Evaluation of interim modifications for extended dosing intervals of durvalumab for locally advanced unresectable stage III non-small cell lung cancer during the COVID-19 pandemic

Introduction

Background

The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on the healthcare system, including disruptions in the availability and access to essential cancer services, such as surgery, radiationtherapy, systemic therapy delivery, and diagnostic imaging. Patients with lung cancers are amongst the most vulnerable populations who are at risk of pulmonary complications from coronavirus disease (1-3). With a view of reducing the risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS‑CoV2) in these at-risk patients, the re-evaluation of dosing protocols for immune checkpoint inhibitors in patients with lung cancer emerged during the early phase of the COVID-19 pandemic (4-6). Several studies consistently demonstrated no compromise in either clinical effectiveness or safety when reducing the frequency of administration at a higher dosage (6-8).

Rationale and knowledge gap

Durvalumab is the first approved immunotherapy PD-L1 agent for patients with stage III non-small cell lung cancer (NSCLC) associated with improving overall survival (OS) (9). It was initially approved by the Food and Drug Administration (FDA) in February 2018 with a dosing schedule of 10 mg/kg every 2 weeks based on positive progression-free survival (PFS) data from the PACIFIC trial (9,10). In Canada, it was approved by Health Canada in May 2018 with the same recommended dose (11). The decision to allow weight-based dosing for durvalumab was informed by a pharmacokinetic model study, which showed a comparable median steady-state exposure for weight-based dosing regimen from 10 mg/kg every 2 weeks to 20 mg/kg every 4 weeks compared to a flat-dosing regimen (12). In January 2020, Ontario Health’s Provincial Drug Reimbursement Program (PDRP) began funding durvalumab for treatment of locally advanced unresectable stage III NSCLC following concurrent chemoradiation. The recommended dose is 10 mg/kg intravenously (IV) once every 2 weeks for up to 12 months, or until disease progression or unacceptable toxicity, whichever occurs first. In response to the disruptions caused by COVID-19, PDRP introduced an alternative dosing schedule of 20 mg/kg IV (up to a maximum of 1,500 mg) every 4 weeks in April 2020. This measure, developed with input from provincial cancer experts, was implemented to reduce patients’ exposure to SARS-CoV-2 and was officially approved in Ontario on June 26, 2024.

In addition to the pharmacokinetic evidence, several real-world studies have investigated the utilization of extended dosing intervals for durvalumab in patients diagnosed with locally advanced unresectable stage III NSCLC (13-16). Real-world studies have suggested extended dosing intervals for durvalumab would be a safe and effective modification for NSCLC patients during the pandemic (13-16). However, these studies have included small sample sizes and comparisons have been made between treatment groups that combine patients that remained on one dosing regimen with patients switching between dosing regimens. The results of studies combining switching and non-switching patients may not be generalizable to patients in Ontario, as patients who initiated durvalumab after the Ontario COVID-19 policy change would have received and remained on extended dosing, while those who started durvalumab prior to the policy change would have remained on standard dosing. Ontario clinicians highlighted that the presence of non-switching standard (STD) and extended dosing (EXT) groups because of the policy change, presented an opportunity to identify potential differences in effectiveness and safety between the two dosing regimens. Further, real-world comparisons can be improved with a larger study cohort that is more representative of patients across the province and can support the application of statistical methods that balance treatment characteristics between treatment groups. Additional real-world investigations can contribute to the existing body of knowledge and increase confidence around extended dosing schedules.

Objective

The objective of this study was to assess the real-world effectiveness and safety of interim modifications of extended dosing intervals (20 mg/kg q4 weeks) of durvalumab compared to standard dosing intervals (10 mg/kg q2 weeks) for patients treated in the adjuvant setting after concurrent chemoradiation for stage III NSCLC during the COVID-19 pandemic. We present this article in accordance with the STROBE reporting checklist (available at https://ace.amegroups.com/article/view/10.21037/ace-24-16/rc).

Methods

This was a retrospective, population-level, observational cohort study conducted in Ontario, Canada using administrative health services data housed at Ontario Health (Cancer Care Ontario). Research ethics approval was not required as per an Ontario Health (Cancer Care Ontario) privacy assessment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Cohort identification

Lung cancer patients were identified from the Ontario Cancer Registry (OCR) using ICD-O-3 codes (C340, C341, C342, C343, C348, and C349) and were linked to the New Drug Funding Program (NDFP) and the Cancer Activity Level Reporting (ALR) databases to identify those who received durvalumab treatments for NSCLC. To be eligible for durvalumab treatment under the NDFP policy, patients had to have locally advanced, unresectable stage III NSCLC and to have already received curative-intent platinum-based concurrent chemoradiation therapy. The study included patients who initiated and received a minimum of two doses of durvalumab between December 19, 2018, and December 31, 2021 within 12 months of diagnosis of NSCLC. Patients were followed until death or until the end of the follow-up period (December 31, 2022). Patients were excluded if they were <18 or >105 years of age or had a missing or invalid health card number.

Durvalumab treatment visits were categorized into two groups: STD and EXT, based on the weight-based dose and interval used during treatment. Standard dosing was 10 mg/kg administered once every 2 weeks, and extended dosing was 20 mg/kg administered once every 4 weeks, up to a maximum of 1,500 mg. Based on the dosing schedule patterns, patients were divided into seven groups, comprising two non-switching groups (STD and EXT) and five switching groups, representing patients who transitioned between dosing schedules during their treatment periods (STD to EXT, EXT to STD, STD to EXT to STD, EXT to STD to EXT, and STD to EXT to STD to EXT). Our study primarily focused on the comparison between the two non-switching groups (STD and EXT). These groups included patients who started STD and remained on STD through the follow-up period, as well as those who started on EXT on or after April 2020 and remained on EXT throughout the follow-up period.

Given that some physicians preferred to initiate all patients with STD dosing and transition to EXT dosing for those exhibiting good tolerance, sensitivity analyses were conducted to evaluate the impact of patients switching from STD to EXT on our findings. The sensitivity analysis included patients who began and remained on STD or EXT throughout the follow-up period and patients who switched from STD to EXT throughout the follow-up period; patients who switched from EXT to STD or who switched more than once between doing schedules were excluded. A descriptive sensitivity analysis included patients who began and remained on STD or EXT throughout the follow-up period, switched STD to EXT, and switched from STD to EXT to STD throughout the follow-up period; patients who switched from EXT to STD, EXT to STD to EXT, and STD to EXT to STD to EXT were excluded.

Covariates and data sources

Demographic characteristics including age at initiation of durvalumab treatment, sex, height, body mass index (BMI) at initiation of durvalumab treatment. Geographic and socioeconomic characteristics included after-tax median household income, rurality, health region (Central, East, North, Toronto, and West Ontario), and the Ontario-Marginalization index summary score quintiles, a measure of neighborhood-level deprivation. These data were obtained from the 2016 Canada Census using the Postal Code Conversion File (PCCF+ version 7D) and the patients’ postal codes recorded at the time of their first durvalumab treatment.

Patient data was linked to the OCR by health card number to obtain the date of NSCLC diagnosis, cancer stage, tumor histologic type, prior history of NSCLC, and other cancer diagnoses. The Eastern Cooperative Oncology Group (ECOG) performance status was captured via NDFP at the time of durvalumab enrollment.

Comorbidity was estimated using the Charlson Comorbidity Index from hospital encounters using the Discharge Abstract Database (DAD) and National Ambulatory Care Reporting System (NACRS) databases and a 3-year look-back period from the start date of durvalumab treatment. Diagnostic codes based on the ICD-10 classification system were used, excluding codes related to cancer (17). Previous history of chemotherapy and radiotherapy were obtained from the ALR database.

Durvalumab treatment characteristics were obtained from the NDFP database and included the number of treatment visits, total dose received, treatment duration (spanning from the first dose to the last dose of durvalumab), as well as the treatment initiation time in relation to the effective date of policy measures and COVID-19 waves.

Outcomes

The primary outcome was OS, measured from time of durvalumab treatment initiation until death from any cause within 2 years or until December 31, 2022, whichever came first. Date of death was obtained from OCR and the Registered Persons Database (RPDB). The data of the last healthcare encounter was obtained from the Ontario Health Insurance Program (OHIP), DAD, and NACRS databases. The follow-up period for mortality assessment was 24 months from initiation of durvalumab treatment.

The secondary outcomes were rate of unscheduled emergency department (ED) visits and hospital admissions from the first date of durvalumab treatment until the last date of durvalumab treatment plus an additional 30 days, or until the date of death, whichever came first. Unplanned ED visits were identified from NACRS, hospital admissions were identified from DAD, and the rates, which allowed multiple visits per patient to be counted, were calculated per 100 person-months.

Statistics

Descriptive statistics were conducted for patients in non-switching and switching groups. The primary analysis compared survival and safety between non-switching groups. A sensitivity analysis compared survival and safety between patients with STD combined with patients that switched from STD to EXT to patients with EXT, only. A second sensitivity analysis compared survival and safety between patients with EXT combined with patients that switched from STD to EXT to patients with STD, only. Comparative analyses of patients who switched from EXT to STD, EXT to STD to EXT, and STD to EXT to STD to EXT were not conducted due to small sample sizes.

Categorical variables were reported as frequencies and percentages; continuous variables were presented as means with standard deviations. Chi-squared tests or Fisher exact tests were used to compare the distribution of categorical variables between treatment groups. T-tests were used to assess differences in the means of continuous variables.

A propensity score matching (PSM) cohort was created to address potential confounding resulting from baseline imbalances between treatment groups. Propensity scores were calculated using multivariable logistic regression, estimating the likelihood of receiving extended dosing versus standard dosing. The logistic regression model was adjusted for 19 covariates, including age, sex, weight, BMI group, income, rurality, ON-Marginalization index summary score, Charlson comorbidity index, chronic obstructive pulmonary disease (COPD) specific comorbidity, ECOG status, staging, tumor histologic type (adenocarcinoma, squamous cell carcinoma, and other), previous NSCLC diagnosis, previous non-NSCLC diagnosis, time from diagnosis to first durvalumab treatment, time from last radiotherapy treatment to first durvalumab treatment, sum dose of previous radiotherapy, time from last chemotherapy treatment to first durvalumab treatment, and previous chemotherapy type. Covariates were selected a priori based on clinical knowledge of factors that could influence treatment assignment and independently impact outcomes. PSM methods employed optimal matching with a caliper distance of 0.2, sampled without replacement, and matched EXT and STD patients in a 1:1 ratio. Patients were hard matched on sex. Standardized differences of the baseline characteristics below 0.1 were considered indicative of appropriate balance between the EXT and STD groups, suggesting PSM methods effectively mitigated potential confounding factors from imbalance of baseline characteristics (18,19). Results were presented for both the crude and PSM cohorts.

All-cause mortality was analyzed descriptively without adjustment. To compare OS between the EXT and STD groups, a time-to-event analysis was conducted, with death considered as the event of interest. Patients were censored at 24 months of follow-up, or end of the study follow-up (December 31, 2022), whichever came first. Descriptive results were presented using Kaplan-Meier plots, and the log-rank test was presented to assess differences in OS between the two groups. Cox proportional hazards regression models were utilized to estimate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Proportionality assumptions were assessed visually through Kaplan-Meier plots and ln(-ln(survival)) plots, with small violations of the assumption taken into consideration. Differences in rates of unscheduled ED visits and hospital admissions were evaluated using zero-inflated negative binomial regression, since the distribution of the safety events was left-skewed and revealed a percentage of zero counts larger than expected (82.9% for unscheduled ED visits and 95.6% for hospital admissions). The natural logarithm of the follow-up time was incorporated as an offset in the analysis to account for varying follow-up durations between the groups.

Two sensitivity analyses comparing survival and safety were conducted: (I) patients who began and remained on STD throughout the follow-up period were compared to a combined group of patients who switched from STD to EXT or who began and remained on EXT throughout the follow-up period, and (II) patients who began and remained on EXT throughout the follow-up period were compared to a combined group of patients who switched from STD to EXT or who began and remained on STD throughout the follow-up period. The sensitivity analyses followed the same analytic methods described for the primary analysis.

Missingness was not identified for the effectiveness and safety outcomes. Missingness was identified for the covariate Stage group. Models were estimated with and without the level “UNK/MISSING” to assess the impact of the missing data on the study estimates (Tables S1,S2). No differences were identified when excluding the level “UNK/MISSING” thus it was not excluded from the study analyses.

All analyses were conducted at Ontario Health using SAS v9.4 (SAS Institute Inc., Cary, USA). Results were considered statistically significant at a two-tailed P<0.05 and were not adjusted for multiple comparisons.

Results

Study cohort and patient characteristics

This study included 771 patients with NSCLC who received at least two doses of durvalumab between December 19, 2018, and December 27, 2022 (Figure 1). Among these patients, 642 (83%) were non-switching, of whom 248 (39%) received EXT and 394 (61%) received STD. The remaining 129 patients switched between the STD and EXT dosing schedules during their treatment period. Among the switching patients, 100 patients receiving STD switched to EXT on or after April 2020. A PSM cohort of non-switching patients was created, resulting in a final cohort of 448 patients with an equal 1:1 ratio of patients in the EXT (n=224) and STD (n=224) groups.

Figure 1 Patient selection. NDFP, new drug funding program; ALR, activity level reporting; OCR, Ontario cancer registry.

The baseline characteristics of the crude and PSM cohorts are presented in Table 1. Following PSM methods, the average age of patients was 67.3 years at first durvalumab and 44.2% were female. All covariates, except health region and time from the last radiation to the first durvalumab within 6 weeks, achieved a favorable balance as indicated by standardized differences being less than 0.1. The durvalumab treatment characteristics for the crude and PSM cohorts are summarized in Table 2. In the PSM cohort, the cumulative total dose was 12,101.6 mg in the EXT group and 13,342.7 mg in the STD group (P=0.05). Treatment duration was similar between the EXT group and the STD group (8.9 vs. 9.1 months; P=0.62). All 224 (100%) patients in the EXT group initiated durvalumab treatment during the pandemic and on or after the interim extended dosing measures took effect (April 9, 2020), while 148 (66%) patients in the STD group initiated durvalumab treatment during pandemic, of whom 138 (93%) initiated durvalumab after the interim measures took effect.

All-cause mortality and OS

In the PSM cohort, patients were followed for a median of 18 months [interquartile range (IQR) 14–24] after starting durvalumab. During the follow-up period, 119 (27%) patients died from any cause. All-cause mortality after 24 months of follow-up was similar between the EXT and STD groups (24.6% vs. 28.6%; P=0.34). There was no significant difference in OS between the two treatment groups (log-rank test P=0.74; HR: 0.94, 95% CI: 0.66–1.35; P=0.74) (Figure 2, Table 3). Health region was the only factor that remained imbalanced within the PSM cohort, 52 (23%) patients from Central region, 73 (33%) patients from East region, 19 (9%) patients from Toronto region, and 80 (36%) patients from West region for the EXT group (Table 1). As such, an additional adjustment for health region was applied during modelling. As a result, adjustment for health region did not change this effect (HR: 0.98, 95% CI: 0.66–1.43; P=0.90) (Table 3).

Figure 2 Kaplan-Meier plots for overall survival by treatment group. (A) For the original cohort. (B) For the PSM cohort. EXT, extended dosing; PSM, propensity score matching; STD, standard dosing.

ED visits and hospital admissions

In the PSM cohort, patients in the EXT group had a higher crude rate of unscheduled ED visits per 100 person-months (5.1 vs. 4.6) and lower rate of hospital admissions (2.3 vs. 2.7) compared to patients in the STD groups. These differences were not statistically significant [ED visits rate ratio (RR): 2.07, 95% CI: 0.84–5.05; P=0.11 and hospital admissions RR: 0.38, 95% CI: 0.09–1.65; P=0.20]. Similar results were obtained in the model after adjusting for health region (Tables 4,5).

Sensitivity analyses

To determine the impact of the patients switching from STD to EXT on our findings, we conducted a sensitivity analysis comparing the STD to EXT group combined with the STD group to the EXT group, and second, comparing the STD to EXT group combined with the EXT group to the STD group. The results of the survival and safety analyses did not differ between the primary analyses and sensitivity analyses (Tables S3-S12, Figures S1,S2). In the sensitivity analysis to examine the association of patients who switched treatment dosing, there was no difference in OS between treatment groups (log-rank test P=0.63) (Tables S13,S14, Figure S3).

Discussion

Key findings

In this retrospective cohort study, we investigated the real-world clinical outcomes of 771 patients receiving durvalumab for NSCLC with EXT versus STD. We found no statistically significant differences in OS between the EXT and STD groups after a median follow-up of 18 months, in line with findings from prior studies (7,15,16). Although we found a numerically higher rate of unscheduled ED visits and lower rate of hospitalizations among the EXT group, these differences did not attain statistical significance.

Explanations of findings and comparisons to similar research

We reported no significant difference in the OS, rate of ED visits, and rate of hospitalization of patients receiving EXT versus STD durvalumab after 24 months of follow-up. Existing literature exploring extended dosing of durvalumab reports a similar lack of significant difference in survival between patients receiving extended and standard dosing. Of note these studies relied on smaller sample sizes and included patients that switched from STD to EXT (13-15). An RWE study conducted in the United Kingdom during the early phase of the pandemic investigated a cohort of 40 patients undergoing 2-weekly durvalumab treatment, with 14 of them transitioning from 2-weekly to 4-weekly schedules (13). The study findings suggest that the shift to a 4-weekly durvalumab regimen was well-tolerated and did not lead to increased levels of toxicity. A retrospective chart review study conducted by the BC Cancer Agency found no significant difference in 12-month survival rates and similar toxicity profiles among 205 patients receiving standard dosing versus extended dosing for durvalumab treatment, based on the dosing schedule used for most of their treatment (16). Additional literature has reported similar toxicity profiles for clinical safety outcomes including immune-mediated adverse events (IMAEs) and brain metastasis recurrence among real-world patients (14,15). Although such clinical safety outcomes are not comparable to our exploration of safety using health service utilization data the recurring real-world trends report similar effectiveness and safety between patients receiving extended and standard durvalumab dosing. The flexibility offered by extended dosing regimens provides a practical means to minimize potential exposure to the virus for this vulnerable patient population, all while ensuring the effectiveness and safety of the treatment remains consistent with receipt of standard dosing (6,15).

The authors acknowledge that the selection of a specific dosing regimen is a complex decision influenced by a variety of medical and non-medical factors. These factors may encompass patient choice, patient health conditions, disease severity, adherence behaviors, and even variations in physician preferences across diverse health regions, thereby introducing the potential for confounding by indication bias in observational studies. For instance, patients might choose the standard dosing schedule due to the severity of their condition, pre-existing comorbidities, and the need for enhanced treatment monitoring. Therefore, an overrepresentation of severely ill patients in the standard dosing group could impact clinical outcomes. Conversely, individuals with more severe conditions might choose extended dosing to minimize hospital visits during the COVID-19 pandemic. Patient adherence to treatment regimens and their willingness to undergo frequent interventions can also vary. Additionally, there were discrepancies in adopting the interim measures of extended dosing interval by geography. Our study demonstrated a greater likelihood of extended dosing intervals among patients residing in Central, Toronto, East, and in urban areas. One might have anticipated patients in rural areas to lean towards extended dosing, seeking increased flexibility and diminished travel costs, however, this anticipated trend was not observed. One potential explanation is that it may take longer for medical oncologists in rural areas to initially become aware of newly implemented policies. Moreover, the presence of satellite units offering drug administration closer to patients’ homes may have also influenced patients’ acceptance of the standard dosing schedule. Additionally, factors such as physician preferences, the prevalence of local SARS-CoV-2 infection, and perceived burden on the healthcare system may also play a role in influencing policy awareness and implementation.

To mitigate the potential confounding by indication in our study, several strategies were employed. Firstly, our data collection for patients who initiated durvalumab continued until the end of 2021, more than 18 months after the implementation of the interim measure policy. This timeframe allowed us to include a significant group of patients who began their treatment using an extended dosing schedule. Different from existing studies, we focused on the comparison of patients who adhered to a single dosing schedule throughout the entire study duration. For instance, earlier investigations conducted by Joshi et al., Mac et al., and Hanna et al. evaluated the distinction between extended and standard dosing by employing a “STD to EXT” switching group and comparing it with the standard group (13-15). Denault et al. classified patients based on their predominant treatment schedule (16). Although studying dose-switching groups provides a snapshot of actual treatment dynamics, where patients may shift between regimens due to evolving clinical considerations, our approach instead centers on a comparison of patients maintaining unwavering adherence to a specific dosing schedule. This approach may better inform decisions on whether to adopt EXT as an alternative treatment strategy because it provides an estimate of the potential impact of a fully realized EXT treatment experience. This reduction in variability stemming from dosing changes minimizes the likelihood of indication bias (since most crossovers were switches from STD to EXT) and fosters a more homogenous comparison. In addition, we conducted sensitivity analyses to evaluate the impact of patients transitioning from standard dosing to extended dosing and found no statistically significant differences in both comparisons. Lastly, we utilized PSM to balance the baseline characteristics of patients between the two dosing groups. By doing so, we aimed to achieve a more balanced distribution of covariates between the groups, thus addressing the potential bias introduced by differences in patient characteristics that may affect treatment choice. Following the matching process in our study, the distribution of health regions remained imbalanced. Consequently, to account for this nonuniformity, we incorporated an additional adjustment for health region in both the Cox proportional model and negative binomial models. While we cannot eliminate the possibility of confounding by indication, our comprehensive approach seeks to minimize its impact and enhance the validity of our study results.

Implications and actions needed

Our findings have significant clinical implications, indicating that an extended dosing interval shows no statistically significant impact on patient outcomes compared to the standard dosing interval. Since the completion of this analysis, EXT has been implemented as an approved regimen in Ontario, affording practitioners and patients the ability to choose a regimen that is suitable for individual circumstances. These findings provide confidence for practitioners and patients seeking more flexible treatment options that may be more cost-effective for the healthcare system. Future research could focus on optimizing dosing regimens, taking into account individual patient characteristics, and exploring long-term outcomes, paving the way for personalized and patient-centered treatment approaches for NSCLC beyond the COVID-19 pandemic.

Limitations

There were several inherent limitations within our study. The retrospective nature of our design may introduce certain biases and confounding factors that challenge the establishment of causality. The relatively modest sample size employed in our study warrants cautious interpretation, as it may somewhat curtail the broad applicability of our findings across more extensive patient cohorts. However, to the best of our knowledge, our study has the largest sample size in the literature. While we employed PSM to mitigate confounding, residual confounding might persist. Moreover, the possibility of unobserved or unmeasured variables that could exert influence on the observed outcomes cannot be entirely dismissed. Lastly, health administrative data do not allow for ascertainment of immune-related adverse events from immune checkpoint inhibitors. The absence of direct phase III randomized controlled trials comparing extended and standard dosing regimens underscores the need for further investigation.

Conclusions

We found no significant differences in all-cause mortality and rates of unscheduled ED visits and hospital admissions between patients receiving extended dosing and standard dosing of durvalumab for NSCLC. The findings suggest both dosing regimens provide comparable clinical outcomes and safety profiles. Our study contributes additional evidence to inform clinical decision-making and improve patient care in the management of NSCLC.

Acknowledgments

The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. Parts of this material are based on data and information provided by Ontario Health (OH). The opinions, results, view, and conclusions reported in this paper are those of the authors and do not necessarily reflect those of OH. No endorsement by OH is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI and the Ontario Ministry of Health.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://ace.amegroups.com/article/view/10.21037/ace-24-16/rc

Data Sharing Statement: Available at https://ace.amegroups.com/article/view/10.21037/ace-24-16/dss

Peer Review FIle: Available at https://ace.amegroups.com/article/view/10.21037/ace-24-16/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ace.amegroups.com/article/view/10.21037/ace-24-16/coif). A.G.R. received payments or honoraria from Merck Sharpe Dohme, Astra-Zeneca, Bristol Myers Squib, and Amgen, and is a member of drug advisory committee for Cancer Care Ontario. M.S.K. received educational grant from AstraZeneca, payments or honoraria from AstraZeneca, Sanofi, Takeda, and BMS, support from Takeda, AstraZeneca, and BMS, participated in PEBC (OH-CCO), Lung DAC (OH-CCO), ASCO guideline development, OCREB, CCTG, and received equipment, materials, drugs, medical writing gifts or other services from Beigene, and AstraZeneca. S.B. has participated in advisory boards for: Merck, Astra Zeneca, Eisai, BMS, Knight Therapeutics, Pfizer, EMD Serono, Takeda. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Ontario Health is a prescribed entity. Research ethics approval was not required as per an Ontario Health (Cancer Care Ontario) privacy assessment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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