%) were for head and neck squamous cell carcinoma, 2 (10.5%) for gastric or gastro-oesophageal junction cancer and 1 (5.3%) for urothelial cancer and renal-cell carcinoma respectively. ASCO scores ranged from 7 to 94.7 with median 40.90. 11 (57.9%) trials met the ESMO criteria for meaningful value achieved. Of 14 trials not meeting the ASCO cutoff score, only 8 did not meet the meaningful ESMO criteria. Agreement between these two frameworks thresholds was only fair (κ = 0.412, P＜0.05). A negative correlation was noted between increment monthly cost and value assessment results. Conclusion: There is only fair correlation between ASCO and ESMO value assessment frameworks. Not all treatment with nivolumab and pembrolizumab meet valuable thresholds.


INTRODUCTION
Influx of innovative therapies, particularly the targeted drugs and immunotherapies have marked major therapeutic advances in oncology. Nevertheless, dramatic rise in prices of these drugs supports the growing concern whether their value demonstrated by evidence is commensurate with the high prices and is challenging to put into practice (Promoting Value, 2018). Favorable evidence for high-value drugs could incentivize the development of novel drug regimens and facilitate conversations in clinical practice. To facilitate value-driven decision-making, an evolving field from the perspective of stakeholders-physicians, patients, health care insurers, etc., including the American Society of Clinical Oncology (ASCO) (Schnipper et al., 2015;Schnipper et al., 2016) and the European Society for Medical Oncology (ESMO) (Cherny et al., 2015;Cherny et al., 2017) have independently proposed frameworks as unbiased tools for systematic assessment of value of anticancer drugs, justifiably evaluating high quality therapies affordable for various cancer disease states.
To date, only a few reports have focused on application of two prominent tools-ASCO Value Framework (ASCO-VF), or the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), or both according to a contemporary cohort of randomized controlled trials (RCTs) to assess the value of anticancer drugs, suggesting that not all approved drugs were significantly associated with meaningful value and additionally exploring the extent of concordance or discordance between these two respective frameworks (Del Paggio et al., 2017;Foote et al., 2017;Vivot et al., 2017;Djatche et al., 2018). However, studies of value assessment were limited.
New anticancer drugs approved by the Food and Drug Administration are expected to be of high value. For example, programmed cell death (PD-1) inhibitors (nivolumab and pembrolizumab) have revolutionized cancer therapy and have shown potential efficacy for a wide range of tumor types based on data from published studies. These approvals have resulted in a widespread prescribing of PD-1 inhibitors in real-world clinical practice. Up to now, numerous RCTs have reported the benefits and safety of PD-1 inhibitors. Unfortunately, not all cancer patients-now and in the future-might be able to afford these drugs because of their high prices. Furthermore, patients know the high prices of these drugs but not their value, or misunderstand the drugs prices and their value, both of which might stifle innovation in the development of anticancer drugs and in turn prevent the patients from achieving optimal cancer care.
Overall, we performed this study to comprehensively integrate the value of two PD-1 inhibitors (nivolumab and pembrolizumab) by ASCO-VF and ESMO-MCBS in a cohort of RCTs and offer insight into the association between these two frameworks as an important structured evidence for clinicians in making clinical decisions.

Study Cohort and Eligibility Criteria
Phase III RCTs that compared nivolumab and pembrolizumab alone or in combination with chemotherapy, hormonal therapy, other targeted agents, etc., to the same regimen without them used in the intervention group irrespective of the cancer type and stage were identified.
Reports of secondary, subset, or pooled data, phase I or II trials, animal studies, or trials that assessed drug delivery or single-drug dosing schedules were excluded.

Literature Search
Systematic search of electronic databases including the Cochrane Controlled Trials Register on the Cochrane Library, MEDLINE, EMBASE, and Science Citation Index was conducted using the terms nivolumab, pembrolizumab and PD-1 inhibitor, with a cutoff date of Nov 30, 2019. Both MeSH and free text terms were used to identify relevant articles. Reference lists of pertinent retrieved articles were reviewed for additional studies, and ClinicalTrials. gov was also checked in June 2019 to ensure that data from previously published trials were updated on the registry.

Study Process
Two authors (HW and HL) independently conducted the literature search, screened titles and abstracts for potential eligibility and full texts for final eligibility. In case of disagreement, a consensus was reached through discussion.
Treatments were classified as curative or palliative according to the trial population. Two reviewers extracted the data using a standardized extraction form, including but not limited to the trial name, phase, cancer type, PD-1 inhibitor used, dosing schedule, follow-up time and outcomes in accordance with the ASCO-VF and ESMO-MCBS for all eligible studies. ASCO-VF scores and ESMO-MCBS grades were independently recorded. Any discrepancies were discussed among all authors to establish a final score or grade.
To assess the monthly cost of therapeutic regimen including the cost of all anticancer drugs in the study regimen, we used the price for branded and generic drugs recorded in the Hospital Information System (HIS). Monthly costs were calculated over an average of 30 days based on the dosage schedule in all eligible trials for a patient weighing 60 kg with a body surface area of 1.70 m 2 . Ultimately, incremental monthly drug costs as the difference between the experimental and control groups were reported. The most expensive one was recorded if there were several options of therapeutic regimen in the control group. All therapeutic regimens were adjusted to provide the price per 4-week period.

Statistical Analysis
All data were collected using structured Excel sheets designed for this study. Statistical analysis was performed using IBM SPSS 25.0. Continuous data of ASCO-VF scores were plotted and analyzed to assess the normality of the underlying distribution. Since ASCO-VF has no explicit definition for what score is deemed "meaningful value achieved"; we split scores at the 75th percentile of ASCO-VF scores as the cutoff score, referring to the meaningful value achieved of ESMO-MCBS as a grade of 4, 5, B, or A. We split the cutoff scores for subsequent analyses. A score above the cutoff was defined as "meaningful value achieved" while a score below the cutoff indicated "meaningful value not achieved". Receiver operating characteristic (ROC) curves were generated to establish the Frontiers in Pharmacology | www.frontiersin.org December 2020 | Volume 11 | Article 574511  predictive value of ASCO-VF score to meet ESMO-MCBS grade and discriminate the agreement of these two value assessment tools. Subgroups analyses were performed according to palliative and curative intent of the eligible trials. Spearman's correlation was used to assess the association between monthly cost and ASCO-VF score/ESMO-MCBS grade. A p < 0.05 was deemed significant for all analyses.

Value Scores/Grades
ASCO-VF scores ranged from 7 to 94.7 (Figure 1), and the scores were normally distributed. Median ASCO-VF score was 40.90, with inter-quartile range (IQR) 33.30. Ten (52.6%) trials fell below, while nine (50.1%) trials were above. Since ASCO-VF has no explicit definition of what score is deemed "meaningful value achieved"; we split scores at the 75th percentile of ASCO-VF scores-63.3 as the cutoff score, referring to the meaningful value achieved of ESMO-MCBS as a grade of 4, 5, B, or A. Therefore, five (26.3%) trials were above the threshold whereas 14 (73.3%) fell below. Eleven (57.9%) of the 19 RCTs met the ESMO-MCBS criteria for meaningful value achieved. Of the 14 trials that did not meet the ASCO-VF cutoff score, only eight did not meet the ESMO-MCBS "meaningful value achieved" criteria.

Association Between ASCO-VF and ESMO-MCBS
ROC curve was used to establish a discrimination threshold of ASCO-VF scores in relation to the ESMO-MCBS criteria, and the threshold score was approximately 40, which was comparatively close to the median ASCO-VF value scores. Nevertheless, the area under the curve was 0.795 (p＜0.05) (Figure 2), suggesting only fair predictive value. Agreement between ASCO-VF and ESMO-MCBS thresholds was only fair (κ 0.412, p＜0.05).

Correlation Between Cost and Value Results
Incremental monthly cost data, ranged from ¥28,426.40 to ¥47,661.88, were not normally distributed and were analyzed with non-parametric statistics. Incremental monthly cost and ASCO-VF scores were negatively correlated (Spearman's ρ −0.272; p 0.260), and a negative correlation was also noted between incremental monthly cost and ESMO-MCBS grades (Spearman's ρ −0.088; p 0.720).  Frontiers in Pharmacology | www.frontiersin.org December 2020 | Volume 11 | Article 574511

Summary of Key Findings
To the best of our knowledge, this was the first study that applied ASCO-VF and ESMO-MCBS to comprehensively address the value of two PD-1 inhibitors, nivolumab and pembrolizumab, and offer insight into the association between these two frameworks.
Most studies focused on NSCLS and melanoma. In addition to NSCLC, melanoma, head and neck squamous cell carcinoma and gastric or gastro-esophageal junction cancer, only one trial compared nivolumab in renal cell carcinoma while another compared pembrolizumab in urothelial cancer (Cella et al., 2016).
There were some conflicting results. For gastric or gastroesophageal junction cancer, ASCO-VF scores and ESMO-MCBS grades showed that both nivolumab and pembrolizumab were of little value, with ASCO-VF scores 7 vs. ESMO-MCBS grade 1 for nivolumab (Reck et al., 2016) and ASCO-VF scores 30 vs. ESMO-MCBS grade 3 for pembrolizumab (Eggermont et al., 2018). For the second-line treatment for recurrent or metastatic head and neck squamous cell carcinoma, nivolumab (ASCO-VF scores 82.5 vs. ESMO-MCBS grade 4) was valuable (Borghaei et al., 2015;Harrington et al., 2017), but pembrolizumab was not (ASCO-VF scores 30.8 vs. ESMO-MCBS grade 3) . For melanoma, discordant ASCO-VF scores and ESMO-MCBS grades were generated except CheckMate 066 (Robert et al., 2015;Long et al., 2016) and CheckMate 037 (Robert et al., 2015) examining the efficacy and safety nivolumab for melanoma. For CheckMate 066, ASCO-VF score was highest and ESMO-MCBS grade was only 4. For NSCLC, results were almost the same with ASCO-VF scores and ESMO-MCBS grades. For CheckMate 017 (Motzer et al., 2015; examining the second-line treatment of nivolumab for squamous-cell stage IIIB or IV NSCLC after platinum-based therapy, and KEYNOTE-024 (Herbst et al., 2016;Brahmer et al., 2017) examining the first-line pembrolizumab treatment for stage IV NSCLC with EGFR and ALK wild type, both ASCO-VF scores and ESMO-MCBS grades were high, demonstrating that they were valuable.

Strengths and Limitations
This study fills a crucial knowledge gap regarding the value of PD-1 inhibitors among cancer patients. Several strengths should be noted. Firstly, each trial had a wide range of ASCO-VF scores. Secondly, not all trials met the ESMO-MCBS "meaningful value achieved" criteria. Thirdly, only a fair association was found between ASCO-VF and ESMO-MCBS. Fourth, there was no correlation between incremental monthly cost and ASCO-VF scores or ESMO-MCBS grades.
Irrespective of whether the trials described patients with specific PD-1 expression level, high ASCO-VF scores and ESMO-MCBS grades were recorded.
Nevertheless, this study also had several limitations. Firstly, the ASCO-VF score and ESMO-MCBS grade of the trials with the largest sample size was not high and did not meet the ASCO-VF cutoff score and the ESMO-MCBS "meaningful value achieved" criteria. Secondly, the association between ASCO-VF and ESMO-MCBS was only moderate in a cohort of 19 trials, substantially similar to those reported by others except one study including only a small number of trials (n 5). Extensive efforts are needed to improve convergence of the two value assessment tools based on our findings. Thirdly, since ASCO-VF has no explicit definition of what score is deemed "meaningful value achieved"; we split scores at the 75th percentile of ASCO-VF scores-63.3 as the cutoff score, referring to the meaningful value achieved of ESMO-MCBS as a grade of 4, 5, B, and A. Nevertheless, changing this cutoff score will change the degree of correlation between these two tools.

Clinical and Research Implications
This study sheds light on the important clinical issue about the comparative value of PD-1-related treatment. Our results demonstrated the value of a drug should not be judged solely by its price. It is necessary to conduct value assessment to insight the date beyond RCTs.

CONCLUSION
There is only fair correlation between ASCO-VF and ESMO-MCBS. Not all treatments with nivolumab and pembrolizumab meet valuable thresholds according to value assessment tools established by ASCO or ESMO. Given the high prices of these drugs, valuable, appropriate and affordable treatment is important for decision-making.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTIONS
QJ study design, drafting out and revising the manuscript critically for important intellectual content. MF study design, analysis and method directing. YPL participated in its design, revising the manuscript. JYL analysis and interpretation of data. HW analysis and interpretation of data. QJ and TY: conceiving of the study, revising the manuscript finally.

FUNDING
Beijing Medical and Health Foundation (B20021CS).