Variations in Patterns of Prescribing Durvalumab in Stage III Lung Cancer: A Survey of Australian Medical Oncologists Free

Stage III non-small cell lung cancer (NSCLC) accounts for up to one-third of all NSCLC diagnoses at initial presentation [1]. Multimodality treatment is often recommended for management of these patients. In Australia, lung cancer continues to be a leading cause of death, and stage III diagnoses are noted in up to one-third of patients at diagnosis [2]. Since the PACIFIC trial, the treatment paradigm for unresectable stage III NSCLC in Australia has evolved to include 1 year of consolidation durvalumab after concurrent chemoradiation, regardless of tumour mutation status or programmed death ligand-1 (PD-L1) expression [3]. The 5-year overall survival (OS) update for the PACIFIC trial demonstrated a median OS of 47.5 months versus 29.1 months with concurrent chemoradiotherapy alone [4]. In 2018, the US Food and Drug Administration (FDA) approved consolidation durvalumab for unresectable stage III NSCLC patients, irrespective of tumour PD-L1 expression and mutation status.

The number of patients with oncogenic driver mutant NSCLC included in the PACIFIC trial was limited. Therefore, no definitive conclusions could be made about the use of consolidation durvalumab in this important subgroup of stage III NSCLC patients [5]. Although the PACIFIC study demonstrated that durvalumab provided benefit in patients regardless of PD-L1 expression [3], recent real-world data has shown that those patients with negative PD-L1 expression may not benefit [6]. Currently, the American Society of Clinical Oncology (ASCO) guidelines advocate for consolidation durvalumab in unresectable stage III NSCLC irrespective of their PD-L1 expression and mutation status [7]. The European Society of Medical Oncology (ESMO) differs, with consolidation durvalumab only recommended in those patients who express PD-L1 (i.e., >1%) [8]. Currently, in Australia, there is no consensus practice guideline on how to manage these patients, undoubtedly leading to differing clinical approaches. Currently, the majority of specialised thoracic oncology centres are located in central metropolitan areas, but many patients with stage III disease are treated regionally and rurally. This undoubtedly would also influence practice, given the differing access to subspecialised oncology services for patients. Thus, we conducted an Australia and New Zealand wide survey of medical oncologists to determine the variations in patterns of prescribing durvalumab in stage III unresectable NSCLC.

This is a prospective cohort study utilising an electronic questionnaire that was distributed to all Australian and New Zealand medical oncologists through the Thoracic Oncology Group of Australasia (TOGA). The questionnaire can be viewed in the online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000535855). We collected data on the characteristics of the prescribing oncologist including location of practice, private versus public hospital practice, years of experience, and proportion of lung cancer patients seen. All participants were then asked five clinical questions regarding their decision-making around prescribing consolidation durvalumab depending on the patient’s oncogenic driver mutation status and PD-L1 expression. We summarised variations in clinical practice and attempted to correlate prescriber characteristics with their decision-making. The project was approved by the Sydney South West Local Health District Human Research Ethics Committee (2019/ETH00337). All data analysis was done using R 4.1.1.

Between May 2023 and July 2023, 32 medical oncologists from Australia and New Zealand completed the survey. Of these, 26 (82%) were Australian and 6 (18%) were from New Zealand. 44% of medical oncologists were working solely as public hospital clinicians, with 53% having an additional private practice to their public work. 34% of oncologists had less than 5 years of experience treating lung cancer, while 32% had more than 10 years’ experience. Majority (68%) of medical oncologists worked in a metropolitan setting, and these results are summarised in Table 1.

All respondents reported that patients with stage III unresectable patients were routinely discussed in multidisciplinary team (MDT) meetings prior to commencement of treatment. Median rate of oncogenic driver mutation testing in the stage III setting was 90% (IQR 70–100) for EGFR, ALK, and ROS-1 mutations, while median PD-L1 testing was 100%.

In patients with EGFR-mutated stage III unresectable NSCLC, 6% of respondents stated that they always prescribed durvalumab for all patients, while an additional 6% strongly recommended treatment. 44% suggested little benefit of consolidation durvalumab in this cohort, with an additional 19% advocating for observation only. 18% also routinely discussed self-funded EGFR-targeted therapy in this patient population. In our cohort, oncologists who practiced in rural/regional settings were more likely to always prescribe or strongly recommend consolidation durvalumab in EGFR-mutated stage III NSCLC (43% vs. 4%, p = 0.13). Years of experience in treating lung cancer and nature of clinical practice did not impact prescribing patterns. In patients with ALK or ROS-1-mutated stage III unresectable NSCLC, 6% of respondents prescribed durvalumab for all patients, while an additional 28% strongly recommended treatment. Over 30% suggested little benefit of consolidation durvalumab in this cohort, with an additional 15% advocating for observation only. Approximately 10% also routinely discussed self-funded ALK/ROS-1-targeted therapy in this patient population. These responders all had more than 10 years of experience treating lung cancer.

In patients with PD-L1 negative (0%) stage III unresectable NSCLC, 13% of respondents prescribed durvalumab for all patients, while an additional 56% strongly recommended treatment. Only 6% suggested little benefit of consolidation durvalumab in this cohort, with an additional 3% advocating for observation only. In our cohort, oncologists who practiced in rural/regional settings were more likely to always prescribe or strongly recommend consolidation durvalumab in PD-L1-negative stage III NSCLC (86% vs. 60%, p = 0.31). Years of experience in treating lung cancer and nature of clinical practice did not impact prescribing patterns. In patients with PD-L1 low (1–49%) stage III unresectable NSCLC, 82% of respondents prescribed durvalumab for all patients, while an additional 18% strongly recommended treatment. No respondent suggested little benefit of consolidation durvalumab or advocated for observation only in this cohort. These results are summarised in Figure 1.

Our survey of Australian and New Zealand medical oncologists has revealed interesting variations in clinical practice that largely remain consistent with either the ASCO or ESMO clinical guidelines. Regional/rural oncologists appear to be adhering with ASCO guidelines with greater use of durvalumab in PD-L1 negative cohorts, while metropolitan oncologists appear to be prescribing in a manner consistent with the ESMO recommendation of observation in this cohort.

Almost 90% of prescribers in our survey did not strongly advocate for consolidation durvalumab in the EGFR-mutated cohort. This perhaps is attributable to the PACIFIC subgroup analysis by Naidoo et al. [5] demonstrating no difference in survival. Notably, a number of real-world studies have also now demonstrated that there is limited benefit of durvalumab in this key subpopulation of EGFR-mutant NSCLC [9, 10]. Real-world median PFS for EGFR-mutant NSCLC treated with consolidation durvalumab has been shown to be between 7.5 and 10.3 months [9, 10], with a median PFS of 11.2 months in the EGFR-mutant subpopulation in the PACIFIC trial [11]. Interestingly, 18%, 10%, and 10% of prescribers discussed self-funded oral tyrosine kinase inhibitor therapy in patients with EGFR, ALK, or ROS-1-mutated NSCLC, respectively, as a substitute for consolidation durvalumab. This is despite any current evidence to support consolidation tyrosine kinase inhibitor use in this setting with results from the LAURA study currently pending [12].

For those with PD-L1-negative disease, real-world data has also alluded to a PFS of less than 12 months [6]. Paz Ares et al. [13] outlined survival outcomes based on PD-L1 expression in the PACIFIC study, showing that OS improvement was demonstrated across all subgroups except those with PD-L1 expression of <1%. However, notably, the trial was not powered to assess survival in this cohort via a post hoc analysis. Our survey demonstrates that almost 70% of prescribers strongly advocate for durvalumab in this cohort, potentially reflecting a lack of definitive data to guide best prescribing practices.

PD-L1 <1% tumours encompassed 33% of the total cohort in the PACIFIC study [13], while EGFR-mutated tumours can range from 10 to 25% of NSCLC cases [14]. Hence, not only does the issue of lack of efficacy arise but also the concern of harm to a sizable population of patients. Real-world data sets have shown that grade 3 pneumonitis secondary to durvalumab are reportedly higher than 15% [15]. Clinicians and patients should be made aware of these risks in the context of potentially limited benefit, especially for those with PD-L1-negative tumours or those with oncogenic-driven cancers. This is important in the shared decision-making model of patient care as outlined in the ESMO clinical practice guidelines.

From a health economics perspective, there is significant financial burden on the healthcare system. Durvalumab costs the Australian health system approximately $12,000 per dose which equates to approximately $156,000 for a complete course of treatment. Oncogenic-driven cancers make up approximately 20% of all NSCLC with PD-L1-negative cancers reportedly as high as 40% of total NSCLC cases [16]. Stage III NSCLC also accounts for up to 25% of all NSCLC cancers at the time of diagnosis [17]. Thus, taking these two subgroups alone into account, healthcare systems may be spending a large amount of money on a drug for a subpopulation, where it may not be efficacious or have modest benefit at best.

Overall, it can be noted that the clinical practice of Australian and New Zealand medical oncologists is variable but largely remains consistent with either the ASCO or ESMO guidelines. Given the complex management of unresectable stage III NSCLC, all cases should be discussed in an MDT setting. Additionally, clinicians should be routinely testing pathology samples for oncogenic driver mutations and PD-L1 expression as these appear to influence decision-making and guideline-based recommendations. Ideally, local practice guidelines are required to ensure consistency in prescribing patterns across Australia. This is particularly important for low-volume and regional/rural oncologists who often are responsible for treating a wide range of tumour streams and may not be aware of new developments in subpopulations that could significantly influence treatment decisions.

This study protocol was reviewed and approved by Sydney South West Local Health District, approval number 2023/ETH00337. All participants consented to the survey, and this was done at the time of online questionnaire completion. Written informed consent to participate was not directly obtained but inferred by completion of the questionnaire.

The authors have no conflicts of interest to declare.

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Udit Nindra: conceptualisation, data analysis, writing draft, and reviewing final manuscript; Victoria Bray, Deme Karikios, Mohsen Shafiei, Shalini Subramaniam, Pei Ding, and Steven Kao: conceptualisation and reviewing final manuscript; and Abhijit Pal: conceptualisation, supervision, and reviewing final manuscript.

The datasets for this manuscript are not publicly available due to privacy reasons but are available from the corresponding Udit Nindra upon reasonable request ([email protected]).