Durvalumab after chemoradiotherapy in non‐small cell lung cancer with EGFR mutation: A real‐world study (HOT2101)

Abstract

Durvalumab has been administered to patients with unresectable stage III non‐small cell lung cancer (NSCLC). However, it remains unclear whether durvalumab benefits these patients with epidermal growth factor receptor (EGFR) mutation. We conducted a retrospective, multicenter study of patients with EGFR mutation who received chemoradiotherapy (CRT) between June 2018 and March 2021. We assessed patient characteristics, efficacy of durvalumab, and durvalumab safety before and after targeted therapy. We collected data on a total of 673 patients, of whom 401 (59.6%) underwent EGFR mutation testing. Fifty‐one patients were EGFR positive and 311 were EGFR negative. In the EGFR‐positive group, there were higher proportions of females, never‐smokers, and patients with adenocarcinoma histology. Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab, with median progression‐free survival of 23.0 and 24.2 months in the positive and negative groups, respectively (hazard ratio 1.03; 95% confidence interval: 0.64–1.67). The main adverse event was pneumonitis (positive group: 62.2%; 4.4% grade 3; negative group: 62.3%; 6.9% grade 3). No treatment‐related deaths were observed. Of the 45 patients in the positive group who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab at the data cutoff. One patient discontinued targeted therapy after developing pneumonitis. In patients with unresectable stage III NSCLC with EGFR mutation, durvalumab after CRT is potentially safe and effective. This may be a suitable treatment sequence for these patients.

We retrospectively evaluated durvalumab after chemoradiotherapy in two groups with and without EGFR mutations. Durvalumab was safe and beneficial in patients with and without EGFR mutations, consistent with previous reports.

Abbreviations

AEs

adverse events

ALK

anaplastic lymphoma kinase

CRT

chemoradiotherapy

CI

confidence interval

DCR

disease control rate

ECOG‐PS

Eastern Cooperative Oncology Group performance status

EGFRm

epidermal growth factor receptor mutation

EGFR

epidermal growth factor receptor

NSCLC

non‐small cell lung cancer

NR

not reached

ORR

objective response rate

OS

overall survival

PD‐L1

programmed death ligand 1

PFS

progression‐free survival

TKI

tyrosine kinase inhibitor

1. INTRODUCTION

Durvalumab, a selective high‐affinity human IgG1 monoclonal anti‐programmed death ligand 1 (PD‐L1) antibody, inhibits PD‐L1 binding to PD‐1 and CD80. ¹ In the phase III, placebo‐controlled PACIFIC trial of patients with unresectable stage III non‐small cell lung cancer (NSCLC), whose disease had not progressed after platinum‐based concurrent chemoradiotherapy (CRT), administration of durvalumab improved median progression‐free survival (PFS) and overall survival (OS) remarkably. ² , ³ , ⁴

An epidermal growth factor receptor (EGFR) mutation (EGFRm) is observed in approximately 50% of lung adenocarcinoma patients in Asia and 20% in Western countries. ⁵ Although the standard of care for patients with stage IV NSCLC with EGFRm is EGFR tyrosine kinase inhibitor (TKI), that for patients with stage III is selected to achieve a cure. ⁶ Among patients with stage III NSCLC with EGFRm, the median PFS after CRT alone was 6–9 months in retrospective studies. ⁷ , ⁸ , ⁹

The PACIFIC trial comprised 713 randomized patients, including 43 (6%) with EGFRm or anaplastic lymphoma kinase (ALK) translocation, out of whom 29 received durvalumab. ² For the EGFRm subgroup, there were no significant differences in PFS or OS between durvalumab and the placebo. ² , ¹⁰ Durvalumab consolidation therapy outcomes have been evaluated in patients with driver‐gene mutation/translocation (n = 43): Limited efficacy was observed in patients with EGFRm. ¹¹ In another retrospective study of patients with stage III NSCLC harboring EGFRm, durvalumab had no significant effect on PFS (n = 37). ¹² Owing to limited case numbers, it remains unclear whether durvalumab benefits patients with EGFRm.

Recent studies have raised concerns regarding the safety of targeted therapy after immunotherapy administration. ¹² , ¹³ In a retrospective study of patients with stage III NSCLC with EGFRm (n = 37), six patients received EGFR‐TKI after durvalumab, with one developing grade 4 pneumonitis. ¹² In a post‐hoc subgroup analysis of 35 patients with EGFRm in the PACIFIC trial, out of the 24 who received durvalumab, 13 received EGFR‐TKIs. ¹⁴ Owing to limited cases, the efficacy and safety of EGFR‐TKI after durvalumab treatment remain unclear.

Therefore, we retrospectively analyzed and compared the data of patients with and without EGFRm, who received CRT in clinical practice, to provide insights into the efficacy and safety of durvalumab consolidation therapy and targeted therapy.

2. MATERIALS AND METHODS

2.1. Study design and population

The Hokkaido Lung Cancer Clinical Study Group Trial 2101 (HOT2101) was a retrospective, observational, multicenter study conducted at 19 institutions in Japan. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Hokkaido University Hospital (021‐0107). Given the retrospective nature of the study, the requirement for informed consent was waived. This study was registered at UMIN‐CTR (UMIN000048100).

We evaluated consecutive patients with locally advanced or postoperative recurrent, unresectable NSCLC with driver‐gene mutation/translocation, who received CRT between June 2018 and March 2021. The eligibility criteria were as follows: histologically or cytologically confirmed NSCLC with the EGFR status. Driver gene testing, via next‐generation sequencing panel or targeted gene assay, was performed during standard‐of‐care evaluations.

Demographic and clinical characteristics, including age, sex, smoking status, tumor histology, cancer stage, type of driver‐gene mutation/translocation, PD‐L1 status, and Eastern Cooperative Oncology Group performance status (ECOG‐PS), were obtained retrospectively from the patient files. Tumor‐cell PD‐L1 status was assessed within standard‐of‐care evaluation via immunohistochemistry using the 22C3 pharmDx assay. Tumor proportion scores of ≥50%, 1%–49%, and <1% were considered high, low, and no expression, respectively. Durvalumab treatment‐related factors, including duration, discontinuation, and adverse events (AEs), were recorded. AEs were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events v. 5.0. Tumor responses, evaluated via computed tomography and magnetic resonance imaging, were defined according to RECIST v. 1.1. Considering the retrospective study design, complete response and partial response did not require confirmation. The assessments were performed at each participating institution. The data cutoff date was December 31, 2021.

2.2. Statistical analysis

Chi‐squared or Fisher's exact test was performed for comparing quantitative variables of proportions of patients based on patient characteristics and tumor factors. The Wilcoxon rank‐sum test was performed for comparing continuous variables of those. PFS was defined as the interval between initial CRT or durvalumab administration and disease progression or death. OS was defined as the interval between initial durvalumab administration and death from any cause. PFS and OS were estimated using the Kaplan–Meier method, and a log‐rank test was performed for inter‐group comparisons. The hazard ratio and 95% confidence interval (CI) were estimated using the log‐rank test. Statistical analyses were performed using GraphPad Prism v. 8.4.3 (GraphPad Software) and STATA v. 18.0 (Stata Corp).

3. RESULTS

3.1. Patient characteristics

In total, 673 patients with unresectable stage III NSCLC received CRT. Of these, 401 (59.6%) underwent EGFRm testing. Fifty‐one patients (12.7%) were EGFR positive: There were 24 with exon 19 deletions, 18 with exon 21 L858R mutations, and 9 with EGFR uncommon mutations. Of the 401 patients who underwent EGFRm testing, 311 (77.6%) were EGFR negative (Figure 1). In the EGFR‐positive group, there were higher proportions of females, never‐smokers, and patients with adenocarcinoma histology (p < 0.0001; Table 1).

FIGURE 1.

Patient selection process.

TABLE 1.

Patient characteristics.

	No. of patients (%)		p‐Value
	EGFR positive (n = 51)	EGFR negative (n = 311)
Median age, years [range]	70 [42–83]	68 [35–85]	0.42
Sex
Male	17 (33.3)	250 (80.4)	<0.0001
Female	34 (66.7)	61 (19.6)
ECOG‐PS
0	30 (58.8)	181 (58.2)	0.92
1	21 (41.2)	130 (41.8)
2	0	1 (0.3)
Smoking status
Current	5 (9.8)	70 (22.5)	<0.0001
Former	16 (31.4)	216 (69.5)
Never	30 (58.8)	24 (7.7)
Unknown	0	1 (0.3)
Histological type
Ad	46 (90.2)	161 (51.8)	<0.0001
Sq	1 (2.0)	107 (34.4)
Others	4 (7.8)	43 (13.8)
Clinical stage
IIIA	20 (39.2)	123 (39.5)	0.71
IIIB	20 (39.2)	119 (38.3)
IIIC	3 (5.9)	32 (10.3)
Postoperative recurrence	8 (15.7)	37 (11.9)
PD‐L1 status
High	16 (31.4)	107 (34.4)	0.67
Low	14 (27.5)	90 (28.9)
No expression	14 (27.5)	88 (28.3)
Unknown	7 (13.7)	26 (8.4)

Note: Tumor‐cell PD‐L1 status was assessed within the standard‐of‐care evaluation, via immunohistochemistry using the 22C3 pharmDx assay. Tumor proportion scores of ≥50%, 1%–49%, and <1% were considered high, low, and no expression, respectively.

Abbreviations: Ad, adenocarcinoma; ECOG‐PS, Eastern Cooperative Oncology Group performance status; PD‐L1, programmed death ligand 1; Sq, squamous cell carcinoma.

3.2. Chemoradiotherapy

The median duration of follow‐up from CRT initiation was 22.0 (range, 1.4–43.4) and 22.7 (2.8–42.8) months in the positive and negative groups, respectively. The details of CRT are listed in Table 2. Weekly carboplatin/paclitaxel was the most frequently selected chemotherapy regimen during CRT (47.1% in the positive group and 55.9% in the negative group), followed by cisplatin/vinorelbine. There was a significant difference in chemotherapy regimens between the positive and negative groups because other regimens, including daily carboplatin, cisplatin/S‐1, or carboplatin/S‐1, were more frequently selected in the negative group. The objective response rates (ORR) and disease control rates (DCR) were 70.6% and 94.1% in the positive group and 72.0% and 94.5% in the negative group, respectively.

TABLE 2.

Details of chemoradiotherapy.

	No. of patients (%)		p‐Value
	EGFR positive (n = 51)	EGFR negative (n = 311)
Chemotherapy regimens
Weekly CBDCA + PTX	24 (47.1)	174 (55.9)	0.026
CDDP + VNR	21 (41.2)	74 (23.8)
Others	6 (11.8)	63 (20.3)
Median radiation dose, Gy [range]	60 [36–66]	60 [16–70]	0.37
Best response to CRT
Complete response	1 (2.0)	9 (2.9)
Partial response	35 (68.6)	215 (69.1)
Stable disease	12 (23.5)	70 (22.5)
Disease progression	2 (3.9)	9 (2.9)
Not evaluable	1 (2.0)	8 (2.6)
Objective response rate (%)	70.6	72.0
Disease control rate (%)	94.1	94.5

Abbreviations: CBDCA, carboplatin; CDDP, cisplatin; CRT, chemoradiotherapy; PTX, paclitaxel; VNR, vinorelbine.

3.3. Efficacy of durvalumab

Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab. Six patients in the positive group did not receive durvalumab: two because of disease progression, two because of the physician's decision, and two because of loss to follow‐up after CRT (Figure 1). The median PFS after CRT was 26.0 months (95% CI: 22.1–not reached [NR]) in patients in both groups administered durvalumab, and 7.5 months (95% CI: 6.3–9.3) in those without durvalumab treatment (HR 0.34; 95% CI: 0.20–0.56; Figure S1A). The median PFS after CRT was 25.1 months (95% CI: 14.8–NR) in patients with EGFRm administered durvalumab and 4.4 months (0.9–8.1) in those without durvalumab treatment (HR 0.12; 95% CI: 0.01–1.23; Figure S1B). The median PFS after CRT was 30.4 months (95% CI: 20.8–NR) in patients without EGFRm administered durvalumab and 7.9 months (6.4–10.8) in those without durvalumab treatment (HR 0.36; 95% CI: 0.22–0.62; Figure S1C).

The median duration of follow‐up from durvalumab initiation was 20.2 months (range, 4.9–37.1) in the positive group and 20.5 months (1.0–40.5) in the negative group. The median time from CRT completion to durvalumab initiation was 16 days (range, 6–41) in the positive group and 14 days (range, 1–91) in the negative group (Table 3). Twenty‐two patients in the positive group and ninety‐eight patients in the negative group completed 1 year of durvalumab treatment, with five and seventeen continuing durvalumab at data cutoff. Eighteen patients in the positive group discontinued durvalumab treatment, with eleven discontinuing due to disease progression and seven due to AEs. The median PFS from durvalumab initiation was 23.0 months (95% CI: 12.7–NR) in the positive group and 24.2 months (20.3–NR) in the negative group (HR 1.03; 95% CI: 0.64–1.67; p = 0.90; Figure 2A). The median OS from durvalumab initiation was NR (NR–NR) and NR (38.7–NR; HR 0.42; 95% CI: 0.20–0.86; p = 0.08; Figure 2B). The ORR and DCR were 62.2% and 91.1% in the positive group and 64.0% and 92.7% in the negative group, respectively (Table 3).

TABLE 3.

Details of durvalumab consolidation therapy.

	No. of patients (%)		p‐Value
	Positive (n = 45)	Negative (n = 247)
Radiation pneumonitis before durvalumab initiation
Grade 0	38 (84.4)	220 (89.1)	0.45
Grade 1	7 (15.6)	27 (10.9)
Median time from CRT completion to durvalumab initiation, days [range]	16 [6–41]	14 [1–91]	0.049
Median no. of cycles [range]	19 [1–27]	14 [1–28]	0.29
Durvalumab discontinuation at data cutoff
Yes	18 (40.0)	132 (53.4)	0.22
No (completed 1 year of durvalumab)	22 (48.9)	98 (39.7)
No (ongoing)	5 (11.1)	17 (6.9)
Best response to durvalumab
Complete response	2 (4.4)	18 (7.3)
Partial response	26 (57.8)	140 (56.7)
Stable disease	13 (28.9)	71 (28.7)
Disease progression	3 (6.7)	13 (5.3)
Not evaluable	1 (2.2)	5 (2.0)
Objective response rate (%)	62.2	64.0
Disease control rate (%)	91.1	92.7

Abbreviation: CRT, chemoradiotherapy.

FIGURE 2.

Progression‐free survival (PFS) and overall survival (OS) from durvalumab initiation. Kaplan–Meier analysis of (A) PFS and (B) OS from durvalumab initiation in the positive or negative group. CI, confidence interval; HR, hazard ratio; NR, not reached.

We evaluated PFS in EGFR and PD‐L1 status subgroups. PFS did not differ significantly by EGFR status. Patients with high PD‐L1 expression showed benefits from durvalumab (Figure S2; Tables S1 and S2). In addition, we aligned the proportion of the histological type in the positive and negative groups. Among patients with adenocarcinoma, the median PFS from durvalumab initiation was NR (95% CI: 12.7–NR) in the positive group and 29.0 months (17.7–NR) in the negative group (HR 0.92; 95% CI: 0.54–1.59; Figure S3A). Although the number of patients with non‐adenocarcinoma was small in the positive group, rendering an exact comparison impossible, the median PFS from durvalumab initiation did not differ significantly between the positive and negative groups (Figure S3B).

3.4. Safety of durvalumab

As of the data cutoff, the median number of durvalumab treatment cycles was 19 (range, 1–27) in the positive group. Of the 45 patients who received durvalumab, 36 presented 58 AEs, with 13.3% at grade 3 (Table 4). The main AE was pneumonitis (62.2%; 4.4% grade 3), followed by hypothyroidism (17.8%) and rash (15.6%). Of the seven patients with grade 1 pneumonitis after completing CRT before durvalumab treatment (Table 3), three patients showed worsened pneumonitis after starting durvalumab. No treatment‐related deaths were observed. AEs in the negative group are also shown in Table 4. Although there was some difference in frequency, AEs did not differ between the positive and negative groups.

TABLE 4.

Adverse events associated with durvalumab therapy in the positive (n = 45) and negative (n = 247) groups.

	Positive (n = 45)				Negative (n = 247)
	Any grade	Grade 1	Grade 2	Grade 3	Any grade	Grade 1	Grade 2	Grade 3	Grade 4
Pneumonitis	28 (62.2%)	11 (24.4%)	15 (33.3%)	2 (4.4%)	154 (62.3%)	63 (25.5%)	73 (29.6%)	17 (6.9%)	0
Hypothyroidism	8 (17.8%)	0	8 (17.8%)	0	15 (6.1%)	3 (1.2%)	12 (4.9%)	0	0
Rash	7 (15.6%)	5 (11.1%)	2 (4.4%)	0	14 (5.7%)	9 (3.6%)	5 (2.0%)	0	0
AST/ALT/ALP increased	2 (4.4%)	0	2 (4.4%)	0	16 (6.5%)	7 (2.8%)	6 (2.4%)	3 (1.2%)	0
Hyperthyroidism	2 (4.4%)	0	2 (4.4%)	0	5 (2.0%)	2 (0.8%)	3 (1.2%)	0	0
Oral mucositis	2 (4.4%)	1 (2.2%)	1 (2.2%)	0	0	0	0	0	0
Myalgia	2 (4.4%)	2 (4.4%)	0	0	0	0	0	0	0
Ischemic colitis	1 (2.2%)	0	0	1 (2.2%)	0	0	0	0	0
Lung infection	1 (2.2%)	0	0	1 (2.2%)	5 (2.0%)	0	2 (0.8%)	3 (1.2%)	0
Pulmonary tuberculosis	1 (2.2%)	0	0	1 (2.2%)	0	0	0	0	0
Diabetic ketoacidosis	1 (2.2%)	0	0	1 (2.2%)	0	0	0	0	0
Fatigue	1 (2.2%)	0	1 (2.2%)	0	5 (2.0%)	3 (1.2%)	0	2 (0.8%)	0
Edema	1 (2.2%)	0	1 (2.2%)	0	1 (0.4%)	1 (0.4%)	0	0	0
Pharyngitis	1 (2.2%)	0	1 (2.2%)	0	0	0	0	0	0
Pruritus	1 (2.2%)	1 (2.2%)	0	0	1 (0.4%)	1 (0.4%)	0	0	0
Dysgeusia	1 (2.2%)	1 (2.2%)	0	0	0	0	0	0	0
Esophagitis	0	0	0	0	16 (6.5%)	4 (1.6%)	12 (4.9%)	0	0
Creatinine increased	0	0	0	0	6 (2.4%)	4 (1.6%)	1 (0.4%)	1 (0.4%)	0
Diarrhea	0	0	0	0	4 (1.6%)	3 (1.2%)	0	1 (0.4%)	0
Fever	0	0	0	0	4 (1.6%)	4 (1.6%)	0	0	0
Platelet count decreased	0	0	0	0	3 (1.2%)	1 (0.4%)	0	2 (0.8%)	0
Enterocolitis	0	0	0	0	3 (1.2%)	0	2 (0.8%)	1 (0.4%)	0
Pneumothorax	0	0	0	0	2 (0.8%)	0	0	2 (0.8%)	0
Shingles	0	0	0	0	2 (0.8%)	0	1 (0.4%)	1 (0.4%)	0
Hyperglycemia	0	0	0	0	2 (0.8%)	1 (0.4%)	0	1 (0.4%)	0
Dry skin	0	0	0	0	2 (0.8%)	2 (0.8%)	0	0	0
Hyponatremia	0	0	0	0	1 (0.4%)	0	0	0	1 (0.4%)
Jejunal perforation	0	0	0	0	1 (0.4%)	0	0	0	1 (0.4%)
Ileus	0	0	0	0	1 (0.4%)	0	0	1 (0.4%)	0
Cholangitis	0	0	0	0	1 (0.4%)	0	0	1 (0.4%)	0
Cerebral infarction	0	0	0	0	1 (0.4%)	0	0	1 (0.4%)	0
Myelitis	0	0	0	0	1 (0.4%)	0	0	1 (0.4%)	0
Myasthenia gravis	0	0	0	0	1 (0.4%)	0	0	1 (0.4%)	0
Nausea	0	0	0	0	1 (0.4%)	0	1 (0.4%)	0	0
Tachycardia	0	0	0	0	1 (0.4%)	0	1 (0.4%)	0	0
Anemia	0	0	0	0	1 (0.4%)	0	1 (0.4%)	0	0
Blood bilirubin increased	0	0	0	0	1 (0.4%)	0	1 (0.4%)	0	0
Infusion‐related reaction	0	0	0	0	1 (0.4%)	0	1 (0.4%)	0	0
Myositis	0	0	0	0	1 (0.4%)	0	1 (0.4%)	0	0
Hypophysitis	0	0	0	0	1 (0.4%)	0	1 (0.4%)	0	0
Anorexia	0	0	0	0	1 (0.4%)	1 (0.4%)	0	0	0
Dizziness	0	0	0	0	1 (0.4%)	1 (0.4%)	0	0	0
Constipation	0	0	0	0	1 (0.4%)	1 (0.4%)	0	0	0
Prolonged QT interval on ECG	0	0	0	0	1 (0.4%)	1 (0.4%)	0	0	0
Adrenal insufficiency	0	0	0	0	1 (0.4%)	1 (0.4%)	0	0	0
Hyperuricemia	0	0	0	0	1 (0.4%)	1 (0.4%)	0	0	0

Abbreviations: ALP, alkaline phosphatase; ALT, aspartate aminotransferase; AST, alanine aminotransferase; ECG, electrocardiogram.

3.5. Targeted therapy after CRT with or without durvalumab

Of the 45 patients with EGFRm who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab: 13 received osimertinib and 1 received erlotinib plus ramucirumab as initial targeted therapy. The median duration of follow‐up from starting targeted therapy was 10.4 months (range, 1.0–23.8). The median time from the last durvalumab dose to starting targeted therapy was 140 days (range, 29–294). One patient (7.1%) discontinued osimertinib after developing pneumonitis, and another one (7.1%) discontinued erlotinib plus ramucirumab after developing fatigue and fever, but no other pneumonitis or AE leading to discontinuation were observed.

Of the 45 patients who received durvalumab, 31 (68.9%) did not receive targeted therapy after durvalumab at data cutoff. Disease progression did not occur in 25 but did occur in 6 patients. The six patients that experienced disease progression did not receive targeted therapy after durvalumab: two patients with an uncommon EGFRm because no corresponding targeted therapy was available; two with a common EGFRm because the interval after durvalumab treatment was too short; one with a common EGFRm because they had complete response following surgery after durvalumab treatment; and one with a common EGFRm based on patient's decision.

Of the six patients who received only CRT without durvalumab consolidation, five (83.3%) received targeted therapy. One patient was lost to follow‐up after CRT.

4. DISCUSSION

For patients with unresectable stage III NSCLC harboring EGFRm, durvalumab consolidation treatment showed some clinical benefits. Furthermore, targeted therapy after durvalumab may be safe, showing no obvious negative effects of post‐CRT durvalumab at the data cutoff. Our study is valuable because it evaluated patients with and without EGFRm besides those who received and did not receive durvalumab, unlike previous studies. We recommend durvalumab for patients with NSCLC with EGFRm.

The consolidation rate of durvalumab after CRT is consistent with that reported previously. ¹⁵ In the cases where post‐CRT durvalumab was not administered, the primary reason was disease progression or the physician's decision, not AEs. This result reveals that CRT is acceptable and well‐tolerated in these patients. We observed better median PFS from CRT initiation with durvalumab (26.0 months) than without durvalumab (7.5 months). The large difference in PFS with and without durvalumab was comparable to that reported in the PACIFIC trial, possibly reflecting the efficacy of durvalumab even in patients with EGFRm. ² , ⁴

In patients with NSCLC with EGFRm, the median PFS from durvalumab initiation (23.0 months) was similar to that in patients without EGFRm (24.2 months) and superior to that reported in the PACIFIC trial and other retrospective studies. ² , ⁴ , ¹¹ , ¹² , ¹⁶ In the IMMUNOTARGET registry, a multicenter retrospective study of patients with advanced NSCLC with EGFRm, single‐agent immunotherapy showed low clinical activity. ¹⁷ Further, in patients with advanced NSCLC with EGFRm, immunotherapy plus chemotherapy showed low activity. ¹⁸ , ¹⁹ However, these studies evaluated patients who received immunotherapy, chemotherapy, or both, but not radiotherapy. ¹⁷ , ¹⁸ , ¹⁹ In a preclinical setting, radiotherapy combined with immunotherapy led to PD‐L1 upregulation on tumor cells and improved local tumor control, ²⁰ suggesting that radiotherapy contributes to tumor control. While this may clarify why post‐CRT durvalumab benefits patients with NSCLC regardless of their EGFRm status, it may also elucidate the heightened efficacy of durvalumab in EGFRm patients experiencing poor responses to immunotherapy. However, in this study, PD‐L1 expression in patients with EGFRm was higher than that reported previously. ²¹ We cannot exclude the possibility that the higher PD‐L1 expression is responsible for the improved PFS observed in patients with EGFRm. Disagreement exists regarding the impact of immunotherapy in EGFRm patients with high PD‐L1 expression, and further study is necessary. ²² Overall, our findings suggest that post‐CRT durvalumab might benefit patients with NSCLC with EGFRm.

We found differences in efficacy between our study and other studies in patients with EGFRm. In a recent post‐hoc subgroup analysis of the PACIFIC trial, PFS and OS outcomes after durvalumab were similar to those with placebo in the EGFRm population (n = 35). ¹⁴ However, these baseline characteristics were unbalanced, with higher proportions of ECOG‐PS 0, stage IIIA, and high PD‐L1 expression with placebo, possibly responsible for the longer PFS with placebo. In a more recent retrospective study of the PACIFIC‐R study, the median PFS was numerically shorter among patients with EGFRm (n = 46). ¹⁶ However, these baseline characteristics of patients with EGFRm were unknown. Moreover, these studies used a limited number of patients. Our EGFRm population (51 patients), wherein the efficacy of durvalumab was revealed, was balanced in terms of PS, stage, and PD‐L1 expression between the groups and was larger than that reported previously. ² , ¹¹ , ¹² , ¹⁴ , ¹⁶ Our report differs from other reports in that our participants were all Japanese (Asian), which included more patients with EGFRm than Westerners. In the FLAURA study, large numerical between‐group differences were observed in the HR for OS of osimertinib between Asian and non‐Asian patients, which may account for possible differences in effect by race. ²³

Although targeted therapy may be a first‐line treatment option for patients with stage III NSCLC with EGFRm, ²⁴ , ²⁵ it cannot cure these patients. In the PACIFIC trial, some patients had long‐term PFS, which might reflect cure. ² , ⁴ In patients with stage III NSCLC, a treatment strategy that allows cure should be pursued.

In our study, the incidence of pneumonitis after durvalumab in patients with EGFRm was 62.2% at any grade (4.4% grade 3), higher than that in the PACIFIC trial, ² but similar to that reported in patients without EGFRm and in retrospective Japanese studies. ¹⁵ , ²⁵ The other safety profiles of durvalumab that we observed were consistent with those previously reported. ² These data suggest that administration of durvalumab is safe and applicable in patients with EGFRm.

The safety of targeted therapy following durvalumab remains a primary concern. Initiating osimertinib after discontinuing immunotherapy within the month led to the incidence of pneumonitis at a high rate. ²⁶ As pneumonitis interferes with targeted therapy, some physicians may avoid durvalumab for fear of losing the opportunity to use targeted therapy. In our study, 14 patients received targeted therapy after durvalumab; of these, one (7.1%) had discontinued targeted therapy because of pneumonitis. Furthermore, of the 31 patients who did not receive targeted therapy after durvalumab at data cutoff, no case was related to durvalumab administration. The median OS of patients with EGFRm was significantly longer than that of patients without EGFRm, suggesting that targeted therapy after durvalumab consolidation may contribute to the prolongation of OS. Our analysis revealed that targeted therapy may be safely administered following durvalumab in disease progression.

Our retrospective observational study included relatively few patients and used a short observation period that was insufficient for evaluating OS and the safety and effects of targeted therapy after durvalumab. Moreover, the relationship between EGFR and PD‐L1 status should be assessed; however, there were relatively few events. Therefore, we plan to analyze this relationship in the next data cutoff.

The key findings are that patients with EGFRm showed efficacy of durvalumab to be similar to that reported in the PACIFIC trial, and the PFS in patients with EGFRm was similar to that in patients without EGFRm. Following CRT for patients with unresectable stage III NSCLC with EGFRm, we recommend durvalumab to maximize the probability of cure. At the current stage, we suggest that durvalumab followed by osimertinib may provide an OS benefit to these patients.

AUTHOR CONTRIBUTIONS

Kosuke Tsuji: Conceptualization; data curation; formal analysis; visualization; writing – original draft. Hidenori Mizugaki: Conceptualization; data curation; formal analysis; visualization; writing – original draft. Keiki Yokoo: Conceptualization; data curation; formal analysis; visualization; writing – original draft. Maki Kobayashi: Writing – review and editing. Yosuke Kawashima: Writing – review and editing. Nozomu Kimura: Writing – review and editing. Hiroshi Yokouchi: Writing – review and editing. Hajime Kikuchi: Writing – review and editing. Toshiyuki Sumi: Writing – review and editing. Yasutaka Kawai: Writing – review and editing. Kenta Kobashi: Writing – review and editing. Ryo Morita: Writing – review and editing. Kenichiro Ito: Writing – review and editing. Yasuo Kitamura: Writing – review and editing. Hiroyuki Minemura: Writing – review and editing. Keiichi Nakamura: Writing – review and editing. Mari Aso: Writing – review and editing. Osamu Honjo: Writing – review and editing. Hisashi Tanaka: Writing – review and editing. Taichi Takashina: Writing – review and editing. Kyoji Tsurumi: Writing – review and editing. Jun Sugisaka: Writing – review and editing. Yoko Tsukita: Writing – review and editing. Satoshi Konno: Writing – review and editing. Satoshi Oizumi: Writing – review and editing.

CONFLICT OF INTEREST STATEMENT

During this study, HY, YT, and SK received grants from AstraZeneca. SO received honoraria and grants from AstraZeneca. The other authors declare no conflict of interest.

ETHICS STATEMENT

Approval of the research protocol by an Institutional Reviewer Board: The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Hokkaido University Hospital (021‐0107).

Informed Consent: Given the retrospective nature of the study, the requirement for informed consent was waived.

Registry and Registration No. of the study/trial: This study was registered at UMIN‐CTR (UMIN000048100).

Animal Studies: N/A.

Supporting information

Figure S1.

Table S1.

Tsuji K, Mizugaki H, Yokoo K, et al. Durvalumab after chemoradiotherapy in non‐small cell lung cancer with EGFR mutation: A real‐world study (HOT2101). Cancer Sci. 2024;115:1273‐1282. doi: 10.1111/cas.16094

DATA AVAILABILITY STATEMENT

The data obtained during this study and used to generate these findings are provided in the manuscript or supporting information.