First-Line Osimertinib for Patients With EGFR-Mutated Advanced Non-Small Cell Lung Cancer

Efficacy and Safety During the COVID-19 Pandemic

Suganija Lakkunarajah; Pauline T. Truong; Jeffrey N. Bone; Curtis Hughesman; Stephen Yip; Deepu Alex; Jason Hart; Philip Pollock; Sarah Egli; Melissa Clarkson; Mary Lesperance; Doran Ksienski

Disclosures

Transl Lung Cancer Res. 2023;12(7):1454-1465.

Abstract and Introduction

Abstract

Background: The FLAURA trial demonstrated improved overall survival (OS) with first-line osimertinib for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). We studied the efficacy and safety of osimertinib in a cohort treated during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: Patients diagnosed with EGFR-mutated advanced NSCLC between 11 March 2020 to 31 December 2021 who received first-line osimertinib in British Columbia, Canada were identified retrospectively. Kaplan-Meier curves of OS and progression-free survival (PFS) from the start of osimertinib were plotted. The associations of baseline characteristics with PFS, and development of pneumonitis or dose reductions due to toxicity with OS were evaluated with hazard ratios estimated using univariable and multivariable Cox models.

Results: The cohort comprised 231 individuals. 58.7% of patients with de novo advanced NSCLC were initially diagnosed after presentation to the Emergency Room. At osimertinib initiation, 31.6% were aged ≥75 years and 45.5% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Median PFS and OS were 18.0 months [95% confidence interval (CI): 16.1–26.2] and 25.4 months (95% CI: 20.3–not reached), respectively. On multivariable analysis, age ≥75 years (vs. <75), ECOG PS 2/3 (vs. 0/1), ECOG PS 4 (vs. 0/1), current smokers (vs. never smokers), programmed death ligand 1 (PD-L1) expression ≥50% (vs. <1%), and L858R mutation (vs. exon 19 deletion) were associated with shorter PFS. Among 110 patients who progressed, 33.6% received subsequent therapy. A proportion of 16.5% of the cohort developed grade ≥3 adverse events. Pneumonitis from osimertinib (3.9% incidence) was weakly associated with shorter OS (hazard ratio: 2.59, 95% CI: 0.94–7.12, P=0.066); dose reductions were not associated with worse OS. 10.8% of patients developed COVID-19.

Conclusions: In a cohort receiving first-line osimertinib during the COVID-19 pandemic, ECOG PS ≥2 was observed in nearly half of patients at treatment initiation contributing to a median OS shorter than in FLAURA. The incidence of severe adverse events was low and dose reduction for drug toxicity did not impact OS. Identifying and reducing barriers to the diagnosis of NSCLC during the COVID-19 pandemic are required.

Introduction

Routine use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in clinical practice has markedly improved prognosis for a subset of patients with advanced non-small cell lung cancer (NSCLC). EGFR mutations occur in approximately 48% of Asian and 19% of Western patients with NSCLC (adenocarcinoma histology).^[1] The most common EGFR mutations are exon 19 deletion (19del) and exon 21 p.Leu858Arg (L858R) mutation. First generation EGFR TKI such as erlotinib and gefitinib improve median progression-free survival (PFS) compared to chemotherapy (11.0 vs. 5.6 months) as an initial treatment for EGFR-mutated advanced NSCLC.^[2]

Osimertinib is an orally administered third generation, irreversible EGFR TKI with marked activity in the central nervous system. The practice-changing phase III FLAURA trial demonstrated superior median PFS (18.9 vs. 10.2 months) and median overall survival (OS, 38.6 vs. 31.8 months) in previously untreated patients with advanced NSCLC harboring exon 19del or L858R mutations.^[3] Importantly, rates for grade ≥3 adverse events were lower with osimertinib than first generation EGFR TKI (34% vs. 45%) as well as drug toxicity leading to treatment discontinuation (13% vs. 18%).

Despite impressive gains in OS and PFS with osimertinib observed in the FLAURA study, knowledge gaps exist regarding drug efficacy and safety in routine clinical practice. For example, only individuals with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 were included in FLAURA even though about 34–42% of patients with advanced NSCLC have ECOG performance status ≥2 at diagnosis.^[4,5] Inoue et al. conducted a phase II study of gefitinib for patients with EGFR-mutated advanced NSCLC who did not qualify for chemotherapy due to poor ECOG performance status.^[6] Impressively, most patients with a baseline ECOG performance status of 3–4 experienced marked improvements in performance status with gefitinib therapy and median OS in the entire cohort was 17.8 months. A prospective observational study of osimertinib in a similar patient population by Igawa et al. (n=16) noted significant improvements in ECOG performance status amongst half of the participants;^[7] however, the need for dose reduction due to adverse events and incidence of interstitial lung disease were numerically higher than in FLAURA.

At the onset of the coronavirus disease 2019 (COVID-19) pandemic, clinical practice guidelines strongly recommended against disruptions in the care of individuals with actionable mutations.^[8] However, frequent contacts with the healthcare system required for cancer diagnosis and treatments, can increase the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure and infection. Moreover, patients with lung cancer who develop COVID-19 are at significant risk of hospitalization and mortality.^[9] To our knowledge, few real-world studies have described the incidence, severity, and management of COVID-19 in advanced NSCLC patients who were prescribed first-line osimertinib.

In this multicenter retrospective study, we evaluated survival outcomes relative to baseline clinical characteristics amongst patients receiving osimertinib as an initial treatment for EGFR-mutated (19del and L858R) advanced NSCLC during the COVID-19 pandemic. In addition, we investigated the prognostic significance of pneumonitis and the need for dose reductions due to adverse events. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-81/rc).

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References
Sidebar

Table 1. Baseline characteristics of 231 patients with EGFR-mutated advanced NSCLC receiving first line osimertinib
Characteristics	Value, n (%)
Age (years)
<65	70 (30.3)
65–74	88 (38.1)
≥75	73 (31.6)
Gender
Male	78 (33.8)
Female	153 (66.2)
ECOG PS
0/1	126 (54.5)
2/3	102 (44.2)
4	3 (1.3)
Histology
Adenocarcinoma	227 (98.3)
Adenosquamous	3 (1.3)
Squamous	1 (0.4)
Charlson Comorbidity Index, median (IQR)	0 (0–1)
Smoking status
Never smoker	136 (58.9)
Former smoker	83 (35.9)
Current smoker	12 (5.2)
EGFR mutation
19del	128 (55.4)
L858R	103 (44.6)
PD-L1 staining
<1%	89 (38.5)
1–49%	66 (28.6)
≥50%	68 (29.4)
Unknown	8 (3.5)
Brain metastases present	57 (24.7)
Initial stage at presentation
I	20 (8.7)
II	10 (4.3)
IIIA	9 (3.9)
IIIB	6 (2.6)
IIIC	2 (0.8)
IV	184 (79.7)
Advanced NSCLC at presentation	189 (81.8)

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, interquartile range; PD-L1, programmed death ligand 1.

Table 2. Univariable and multivariable time dependent Cox regression analysis of progression free survival for 231 patients with EGFR-mutated advanced NSCLC treated with first-line osimertinib
Variables	Univariable		Multivariable
Variables	HR (95% CI)	P	HR (95% CI)	P
Age (≥75 vs. <75 years)	1.37 (0.93–2.00)	0.11	1.89 (1.25–2.78)	0.0021
Gender (male vs. female)	1.06 (0.72–1.56)	0.77	1.17 (0.82–1.69)	0.39
ECOG performance status
2/3 vs. 0/1	2.53 (1.72–3.72)	<0.001	2.45 (1.72–3.49)	<0.001
4 vs. 0/1	15.56 (4.72–51.31)	<0.001	22.27 (6.35–78.10)	<0.001
CCI (per 1 unit increase)	0.95 (0.80–1.13)	0.57	0.84 (0.71–1.00)	0.056
Smoking status
Former vs. never	1.44 (0.97–2.15)	0.070	1.01(0.69–1.48)	0.95
Current vs. never	4.77 (2.47–9.20)	<0.001	5.21 (2.90–9.36)	<0.001
Present with advanced NSCLC (yes vs. no)	1.23 (0.74–2.07)	0.42	0.85 (0.52–1.41)	0.53
Brain metastases at baseline (present vs. none)	1.37 (0.91–2.06)	0.13	1.29 (0.87–1.92)	0.21
EGFR mutation (L858R vs. 19del)	1.57 (1.08–2.27)	0.017	1.43 (1.00–2.06)	0.050
PD-L1 tumor proportion score
≥50% vs. <1%	1.74 (1.13–2.68)	0.012	1.59 (1.07–2.36)	0.023
1–49% vs. <1%	0.96 (0.59–1.55)	0.85	1.16 (0.75–1.80)	0.50
Unknown vs. <1%	0.99 (0.31–3.21)	0.99	0.99 (0.30–3.23)	0.99
Adverse event ≥ grade 2 (present vs. none)	1.20 (0.81–1.76)	0.36	0.79 (0.53–1.17)	0.24

CCI, Charlson Comorbidity Index; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1.

Table 3. Univariable and multivariable time dependent Cox regression analysis of overall survival for 231 patients with EGFR-mutated advanced NSCLC treated with first-line osimertinib
Variables	Univariable		Multivariable
Variables	HR (95% CI)	P	HR (95% CI)	P
Age (≥75 vs. <75 years)	1.45 (0.94–2.22)	0.087	1.42 (0.86–2.38)	0.16
Gender (male vs. female)	1.03 (0.67–1.58)	0.91	1.13 (0.71–1.81)	0.60
ECOG performance status
2/3 vs. 0/1	2.66 (1.72–4.12)	<0.001	2.46 (1.55–3.88)	<0.001
4 vs. 0/1	20.01 (5.94– 67.39)	<0.001	30.77 (8.51–111.34)	<0.001
CCI (per 1 unit increase)	1.03 (0.86–1.23)	0.75	0.91 (0.74–1.13)	0.39
Smoking status
Former vs. never	1.60 (1.04–2.48)	0.034	1.31 (0.81–2.12)	0.26
Current vs. never	3.23 (1.51–6.90)	0.002	2.91 (1.31–6.50)	0.0090
Present with advanced NSCLC (yes vs. no)	1.21 (0.67–2.17)	0.53	0.97 (0.50–1.89)	0.92
Brain metastases at baseline (present vs. none)	1.57 (1.00–2.45)	0.048	1.68 (1.04–2.71)	0.035
EGFR mutation (L858R vs. 19del)	1.61 (1.06–2.43)	0.025	1.26 (0.80–1.99)	0.32
PD-L1 tumor proportion score
≥50% vs. <1%	1.71 (1.06–2.76)	0.027	1.82 (1.10–2.99)	0.019
1–49% vs. <1%	0.92 (0.53–1.59)	0.76	1.14 (0.64–2.01)	0.66
Unknown vs. <1%	0.91 (0.22–3.82)	0.90	1.28 (0.30–5.48)	0.74
Adverse event ≥ grade 2 (present vs. none)	1.09 (0.73–1.63)	0.70	1.26 (0.78–2.02)	0.34

CCI, Charlson Comorbidity Index; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1.

Table 4. Adverse events ≥ grade 2 attributed to osimertinib during all follow-up
Adverse event	Grade 2, n (%)	Grade 3, n (%)	Grade 4, n (%)	Grade 5, n (%)
Any	85 (36.8)	35 (15.2)	2 (0.9)	1 (0.4)
Alopecia	1 (0.4)	0	0	0
Arthralgias	2 (0.9)	0	0	0
Cardiomyopathy	0	1 (0.4)	0	0
Diarrhea	22 (9.5)	6 (2.6)	0	0
Dermatitis	29 (12.6)	8 (3.5)	0	0
Fatigue	1 (0.4)	4 (1.7)	0	0
Hand and Foot Syndrome	1 (0.4)	0	0	0
Hepatitis	0	3 (1.3)	0	0
Increased creatinine	1 (0.4)	0	0	0
Mucositis	7 (3.0)	2 (0.9)	0	0
Nausea	4 (1.7)	1 (0.4)	0	0
Pancytopenia	1 (0.4)	1 (0.4)	0	0
Paronychia	13 (5.6)	3 (1.3)	0	0
Pericardial effusion	1 (0.4)	0	0	0
Peripheral edema	1 (0.4)	0	0	0
Pneumonitis	1 (0.4)	5 (2.2)	2 (0.9)	1 (0.4)
Thrombocytopenia	0	1 (0.4)	0	0

n, number of patients with adverse event; %, number of patients who developed adverse event/231

Table S1. Comparison of baseline characteristics amongst patients with ECOG performance status 0–1 (n=126) and 2–4 (n=105) at initiation of osimertinib
Characteristic	ECOG PS 0–1, n (%)	ECOG PS 2–4, n (%)	P
Age ≥75 years	38 (30.2)	35 (33.3)	0.71^‡
Gender			0.99†
Male	42 (33.3)	36 (34.3)
Female	84 (66.7)	69 (65.7)
EGFR mutation			0.48^†
del19	73 (57.9)	55 (52.4)
L858R	53 (42.1)	50(47.6)
PD-L1 expression			0.30^†
<50%/unknown	93 (73.8)	70 (66.7)
≥50%	33 (26.2)	35 (33.3)
Smoking status			0.11^†
Never	81 (64.3)	55 (52.4)
Former	41 (32.5)	42 (40.0)
Current	4 (3.2)	8 (7.6)
CCI, median	0	0	0.90^‡
Brain metastases (present)	22 (17.5)	35 (33.3)	0.008^†

†, P value for Chi-squared test; ‡, P value for Kruskal-Wallis rank sum test. Charlson Comorbidity Index, CCI; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; n, number of patients; PD- L1, programmed death ligand 1.