## 4 Discussion
In consideration of the recent NCCN Guidelines change that recommends pembrolizumab plus EV as the preferred 1L therapy, careful sequencing of agents should be considered regarding factors includingpatient characteristics (age, comorbidities) and treatment burden (toxicity, dosing schedule, costs) [33]. As value-based oncology care is becoming increasingly important in the US, the lower costs of 1L PBC followed by avelumab 1 LM compared with pembrolizumab plus EV should be taken into consideration [34]. Given that this analysis was based on retrospective, nonrandomized data, these results, while consistent with what is known from JB100 and other clinical trial data, should be interpreted with caution. As with all retrospective database studies, certain limitations apply, including the lack of patient randomization to treatment, prohibiting any causal inferences from being formed. The level of missing data for some variables in the database must be considered when interpreting the results of this study. Treatment sequences and discontinuation information are based on information in the patients' EHRs. Tumor progression was based on radiologist assessment or physician notes, which is subject to the physician's assessment. The complete care pathway is not captured in the Flatiron Health database, which does not contain inpatient data or complete medical history outside of the oncology EHR, which may have resulted in underreporting of treatments. In addition, cause of death data are not captured by the database, precluding a cancer-specific survival analysis. Clinical characteristics and lab values were frequently missing, which limits the interpretation of survival outcomes in this study. Namely, disease stage at initial diagnosis was not reported in 44% (n = 94) of patients, ECOG PS was not reported in 13% (n = 28) of patients, and PD-L1 status was missing in 70% (n = 150) of patients. Whereas disease stage at diagnosis was missing in 44% (n = 94) of patients, and 46% (n = 99) of patients were diagnosed with stage IV disease. Although this study included some patients with EGOG PS \(\geq\) 2 (n = 21, 9.8%) who would not have been eligible for enrolment in JB100, most patients had an ECOG of 0 or 1, similar to JB100 [5]. Of note, while the JB100 trial included survival outcomes by PD-L1 status, a post hoc analysis reported that no significant interaction between treatment and PD-L1 status was observed for OS, supporting the use of avelumab 1 LM, regardless of PD-L1 status [35]. Additionally, a recorded response to treatment was not reported in 20% (n = 43) of patients that received avelumab 1 LM, and less is known about the determination of these responses, which was not verified by the same blinded centralized review process performed in clinical trials. The results reported in this study are based on data collected from centers included in the Flatiron EHR network and may not reflect practice patterns observed in other cancer treatment institutions or patient populations. Finally, the study period represents a limitation, capturing patients who received avelumab 1 LM following US Food and Drug Administration approval in July 2020, through the end of the study period on December 31, 2022. As such, assessments were limited to approved treatments during that time, and treatments approved and incorporated into clinical guidelines in the time since the study period end have not been captured. An analysis of more recent data might reflect the use of therapies not available during the current study's time period and also reflect changes in NCCN Guidelines.