# Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R

A. R. Filippi, J. Bar, C. Chouaid, D. C. Christoph, J. K. Field, R. Fietkau, M. C. Garassino, P. Garrido, V. D. Haakensen, S. Kao, et al.

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A. R. Filippi, J. Bar, C. Chouaid, D. C. Christoph, J. K. Field, et al. Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R. ESMO Open, 2024, 9 (6), 10.1016/j.esmoop.2024.103464. hal-04724639

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ORIGINAL RESEARCH

# Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R

A. R. Filippi<sup>1+†</sup>, J. Bar<sup>2,3</sup>, C. Chouaid<sup>4</sup>, D. C. Christoph<sup>5</sup>, J. K. Field<sup>6</sup>, R. Fietkau<sup>7</sup>, M. C. Garassino<sup>8</sup>, P. Garrido<sup>9</sup>, V. D. Haakensen<sup>10</sup>, S. Kao<sup>11</sup>, B. Markman<sup>12</sup>, F. McDonald<sup>13</sup>, F. Mornex<sup>14</sup>, M. Moskovitz<sup>15†</sup>, S. Peters<sup>16</sup>, A. Sibille<sup>17</sup>, S. Siva<sup>18</sup>, M. van den Heuvel<sup>19</sup>, P. Vercauter<sup>20</sup>, S. Anand<sup>21</sup>, P. Chander<sup>21</sup>, M. Licour<sup>22</sup>, A. R. de Lima<sup>21</sup>, Y. Qiao<sup>21</sup> & N. Girard<sup>23,24</sup>

<figure><img src="image_2.png" /></figure>

Available online 3 June 2024

**Background:** Based on the findings of the PACIFIC trial, consolidation durvalumab following platinum-based chemoradiotherapy (CRT) is a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). An earlier analysis from the ongoing PACIFIC-R study (NCT03798535) demonstrated the effectiveness of this regimen in terms of progression-free survival (PFS). Here, we report the first planned overall survival (OS) analysis.

**Patients and methods:** PACIFIC-R is an observational/non-interventional, retrospective study of patients with unresectable, stage III NSCLC who started durvalumab (10 mg/kg intravenously every 2 weeks) within an AstraZeneca-initiated early access program between September 2017 and December 2018. Primary endpoints are OS and investigator-assessed PFS, estimated using the Kaplan-Meier method.

**Results:** By 30 November 2021, the full analysis set included 1154 participants from 10 countries (median follow-up in censored patients: 38.7 months). Median OS was not reached, and the 3-year OS rate was 63.2% (95% confidence interval 60.3% to 65.9%). Three-year OS rates were numerically higher among patients with programmed death-ligand 1 (PD-L1) expression on ≥1% versus <1% of tumor cells (TCs; 67.0% versus 54.4%) and patients who received concurrent CRT (cCRT) versus sequential CRT (sCRT) (64.8% versus 57.9%).

**Conclusions:** PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Better outcomes were observed among patients with PD-L1 TCs ≥1% and patients who received cCRT. Nevertheless, encouraging outcomes were still observed among patients with TCs <1% and patients who received sCRT, supporting use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

**Key words:** durvalumab, immunotherapy, PD-L1, real-world evidence, locally advanced NSCLC

INTRODUCTION

Approximately 20%-35% of patients with non-small-cell lung cancer (NSCLC) are diagnosed with stage III disease,<fnref n="1" />⁻³ and median survival for stage III NSCLC is reported to range from 9 to 34 months.<fnref n="1" /> Therefore, there has been a focus on developing treatments to improve outcomes in these patients. The results of the placebo-controlled, phase III PACIFIC trial (NCT02125461) established consolidation immunotherapy with durvalumab for up to 12 months

<footnote n="1"><sup>1</sup>Radiation Oncology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy; <sup>2</sup>Institute of Oncology, Sheba Medical Centre, Ramat Gan; <sup>3</sup>Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; <sup>4</sup>Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France; <sup>5</sup>Department of Medical Oncology, Evang. Kliniken Essen-Mitte, Evang. Huyssens-Stiftung Essen-Huttrop, Essen, Germany; <sup>6</sup>Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK; <sup>7</sup>Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany; <sup>8</sup>Department of Hematology/Oncology, The University of Chicago, Chicago, USA; <sup>9</sup>Medical Oncology Department, Hospital Ramón y Cajal, Universidad de Alcalá, Madrid, Spain; <sup>10</sup>Department of Oncology and Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; <sup>11</sup>Chris O'Brien Lifehouse, Sydney; <sup>12</sup>Cabrini Hospital and Monash University, Melbourne, Australia; <sup>13</sup>Lung Unit, The Royal Marsden NHS Foundation Trust, London, UK; <sup>14</sup>Department of Radiation Oncology, Centre Hospitalier Universitaire de Lyon, Lyon, France; <sup>15</sup>Rambam Health Care Campus, Haifa, Israel; <sup>16</sup>Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; <sup>17</sup>Department of Pneumology, Centre Hospitalier Universitaire de Liège, Liège, Belgium; <sup>18</sup>Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Australia; <sup>19</sup>Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; <sup>20</sup>Department of Pneumology, OLV Hospital Aalst, Aalst, Belgium; <sup>21</sup>AstraZeneca, Gaithersburg, USA; <sup>22</sup>AstraZeneca, Courbevoie, France; <sup>23</sup>Institut du Thorax Curie Montsouris, Institut Curie, Paris; <sup>24</sup>UVSQ, Paris Saclay, Versailles, France</footnote>

<footnote>*Correspondence to: Prof. Andrea R. Filippi, Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy. Tel: +39-349-4694526
E-mail: andreariccardo.filippi@istitutotumori.mi.it (A. R. Filippi).</footnote>

<footnote>†Present address: Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori and Department of Oncology, University of Milan, Milan, Italy.</footnote>

<footnote>‡Present address: Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.</footnote>

<footnote>2059-7029/© 2024 The Authors. Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</footnote>
following platinum-based chemoradiotherapy (CRT) (the
'PACIFIC regimen') as a global standard of care for patients
with unresectable, stage III NSCLC.⁴⁻⁸ The primary analyses
demonstrated significant improvements in overall survival
(OS) and progression-free survival (PFS) with durvalumab in
patients whose disease had not progressed following
platinum-based, concurrent CRT (cCRT).⁴,⁵ Furthermore,
durvalumab was associated with a manageable safety profile
and did not detrimentally impact patient-reported quality of
life.⁴,⁵,⁹ Following publication of the primary results, subse-
quent updates from PACIFIC demonstrated that the benefit
of durvalumab is sustained over time.⁸,¹⁰ At the most recent
update, median OS was 47.5 months [95% confidence in-
terval (CI) 38.1-52.9 months] with durvalumab versus 29.1
months (95% CI 22.1-35.1 months) with placebo [hazard ratio
(HR) 0.72, 95% CI 0.59-0.89]; 3-year OS rates were 56.7%
versus 43.6% with durvalumab versus placebo, and 5-year OS
rates were 42.9% versus 33.4%, respectively.⁸ At the same
update, median PFS was 16.9 months (95% CI 13.0-23.9
months) with durvalumab versus 5.6 months (95% CI 4.8-7.7
months) with placebo (HR 0.55, 95% CI 0.45-0.68); 3-year PFS
rates were 39.7% versus 20.8% with durvalumab versus
placebo, and 5-year PFS rates were 33.1% versus 19.0%,
respectively.

Real-world evidence is required to confirm if the benefit
seen with durvalumab in the clinical trial setting is achieved
in everyday clinical practice. The observational, retrospec-
tive PACIFIC-R study (NCT03798535) was initiated with the
aim of providing the first, longitudinal, real-world data on
patients with unresectable, stage III NSCLC who received
durvalumab after CRT. Participants were recruited from the
global PACIFIC early access program (EAP), which opened
before durvalumab received regulatory approvals (to pro-
vide ethical access to durvalumab following the initial data
readout from PACIFIC). In addition to patients who qualified
because their clinical characteristics reflected those of the
primary target population for PACIFIC [e.g. receipt of cCRT
and initiation of durvalumab ≤42 days after finishing
radiotherapy (RT)], patients who received sequential CRT
(sCRT) and patients who started durvalumab >42 days after
finishing RT were also enrolled into PACIFIC-R. Furthermore,
PACIFIC-R included patients with programmed death-ligand
1 (PD-L1) expression on <1% of tumor cells (TCs), a
population enrolled in PACIFIC that was included in the
United States Food and Drug Administration (FDA)-
approved label for durvalumab but was excluded from the
European Medicines Agency (EMA)-approved label based
on a post hoc analysis.⁷,¹¹⁻¹³ Inclusion of a wider range of
patients in PACIFIC-R reflects the real-world variability in
multidisciplinary treatment approaches for unresectable,
stage III NSCLC.

PACIFIC-R comprises a series of retrospective chart ex-
tractions spread over a 5-year period. A previous publica-
tion reported analyses from the second chart extraction,
with ~2 years of follow-up, including the first planned
analysis of investigator-assessed PFS and an unplanned,
preliminary analysis of OS¹⁴; the 2-year PFS and OS rates
were 48.2% and 71.2%, respectively. Here, we report

analyses from the third chart extraction, with ~3 years of
follow-up, including the first planned analysis of OS and an
updated analysis of PFS.

PATIENTS AND METHODS

Study design

PACIFIC-R is an ongoing, international, observational/non-
interventional, retrospective study of a cohort of adult pa-
tients with a histologically/cytologically documented diag-
nosis of stage III, unresectable NSCLC (according to the
seventh or eighth editions of the American Joint Committee
on Cancer staging manual, as per local practice) who started
durvalumab (10 mg/kg intravenously every 2 weeks) within
an AstraZeneca-initiated EAP between September 2017 and
December 2018. Comprehensive details regarding the EAP
and the design of PACIFIC-R are published elsewhere.¹⁴
Briefly, the EAP provided ethical access to durvalumab for
patients who had completed CRT for unresectable, stage III
NSCLC and who, in their treating physician's opinion, had an
unmet clinical need that could not be treated with
approved and commercially available therapies. PACIFIC-R
comprises a retrospective review of established medical
records, with several planned chart extractions sequenced
over a 5-year period starting from the date of the first
durvalumab infusion within the EAP (the index date)
(Supplementary Figure S1, available at https://doi.org/10.
1016/j.esmoop.2024.103464).

Eligible patients had no evidence of disease progression
following platinum-based cCRT or sCRT and had provided
informed consent as per local regulations (if applicable) for
data to be retrieved from their medical records. In
compliance with local regulations, patients were eligible to
enter PACIFIC-R once the EAP enrollment had closed in their
country; patients who died during or after the EAP but
before the study enrollment for PACIFIC-R opened were
eligible where local regulations allowed for a consent
waiver or next-of-kin consent.

Objectives

The primary objective of PACIFIC-R was to evaluate the
effectiveness of durvalumab in terms of OS and
investigator-assessed PFS in the full analysis set. Secondary
objectives reported in this article include OS and PFS for
subgroups of interest and time to death or distant metas-
tasis (TTDM), time to death or local recurrence (TDLR), and
time to death or first subsequent treatment after durvalu-
mab (TFST) in the full analysis set. Multivariable analyses of
prognostic factors for OS and PFS are also reported.

Statistical analysis

Analyses were based on the full analysis set, which
included all screened patients who met key inclusion
criteria and had provided written informed consent as
required by local regulations (if applicable). In a previous
report from PACIFIC-R, which presented analyses based on
the second planned chart extraction,¹⁴ data for Spanish
patients were integrated into the full analysis set; the data sourced were from an externally sponsored, locally initiated study with the same design and study materials as PACIFIC-R (NCT04285866). Additional data from this external study were not available for integration into the current analyses, based on the third planned chart extraction, as regulatory restrictions in Spain only allowed one chart extraction.

The main analyses were descriptive in nature with summary statistics for continuous variables or numbers and frequency for calculation of categorical variables. Missing values were not imputed. Medians and landmark rates for time-to-event endpoints were estimated using the Kaplan-Meier method; time-to-event endpoints were measured from the date that durvalumab was initiated within the EAP (i.e. the PACIFIC-R index date). All analyses in this article were based on the third planned chart extraction (end date: 30 November 2021), which was timed for maturity of the survival data to provide an accurate estimate of the 3-year OS rate. The last date of data entry for the analyses reported in this article was 30 November 2021; data cleaning was carried out up to a database cut-off date of 7 February 2022.

Sensitivity analyses were carried out to assess the robustness of the main OS and PFS results. PACIFIC-R is subject to selection bias as local regulations in the UK and Germany did not allow for informed consent to be waived, so EAP participants who died before PACIFIC-R enrollment opened in these two countries were not taken into consideration for data collection. Therefore, outcomes could be overestimated for these two countries as patients with the worst prognoses (namely, those who died before consent could be given) were not included in PACIFIC-R. We carried out two sensitivity analyses to explore the impact of this selection bias on OS and PFS. The first analysis excluded UK and German data from the full analysis set (and is referred to as the 'informed consent sensitivity analysis'), and the second analysis used an immortal bias adjustment method (which is described in the Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2024.103464). An additional sensitivity analysis of PFS was also conducted to explore the impact of excluding patients with unknown progression status (as recorded in the electronic case report form; patients with unknown progression status were censored at the most recent date they were known not to have progressed in the main analysis).

To assess the prognostic association of patient characteristics with outcomes, Cox regression models were built for both OS and PFS using a backward selection model with variable selection based on Akaike information criterion. The variables considered for the backward selection model were: age (as a continuous predictor), sex, country, medical condition and/or history of another cancer, smoking status, disease stage (at stage III diagnosis), type of histology at stage III diagnosis, PD-L1 expression status, initiation of durvalumab relative to end of RT, previous RT total dose, previous type of CRT, platinum used for CRT, secondary chemotherapy agent, and induction chemotherapy.

Adjusted HRs were calculated by fitting a multivariable Cox regression model that included the selected variables.

# RESULTS

## Patients and treatment

As of 30 November 2021 (the end date of the third chart extraction), the full analysis set included 1154 participants from 10 different countries, including France (342 patients), Australia (165), the Netherlands (154), Belgium (118), Italy (116), Israel (92), Germany (62), the UK (54), Norway (36), and Switzerland (15). The median duration of follow-up among patients who were censored at the end of the third chart extraction was 38.7 months (range 13.6-49.0 months).

Patients in the full analysis set had a median age of 65 years (range 26-88 years), and 102 of 1154 patients (8.8%) were aged ≥75 years (Table 1). Most were male [748/1154 (64.8%)] and current or former smokers [1051/1154 (91.1%)]. Among patients with available data, nearly all had a performance status of 0 or 1 [744/756 (98.4%)], most had non-squamous tumor histology [752/1153 (65.2%)], and over half of them had stage IIIB or IIIC disease [585/1091 (53.6%)]. Overall, 790 patients had available data regarding PD-L1 expression and most of these patients had PD-L1 expression on ≥1% of TCs [573/790 (72.5%)]. While the antibody used to assess PD-L1 expression was unknown or missing for most patients [447/790 (56.6%)], the most common among those with available data was DACO 22C3 [228/343 (66.5%)]. Most patients received cCRT [900/1063 (84.7%)] and started durvalumab >42 days [732/1130 (64.8%)] following the end of RT.

## OS and updated PFS

In total, 446 of 1154 patients (38.6%) in the full analysis set had died at the time of the database cut-off; median OS was not reached (95% CI 46.3 months-not estimable) and the 2-and 3-year OS rates were 72.3% (95% CI 69.7% to 74.8%) and 63.2% (95% CI 60.3% to 65.9%), respectively (Figure 1A). Overall, 666 of 1154 patients (57.7%) in the full analysis set had either experienced progression (n = 595) or had died in the absence of progression (n = 71); median PFS was 24.1 months (95% CI 20.2-27.8 months) and the 2-and 3-year PFS rates were 50.1% (95% CI 47.2% to 53.0%) and 42.2% (95% CI 39.2% to 45.1%), respectively (Figure 1B).

Three-year OS rates were numerically higher among patients with PD-L1 expression on ≥1% versus <1% of TCs [67.0% (95% CI 63.0% to 70.8%) versus 54.4% (95% CI 45.7% to 62.4%), respectively]; patients who received cCRT versus sCRT [64.8% (95% CI 61.5% to 67.9%) versus 57.9% (95% CI 49.8% to 65.2%), respectively]; patients who started durvalumab ≤42 days versus >42 days following the end of RT [66.0% (95% CI 61.1% to 70.5%) versus 61.8% (95% CI 58.1% to 65.2%), respectively]; and patients with non-squamous versus squamous tumor histology [68.0% (95% CI 64.5% to 71.2%) versus 53.2% (95% CI 48.0% to 58.1%), respectively] (Figure 2). Meanwhile, 3-year OS rates were numerically similar between patients with stage IIIA and
<table><caption>**Table 1.** Patient demographics, disease characteristics, and treatment characteristics</caption><thead><tr><th>Characteristics<sup>a</sup></th><th>n (%)</th></tr></thead><tbody><tr><td>Age category at EAP inclusion (N = 1154)<sup>b</sup></td><td></td></tr><tr><td>&lt;70 years</td><td>806 (69.8)</td></tr><tr><td>70-75 years</td><td>246 (21.3)</td></tr><tr><td>&gt;75 years</td><td>102 (8.8)</td></tr><tr><td>Sex (N = 1154)</td><td></td></tr><tr><td>Male</td><td>748 (64.8)</td></tr><tr><td>Female</td><td>406 (35.2)</td></tr><tr><td>Smoking status at EAP inclusion (N = 1154)<sup>b</sup></td><td></td></tr><tr><td>Never</td><td>64 (5.5)</td></tr><tr><td>Current</td><td>300 (26.0)</td></tr><tr><td>Former</td><td>751 (65.1)</td></tr><tr><td>ECOG PS (N = 756)<sup>b</sup></td><td></td></tr><tr><td>0 or 1</td><td>744 (98.4)</td></tr><tr><td>&gt;2</td><td>12 (1.6)</td></tr><tr><td>Disease stage (N = 1091)<sup>b,c</sup></td><td></td></tr><tr><td>IIIA</td><td>506 (46.4)</td></tr><tr><td>IIIB or IIIC</td><td>585 (53.6)</td></tr><tr><td>Tumor histology (N = 1153)<sup>b</sup></td><td></td></tr><tr><td>Squamous</td><td>386 (33.5)</td></tr><tr><td>Non-squamous</td><td>752 (65.2)</td></tr><tr><td>Unknown</td><td>15 (1.3)</td></tr><tr><td>PD-L1 expression level (N = 790)<sup>b</sup></td><td></td></tr><tr><td>TC ≥1%</td><td>573 (72.5)</td></tr><tr><td>TC &lt;1%</td><td>138 (17.5)</td></tr><tr><td>Unknown</td><td>79 (10.0)</td></tr><tr><td>EGFR status (N = 483)<sup>b</sup></td><td></td></tr><tr><td>Mutated</td><td>44 (9.1)</td></tr><tr><td>Non-mutated</td><td>422 (87.4)</td></tr><tr><td>Unknown</td><td>17 (3.5)</td></tr><tr><td>Prior CRT type (N = 1063)<sup>b</sup></td><td></td></tr><tr><td>Concurrent</td><td>900 (84.7)</td></tr><tr><td>Sequential</td><td>163 (15.3)</td></tr><tr><td>Total prior RT dose (N = 1120)</td><td></td></tr><tr><td>≤60 Gy</td><td>485 (43.3)</td></tr><tr><td>>60 Gy</td><td>635 (56.7)</td></tr><tr><td>Time elapsed between the end of RT and the start of durvalumab (N = 1130)<sup>b</sup></td><td></td></tr><tr><td>≤42 days</td><td>398 (35.2)</td></tr><tr><td>>42 days</td><td>732 (64.8)</td></tr></tbody></table>

CRT, chemoradiotherapy; EAP, early access program; ECOG, Eastern Cooperation Oncology Group; Gy, units of gray; PD-L1, programmed death-ligand 1; PS, performance status; RT, radiotherapy; TC, tumor cell.

<sup>a</sup>All characteristics are summarized based on the full analysis set for the third chart extraction from PACIFIC-R (end date: 30 November 2021).

<sup>b</sup>Summaries are based on patients with available information for each characteristic (i.e. patients with missing responses are not included).

<sup>c</sup>Disease stage could be determined according to the seventh or eighth editions of the American Joint Committee on Cancer staging manual.

stage IIIB/IIIC disease [62.3% (95% CI 57.8% to 66.4%) versus 63.7% (95% CI 59.6% to 67.5%), respectively]. Similar trends were observed across these subgroups for PFS (Figure 3).

## Sensitivity analyses of OS and PFS

Results from the informed consent sensitivity analysis, which was carried out to assess the impact of selection bias brought about by the local regulations in the UK and Germany not allowing consent to be waived for deceased patients, are reported in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.103464; among patients not from the UK and Germany (n = 1038), median OS was not reached (44.6 months-not estimable), the 3-year OS rate was 60.8% (95% CI 57.7% to 63.7%), median PFS

was 21.7 months (95% CI 18.7-25.6 months), and 3-year PFS rate was 40.4% (95% CI 37.2% to 43.5%). Similar results were obtained when utilizing an immortal bias adjustment method; median OS was not reached (95% CI not estimable-not estimable), the 3-year OS rate was 60.4% (95% CI 60.4% to 60.4%), median PFS was 21.3 months (95% CI 20.8-21.4 months), and the 3-year PFS rate was 40.3% (95% CI 40.3% to 40.4%). In an additional sensitivity analysis of PFS that excluded patients with unknown progression status, median PFS was 24.3 months (95% CI 20.5-28.2 months), and the 3-year PFS rate was 42.4% (95% CI 39.4% to 45.4%) among the patients with known progression status (n = 1145).

## Identification of factors associated with OS and PFS

Multivariable analyses demonstrated that non-squamous tumor histology is a favorable prognostic factor for OS compared with squamous histology and that the use of carboplatin during CRT is an unfavorable prognostic factor for OS compared with the use of cisplatin (i.e. the adjusted HR 95% CI did not cross 1 for these comparisons) (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.103464). These analyses also demonstrated that non-squamous tumor histology is a favorable prognostic factor for PFS compared with squamous tumor histology and that current or former smoking status is a favorable prognostic factor for PFS compared with never having smoked (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2024.103464).

## TTDM, TDLR, and TFST in the full analysis set

Median TTDM was 35.5 months (95% CI 32.2-38.0 months), with 49.5% (95% CI 46.4% to 52.6%) of the patients estimated to be alive and without any distant metastases at 3 years (Figure 4A). Median TDLR was not reached (95% CI 42.3 months-not estimable), with 65.6% (95% CI 62.2% to 68.8%) of the patients estimated to be alive and without local recurrence (i.e. recurrence within the thoracic RT field) at 3 years (Figure 4B). Median TFST was 35.9 months (95% CI 31.3-42.9 months), with 49.9% (95% CI 47.0% to 52.8%) of the patients estimated to be alive and without subsequent treatment (post-durvalumab) at 3 years (Figure 4C).

## DISCUSSION

With ~3 years of follow-up, median OS was not reached in the current analysis from PACIFIC-R. Over 60% of all patients were estimated to remain alive 3 years after starting durvalumab, and >40% of all patients remained both alive and without disease progression at this time point. The findings of PACIFIC-R are broadly consistent with outcomes from the PACIFIC trial,⁴,⁵,⁸ as well as observational studies of patients receiving the PACIFIC regimen,¹⁵,¹⁶ and support the real-world effectiveness of consolidation durvalumab after CRT.

We observed favorable OS and PFS outcomes with durvalumab across different subgroups. The updated PFS results from the current chart extraction are consistent with the earlier PFS findings from PACIFIC-R.¹⁴ Moreover, aligned
<figure><img src="image_3.png" /><figcaption>**Figure 1.** OS and investigator-assessed PFS in the full analysis set. Shown are Kaplan-Meier distributions of (A) OS and (B) investigator-assessed PFS. The tick marks on each trendline represent censored observations, and the dashed lines arising from the x-axes represent 2- and 3-year landmark analyses. OS was defined as the time from the index date to the date of death from any cause, or the last recorded date the patient was known to be alive for censored patients. PFS was defined as the time from the index date to the date of investigator-determined disease progression, or death from any cause (in the absence of progression), whichever occurred first; if no progression or death occurred, patients were censored at the time of the last available tumor assessment. Note: given the real-world nature of PACIFIC-R, progression could be determined by either investigator's assessment or according to the Response Evaluation Criteria in Solid Tumors version 1.1, depending on local practice. The median duration of follow-up in patients censored at the time of database cut-off was 38.7 months (range 13.6-49.0 months). CI, confidence interval; NE, not estimable; OS, overall survival; PFS, progression-free survival.</figcaption></figure>

with results from the PACIFIC trial, survival outcomes were better among patients with PD-L1 expression on ≥1% of TCs, patients who started durvalumab closer to the end of RT, and patients with non-squamous tumor histology.⁸,¹²,¹⁷ Sensitivity analyses exploring potential biases yielded similar findings to the main analyses of OS and PFS, confirming the robustness of the PACIFIC-R results and further supporting the real-world effectiveness of consolidation durvalumab.

Results from the multivariable Cox analyses identified non-squamous tumor histology as a favorable prognostic factor for OS compared with squamous tumor histology, while the use of carboplatin during CRT was an unfavorable prognostic factor compared with the use of cisplatin. In addition, non-squamous tumor histology (versus squamous histology) and a history of smoking (versus never having smoked) were identified as favorable prognostic factors for PFS. Aligned with findings from PACIFIC-R, non-squamous tumor histology was also identified as a favorable prognostic factor for OS and PFS in PACIFIC.⁸ The other prognostic factors identified in PACIFIC-R (i.e. smoking status and the platinum agent used during CRT) were also identified in external studies of patients with stage III NSCLC.⁸,¹⁸ The association of smoking status with PFS seen in PACIFIC-R aligns with findings from other studies, which suggest that patients with a history of smoking benefit more from immunotherapy compared with patients who have never smoked.¹⁹ This phenomenon could be attributed to higher neoantigen load among smokers or the presence of unobserved driver mutations among patients who have never smoked. While the optimal chemotherapeutic agent(s) in the context of the PACIFIC regimen is not yet known, *post hoc* analysis of data from PACIFIC found a PFS and OS benefit with durvalumab versus placebo regardless of the prior chemotherapeutic agents received.¹⁷ The worse OS prognosis associated with carboplatin use in PACIFIC-R could, at least partially, be linked to factors that influence

the physician's choice of platinum agent; indeed, findings from other real-world studies suggest that the choice is influenced by baseline patient and disease characteristics, with cisplatin typically being reserved for fitter patients.²⁰,²¹

The better outcomes observed among patients with PD-L1-expressing tumors in PACIFIC-R aligned with our expectations. Higher PD-L1 expression is, to a certain extent, considered a predictive biomarker for response to immune checkpoint inhibitors in patients with advanced NSCLC. However, expression of PD-L1 is a labile parameter that can be influenced by external factors, making it a useful, but sub-optimal, biomarker for response to immunotherapy.²²,²³ For example, PD-L1 expression can vary according to anatomical sites and the immunohistochemistry assays used to determine expression.²² Moreover, RT can induce up-regulation of tumoral PD-L1 expression,²⁴,²⁵ which is relevant in the context of the PACIFIC regimen as tumoral PD-L1 expression is typically determined from tumor samples obtained before receiving CRT. The label approved for durvalumab by the EMA excludes patients with PD-L1 expression on <1% of TCs based on a *post hoc* analysis,⁷,¹² while similar restrictions are not applied by other regulatory bodies, including the United States FDA.¹³ Nevertheless, encouraging outcomes were still observed among patients with PD-L1 expression on <1% of TCs in the present study, with over 50% of these patients estimated to remain alive at 3 years.

Historically, use of sCRT alone was associated with inferior survival compared with cCRT alone in several studies, including a meta-analysis of several randomized trials.²⁶ Therefore, as recommended by international treatment guidelines, physicians should provide cCRT when possible, reserving sCRT for frailer patients who may be unable to tolerate cCRT.⁶,²⁷,²⁸ We observed encouraging outcomes with durvalumab among patients who received sCRT, with nearly 60% of these patients estimated to remain alive at 3 years in PACIFIC-R. Reflecting the clinical characteristics that
<figure><img src="image_4.png" /><figcaption>**Figure 2.** OS for subgroups of interest. Shown are Kaplan-Meier distributions of OS according to (A) PD-L1 expression level; (B) prior CRT type; (C) time elapsed between the end of RT and the start of durvalumab; (D) disease stage; and (E) tumor histologic type. The tick marks on each trendline represent censored observations, and the dashed lines arising from the x-axes represent 2- and 3-year landmark analyses.</figcaption></figure>

CI, confidence interval; cCRT, concurrent chemoradiotherapy; NE, not estimable; NR, not reached; OS, overall survival; PD-L1, programmed death-ligand 1; RT, radiotherapy; sCRT, sequential chemoradiotherapy; TC, tumor cell.

we would expect to correlate with sCRT use, patients in PACIFIC-R who received sCRT were typically older and had more advanced disease (i.e. stage IIIB/IIIC disease) versus those who received cCRT.¹⁴ Although PACIFIC trial enrollment was restricted to patients who received cCRT,⁵,⁸ the findings from PACIFIC-R provide support for the effectiveness of durvalumab after sCRT and are complemented by the promising efficacy observed with this treatment

approach in the phase II, single-arm, PACIFIC-6 trial (NCT03693300).²⁹

Utilizing the large sample size available in PACIFIC-R, which enrolled >1000 patients across all participating countries, the present article reports analyses based on the global study cohort to allow generalizability of the findings to a broad population. A limitation of this approach is that it does not account for the substantial heterogeneity in
<figure><img src="image_5.png" /><figcaption>**Figure 3.** Investigator-assessed PFS for subgroups of interest. Shown are Kaplan-Meier distributions of investigator-assessed PFS according to (A) PD-L1 expression level; (B) prior CRT type; (C) time elapsed between the end of RT and the start of durvalumab; (D) disease stage; and (E) tumor histologic type. The tick marks on each trendline represent censored observations, and the dashed lines arising from the x-axes represent 2- and 3-year landmark analyses. Note: given the real-world nature of PACIFIC-R, progression could be determined by either investigator's assessment or according to the Response Evaluation Criteria in Solid Tumors version 1.1, depending on local practice. CI, confidence interval; cCRT, concurrent chemoradiotherapy; NE, not estimable; NR, not reached; PFS, progression-free survival; PD-L1, programmed death-ligand 1; RT, radiotherapy; sCRT, sequential chemoradiotherapy; TC, tumor cell.</figcaption></figure>

clinical characteristics and investigations across different countries and hospital sites. For example, the outcomes reported for PD-L1 subgroups may be biased by real-world differences in the uptake of PD-L1 testing, the approach used for tissue sampling, and the choice of assay for determining tumoral PD-L1 expression (as lower concordance has been observed between certain assays).³⁰ Country- or region-specific analyses from PACIFIC-R may

provide further insights. Additionally, PACIFIC-R enrolled a predominantly European population, so the findings cannot necessarily be extrapolated to patients of all ethnic or racial backgrounds. Recently published findings from PACIFIC-KR (N = 157), an observational study of patients who received durvalumab through the EAP in South Korea, were aligned with the findings from PACIFIC-R (with 3-year OS and PFS rates of 69.2% and 43.5%, respectively),³¹
<figure><img src="image_6.png" /><figcaption>**Figure 4.** TTDM, TDLR, and TFST in the full analysis set. Shown are Kaplan-Meier distributions of (A) TTDM, (B) TDLR, and (C) TFST. The tick marks on each trendline represent censored observations, and the dashed lines arising from the x-axes represent 2- and 3-year landmark analyses. TTDM was defined as the time from the index date to the date of first distant metastasis, as determined by the investigator, or death in the absence of distant metastasis; patients who had not developed a distant metastasis, and who had not died at the time of the analysis, were censored for TTDM at the time of their last available tumor assessment. TDLR was defined as time from the index date until the date of first documentation of local recurrence (i.e. recurrence within the thoracic radiation field), as determined by the investigator; local recurrence was only applicable when there was no distant relapse at the same time or before the local recurrence (in the latter case, it was considered distant relapse and the censoring date was the date of diagnosis in the metastatic setting). Patients who did not experience a local recurrence, or experienced local recurrence and distant metastasis at the same time, or experienced distant metastasis only, were censored; death in the absence of both local recurrence and distant metastasis was considered an event. TFST was defined as time from the index date until the start date of the first subsequent treatment after durvalumab discontinuation or death from any cause, whichever occurred first. CI, confidence interval; NE, not estimable; TDLR, time to death or local recurrence; TFST, time to death or first subsequent treatment after durvalumab; TTDM, time to death or distant metastasis.</figcaption></figure>

suggesting that similar outcomes can be achieved among non-European populations.

In conclusion, durvalumab has been demonstrated to provide improvements in OS and PFS following cCRT in unresectable, stage III NSCLC,⁴,⁵ with PFS benefits being seen across a range of PD-L1 expression levels.¹² Moreover, durvalumab shows promising signs of efficacy after sCRT in unresectable, stage III NSCLC.²⁹ The PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Consistent with PFS findings from a previous analysis of this ongoing study,¹⁴ better OS and PFS outcomes were observed among patients with PD-L1 expression on ≥1% of TCs and patients who received cCRT in the current analysis. Nevertheless, encouraging outcomes were still observed among patients with PD-L1 expression on <1% of TCs and patients who received sCRT, supporting the use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

## ACKNOWLEDGEMENTS

Medical writing support, under the direction of the authors, was provided by Werner Gerber, PhD (Fourways, South

Africa), and Aaron Korpal, PhD (Manchester, UK), of Ashfield MedComms, an Inizio Company, and was funded by AstraZeneca.

## FUNDING

This work was supported by AstraZeneca (no grant number) to The PACIFIC-R study (NCT03798535) was supported by AstraZeneca (no grant number).

## DISCLOSURE

ARF reports grants or contracts from AstraZeneca, Merck Sharp & Dohme, and Roche; consulting fees from AstraZeneca and Radiomics; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca and Roche. JB reports honoraria for participation in the PACIFIC-R Scientific Committee Meeting; grants or contracts paid to the institution from Merck Sharp & Dohme, AstraZeneca, Roche, Bristol Myers Squibb, Takeda, AbbVie, Bayer, Boehringer Ingelheim, and Pfizer; consulting fees from AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Takeda, AbbVie, Pfizer, Bayer, and VBL Therapeutics; and a leadership or fiduciary role in other
board, society, committee, or advocacy group for the Lung Ambition Consortium, Israel Lung Cancer Group, and IASLC committee. CC reports grants or contracts paid to the institution, consulting fees, and support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche, Sanofi Aventis, Bristol-Myers Squibb, Merck Sharp & Dohme, Lilly, Novartis, Pfizer, Takeda, Bayer, and Amgen. DCC reports consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and payment for expert testimony from, and participation on a Data Safety Monitoring Board or Advisory Board for, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, Novocure, Pfizer, Roche, Sanofi, and Takeda; and support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda. RF reports grants or contracts from AstraZeneca, Merck Sharp & Dohme, Novocure, and Siemens; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Serono, AstraZeneca, Merck Sharp & Dohme, Novocure, and Siemens; support for attending meetings and/or travel from Promedicis, Merck Sharp & Dohme, AstraZeneca, Siemens, Novocure, and Bristol Myers Squibb; and participation on a Data Safety Monitoring Board or Advisory Board for Merck Sharp & Dohme, AstraZeneca, and Novocure. MCG reports research funding from Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, AstraZeneca/MedImmune, AstraZeneca, Pfizer, GlaxoSmithKline, Novartis, Merck, Incyte, Takeda, Spectrum Pharmaceuticals, Blueprint Medicines, Eli Lilly, Ipsen, Janssen, Exelixis, MedImmune, Sanofi, Pfizer, and Amgen; consulting fees from Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Novartis, Takeda, Roche, Sanofi-Aventis, Celgene, Daiichi Sankyo, Pfizer, Seattle Genetics, Eli Lilly, GlaxoSmithKline, Bayer Healthcare Pharmaceuticals, Blueprint Medicines, Janssen, Regeneron, Bayer, AbbVie, Mirati, Merck, and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol-Myers Squibb, Daiichi Sankyo/AstraZeneca, Regeneron, Pfizer, Blueprint Pharmaceutic, Novartis, and Sanofi/Aventis; and other non-financial interests with Merck. PG reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Merck Sharp & Dohme, Novartis, Medscape, Takeda, and TouchTime; support for attending meetings and/or travel from AstraZeneca, Roche, and Janssen; an advisory role for AbbVie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda; and a Steering Committee role for Novartis and IO Biotech IO102 Janssen. VDH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from

AstraZeneca, Takeda, Bristol Myers Squibb, Janssen (Johnson & Johnson), Roche, Pfizer, and Merck Sharp & Dohme; participation on a Data Safety Monitoring Board or Advisory Board for Novartis, AstraZeneca, and Bristol Myers Squibb; and is a board member for the Lung Cancer Patient Organization. SK reports grants or contracts and support for attending meetings and/or travel from AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Beigene, AstraZeneca, Pfizer, and Takeda; and participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Pfizer, Merck Sharp & Dohme, Beigene, Bristol Myers Squibb, Roche, and Amgen. BM reports participation on advisory boards for Amgen, Bristol Myers Squibb, Merck, Beigene, and AstraZeneca. FM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events and support for attending meetings and/or travel from AstraZeneca. MM reports grants or contracts from AstraZeneca; consulting fees from Amgen, Bayer, Merck Sharp & Dohme, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Sharp & Dohme, AstraZeneca, Roche, Takeda, and Pfizer; support for attending meetings and/or travel from Pfizer and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Merck Sharp & Dohme. SP reports funding paid to the institution from AstraZeneca; grants or contracts paid to the institution from Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, and Roche/Genentech; consulting fees from AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, MedToday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, and Vaccibody; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events paid to the institution from AiCME, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Mirati, Novartis, Peerview, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, and Takeda; support for attending meetings and/or travel paid to the institution from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme,
Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, Oncology Education, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, and Vaccibody; and is a member of the Board of Directors for Galencia. AS reports participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. SS reports salary support from Cancer Council Victoria (CCV) Colebatch Fellowship (since 2020); grants or contracts paid to the institution from Varian Medical Systems, Bayer Pharmaceuticals, and Merck Sharp & Dohme; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events paid to the institution from AstraZeneca and Varian Medical Systems; and leadership or fiduciary role in other board, society, committee, or advocacy group for the American Society of Radiation Oncology (ASTRO), Advanced Radiotherapy Techniques (ART) committee of the International Association for the Study of Lung Cancer (IASLC), and the Radiosurgery Society (RSS). MvdH reports grants or contracts from Amgen, AstraZeneca, Bristol Myers Squibb, Janssen Pharmaceutical, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Roche Diagnostics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; a leadership or fiduciary role for the Oncology Working Group and NVALT Research Foundation. PV reports consulting fees from AstraZeneca, Merck Sharp & Dohme, and Bristol Myers Squibb; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca. SA reports employment and stock ownership with AstraZeneca. PC reports employment and stock ownership with AstraZeneca. ML reports former employment with AstraZeneca, and stock ownership with AstraZeneca. ARdL reports employment and stock ownership with AstraZeneca. YQ reports employment and stock ownership with AstraZeneca. NG reports research grants/support from Abbvie, Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Roche, Janssen, LeoPharma, Lilly, Merck Sharp & Dohme, Novartis, Sivan; consultative services for Abbvie, Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, Daiichi Sankyo, Gilead, Ipsen, Roche, Janssen, LeoPharma, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Sanofi, Takeda; participation on a Data Safety Monitoring Board for Roche; employment of a family member with AstraZeneca; and a leadership role in the International Thymic Malignancy Interest Group. All other authors have declared no conflicts of interest.

## DATA SHARING

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data

sharing policy described at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at: www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at: https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. The AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.

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