Outcomes of EGFR tyrosine kinase inhibitors and immune checkpoint inhibitors for advanced EGFR-mutated non-small cell lung cancer

doi:10.21203/rs.3.rs-2128762/v1

Purpose No clinical trial has compared osimertinib with afatinib. We reviewed clinical data of patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) to identify predictive factors for clinical outcome of first-line EGFR tyrosine kinase inhibitors (TKIs), efficacy and safety of several EGFR-TKIs, and efficacy of immune checkpoint inhibitors (ICIs).

Methods We retrospectively studied 170 patients with EGFR-mutated NSCLC who received first-line EGFR-TKIs from January 1, 2011 to March 31, 2021.

Results Programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) was available in 66 patients, of whom 14, 25, and 27 had PD-L1 TPS ≥50%, 1-49%, and <1%, respectively. Twenty-four patients received ICIs after EGFR-TKIs. Objective response rate (ORR) and median progression-free survival (PFS) and overall survival (OS) with EGFR-TKIs were 65.3% and 9.1 and 31.4 months, respectively. By multivariate analysis, osimertinib was associated with favorable ORR and median PFS but not with median OS, whereas ICI treatment was associated with favorable median OS. Osimertinib caused less diarrhea, stomatitis, and liver injury. Pneumonitis and neutropenia (mostly grade <2) were more frequent with osimertinib. ORR and median PFS and OS of ICIs were 25.0%, 2.3 months, and not reached (NR), respectively. Particularly, ICIs were more effective in patients with PD-L1 TPS ≥50% than 1-49% or <1% (ORR, 66.7 vs. 12.5 vs. 0.0%; median PFS, 14.3 vs. 3.4 vs. 1.2 months; median OS, NR vs. NR vs. 14.8 months).

Conclusion Osimertinib was more effective and less frequently caused severe adverse events. Patients treated with ICIs had better prognosis.

Epidermal growth factor receptor

Immune checkpoint inhibitor

Non-small cell lung cancer

Programmed cell death ligand-1

Tyrosine kinase inhibitor

Among patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitors (TKIs) are standard treatment. In the FLAURA trial, patients treated with osimertinib had longer median progression-free survival (PFS) and median overall survival (OS) than those treated with gefitinib or erlotinib (Ramalingam et al. 2020; Soria et al. 2018). The LUX-Lung 7 trial also showed that patients treated with afatinib had longer median PFS and OS than those treated with gefitinib (Park et al. 2016). Although no clinical trial has compared the efficacy and safety of osimertinib versus afatinib, osimertinib was generally used for first-line treatment because of its fewer toxicities.

Immune checkpoint inhibitors (ICIs) have become a standard treatment for NSCLC. Patients with NSCLC treated with ICI monotherapy had longer OS than those treated with conventional chemotherapy (Borghaei et al. 2015; Brahmer et al. 2015; Herbst et al. 2016; Mok et al. 2019; Reck et al. 2016; Rittmeyer et al. 2017). Additionally, efficacy of ICIs plus platinum-based chemotherapy and the combination of multiple ICIs in NSCLC patients was reported in clinical trials (Gandhi et al. 2018; Hellmann et al. 2019; Paz-Ares et al. 2018, 2021; Socinski et al. 2018). However, the clinical benefits of ICIs for EGFR-mutated NSCLC patients remain unclear because patients were either excluded or only a few were included in clinical trials.

Therefore, we retrospectively reviewed the clinical data of patients with EGFR-mutated NSCLC and aimed to identify predictive factors for clinical outcome of first-line EGFR-TKIs, differences in efficacy and safety between several EGFR-TKIs, and the efficacy of ICIs.

Subjects

From January 1, 2011 to March 31, 2021, 170 patients with unresectable advanced EGFR-mutated NSCLC were treated with first-line EGFR-TKIs including gefitinib, erlotinib, afatinib, and osimertinib at our institution. The diagnosis of lung cancer was based on pathology or cytology findings. The clinical stage was established according to the 8th edition of the TNM classification. Information concerning tumor-related characteristics including pathological type, subtype of EGFR mutation, and programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) was collected, as was information about treatment including ICIs after first-line EGFR-TKIs. The PD-L1 TPS was assessed by means of the PD-L1 immunohistochemistry 22C3 pharmDx assay. EGFR-TKIs and ICIs were administered until disease progression, intolerable toxicity, or patient refusal occurred.

Study design

We retrospectively investigated patients’ background, objective response rate (ORR), PFS, OS, and development of adverse events (AEs). We also investigated the predictive factors for ORR, PFS, and OS of first-line EGFR-TKIs. Clinical data were collected from medical records. Baseline clinical parameters were obtained within 1 month of the initial diagnosis. Pre-existing respiratory diseases were divided into interstitial lung diseases (ILDs) with or without pulmonary emphysema, pulmonary emphysema without ILDs, and others. ORR was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al. 2009). PFS was measured from first administration of treatment to disease progression. OS was measured from first administration of treatment to death. The data cut-off date was December 31, 2021. The AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

This study was conducted in accordance with the Declaration of Helsinki, and it was approved by the institutional review board of Saitama Cardiovascular and Respiratory Center (approval no.: 2021022), which waived the necessity to obtain informed consent.

Statistical analysis

Categorical data are summarized by frequency and percent, and continuous data are reported as the median and range. Fisher’s exact test was applied to compare categorical variables. The Kaplan-Meier method was used to estimate median values of PFS and OS. Univariate and multivariate analyses were performed using a logistic regression model to determine predictors for ORR, and a Cox proportional hazards model was used to determine predictors for PFS and OS. A P value of < 0.05 was considered to indicate statistical significance. All statistical analyses were performed with EZR version 1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (version 4.1.2; The R Foundation for Statistical Computing, Vienna, Austria) (Kanda 2013).

Patient characteristics

In total, 170 patients with advanced NSCLC underwent first-line treatment with EGFR-TKIs (Table 1). The median patient age was 71 (range, 34–94) years, 40.0% of the patients were male, 35.9% were smokers, 88.2% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, 8.2% had pulmonary emphysema, 2.3% had ILDs, 90.6% were stage Ⅳ, 31.8% had brain metastases, and 97.6% had adenocarcinoma. Among the patients, exon 19 deletion, L858R, de novo T790M, and uncommon mutations were present in 53.5%, 42.4%, 1.2%, and 4.7%, respectively. Patients with PD-L1 TPS ≥ 50%, 1–49%, < 1%, and not available (NA) were 8.2%, 14.7%, 15.9%, and 61.2%, respectively. The median follow-up period from first administration of first-line EGFR-TKIs was 24.5 (range, 0.7–122.5) months. Seventy-four (43.5%) patients received gefitinib, 38 (22.4%) received erlotinib, 17 (10.0%) received afatinib, and 41 (24.1%) received osimertinib. Among the patients treated with afatinib, only one patient was aged ≥ 75 years, and no patients had an ECOG PS of 2 or 3 or L858R. In total, 99 patients (58.2%) received any kind of treatment after first-line EGFR-TKIs. Twenty-five patients (14.7%) were treated with osimertinib as second-line treatment or later, 24 patients (14.1%) were treated with ICIs, with 17 receiving it as third-line treatment or later, and 6 received ICIs plus platinum-based chemotherapy.

Table 1

Characteristics and objective response rate of patients treated with EGFR-TKIs
Background	Overall (n = 170)	Gefitinib (n = 74)	Erlotinib (n = 38)	Afatinib (n = 17)	Osimertinib (n = 41)
Age (years)	71 (34–94)	71 (46–94)	71 (34–88)	70.5 (42–78)	71.5 (47–86)
Patients aged ≥ 75 years	67 (39.4)	39 (52.7)	13 (34.2)	1 (5.9)	14 (41.0)
Sex, male	68 (40.0)	33 (44.6)	12 (31.6)	6 (35.3)	17 (41.5)
Smoker	61 (35.9)	26 (35.1)	12 (31.6)	5 (29.4)	18 (43.9)
ECOG PS
0 or 1	150 (88.2)	62 (83.8)	33 (86.8)	17 (100.0)	38 (92.7)
2 or 3	20 (11.8)	12 (16.2)	5 (13.2)	0 (0.0)	3 (7.3)
Pre-existing respiratory diseases
Pulmonary emphysema	14 (8.2)	5 (6.8)	2 (5.3)	1 (5.9)	6 (14.6)
ILDs	4 (2.3)	1 (1.4)	2 (5.3)	0 (0.0)	1 (2.4)
IIPs	3 (1.8)	0 (0.0)	2 (5.3)	0 (0.0)	1 (2.4)
Radiation-induced pulmonary fibrosis	1 (0.6)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)
Asthma	8 (4.7)	1 (1.4)	2 (5.3)	1 (5.9)	4 (9.8)
NTM	7 (4.1)	3 (4.1)	0 (0.0)	0 (0.0)	4 (9.8)
Old tuberculosis	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.4)
Stage
Ⅲ	16 (9.4)	5 (6.8)	4 (10.5)	1 (5.9)	6 (14.6)
Ⅳ	154 (90.6)	69 (93.2)	34 (89.5)	16 (94.1)	35 (85.4)
Brain metastases	54 (31.8)	19 (25.7)	18 (47.4)	6 (35.3)	11 (26.8)
Histologic type
Adenocarcinoma	166 (97.6)	72 (97.3)	37 (97.4)	17 (100.0)	40 (97.6)
Squamous cell carcinoma	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.4)
NOS	2 (1.2)	2 (2.7)	0 (0.0)	0 (0.0)	0 (0.0)
Pleomorphic carcinoma	1 (0.6)	0 (0.0)	1 (2.6)	0 (0.0)	0 (0.0)
EGFR mutation
Exon 19 deletion	91 (53.5)	39 (52.7)	18 (47.4)	13 (76.5)	21 (51.2)
L858R	72 (42.4)	32 (43.2)	20 (52.6)	0 (0.0)	20 (48.8)
De novo T790M	2 (1.2)	2 (2.7)	0 (0.0)	0 (0.0)	0 (0.0)
Uncommon mutation	8 (4.7)	3 (4.1)	0 (0.0)	4 (23.5)	0 (0.0)
PD-L1 TPS
≥ 50%	14 (8.2)	1 (1.4)	1 (2.6)	2 (11.8)	10 (24.4)
1–49%	25 (14.7)	2 (2.7)	4 (10.5)	6 (35.3)	13 (31.7)
< 1%	27 (15.9)	8 (10.8)	3 (7.9)	1 (5.9)	15 (36.6)
NA	104 (61.2)	63 (85.1)	30 (78.9)	8 (47.1)	3 (7.3)
Follow-up period (months)	24.5 (0.7-122.5)	24.5 (0.7-122.5)	24.5 (1.6–79.7)	27.3 (4.7–75.9)	19.7 (1.3–37.9)
Treatment after first-line EGFR-TKIs
Continuation of first-line EGFR-TKIs	31 (18.2)	5 (6.8)	1 (2.6)	1 (5.9)	24 (58.5)
Best supportive care	40 (23.5)	22 (29.7)	10 (26.3)	2 (11.8)	6 (14.6)
Any treatment
Treatment without ICIs	75 (44.1)	41 (55.4)	21 (55.3)	7 (41.2)	6 (14.6)
Use of osimertinib	25 (14.7)	12 (16.2)	10 (26.3)	3 (17.6)	NA
Treatment with ICIs	24 (14.1)	6 (8.1)	6 (15.8)	7 (41.2)	5 (12.2)
Second-line	7 (4.1)	1 (1.4)	0 (0.0)	3 (17.6)	3 (7.3)
Third-line or later	17 (10.0)	5 (6.8)	6 (15.8)	4 (23.5)	2 (4.9)
Nivolumab	10 (5.9)	5 (6.8)	2 (5.3)	2 (11.8)	1 (2.4)
Pembrolizumab	8 (4.7)	0 (0.0)	3 (7.9)	4 (23.5)	1 (2.4)
Pembrolizumab + CDBCA + PEM	3 (1.8)	0 (0.0)	0 (0.0)	1 (5.9)	2 (4.9)
Pembrolizumab + CDDP + PEM	1 (0.6)	0 (0.0)	1 (2.6)	0 (0.0)	0 (0.0)
Pembrolizumab + CDBCA + nab-PTX	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.4)
Atezolizumab + CDBCA + PTX + BEV	1 (0.6)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)
Best overall response
CR	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.4)
PR	110 (64.7)	38 (51.4)	26 (68.4)	14 (82.4)	32 (78.0)
SD	34 (20.0)	21 (28.4)	5 (13.2)	3 (17.6)	5 (12.2)
PD	25 (14.7)	15 (20.3)	7 (18.4)	0 (0.0)	3 (7.3)
ORR	65.3	51.4	68.4	82.4	80.5
Data are presented as n, median (range) or n (%). ORR are presented as % EGFR-TKIs epidermal growth factor receptor tyrosine kinase inhibitors; ECOG PS Eastern Cooperative Oncology Group performance status; ILDs interstitial lung diseases; IIPs idiopathic interstitial pneumonias; NOS not otherwise specified; PD-L1 TPS programmed cell death ligand-1 tumor proportion score; NA not available; NTM non-tuberculous mycobacterial infection; ICIs immune checkpoint inhibitors; CBDCA carboplatin; PEM pemetrexed; CDDP cisplatin; nab-PTX nanoparticle albumin-bound paclitaxel; PTX paclitaxel; BEV bevacizumab; CR complete response; PR partial response; SD stable disease; PD progressive disease; ORR objective response rate

Predictive factors of ORR

Of the 170 patients treated with first-line EGFR-TKIs, one patient achieved complete response (CR), 110 (64.7%) had partial response (PR), 34 (20.0%) had stable disease (SD), and 25 (14.7%) had progressive disease (PD). The overall ORR was 65.3% and was 51.4% with gefitinib, 68.4% with erlotinib, 82.4% with afatinib, and 80.5% with osimertinib (Table 1). Univariate analysis indicated that age, ECOG-PS, brain metastases, and type of EGFR-TKIs were associated with ORR (Table 2). In a multivariate logistic regression model, only gefitinib was significantly associated with poor ORR.

Table 2

Univariate and multivariate analyses of ORR
Parameter	n	ORR (%)	Univariate		Multivariate
Parameter	n	ORR (%)	OR (95% CI)	P value	OR (95% CI)	P value
Age (years)
≥ 75	67	53.7	Reference		Reference
< 75	103	72.8	2.310 (1.210–4.410)	0.011	1.520 (0.741–3.120)	0.253
Sex
Male	68	63.2	Reference
Female	102	66.7	1.160 (0.612–2.210)	0.645
Smoking history
Smoker	61	62.3	Reference
Never-smoker	109	67.0	1.230 (0.638–2.360)	0.539
ECOG PS
2 or 3	20	40.0	Reference		Reference
0 or 1	150	68.7	3.290 (1.260–8.580)	0.015	2.530 (0.915–6.980)	0.074
Pre-existing respiratory diseases
None	141	66.0	1.450 (0.477–4.430)	0.511
ILDs	4	25.0	Reference
Emphysema	14	57.1	0.250 (0.021–3.040)	0.277
Others	11	81.8	3.370 (0.524–21.700)	0.200
Histologic type
Non-adenocarcinoma	4	50.0	Reference
Adenocarcinoma	166	65.7	1.910 (0.262–13.900)	0.522
Stage
Ⅳ	154	64.3	Reference
Ⅲ	16	75.0	1.670 (0.513–5.420)	0.396
Brain metastases
None	116	60.3	Reference		Reference
Present	54	75.9	2.070 (1.000-4.290)	0.049	1.830 (0.829–4.050)	0.135
EGFR mutation
Uncommon	7	28.6	Reference
Exon 19 deletion	91	67.0	5.080 (0.931–27.700)	0.060
L858R	72	66.7	5.000 (0.903–27.700)	0.065
PD-L1 TPS
< 1%	27	63.0	Reference
1–49%	25	84.0	3.090 (0.822–11.600)	0.095
≥ 50%	14	64.3	1.060 (0.276–4.060)	0.934
NA	104	61.5	0.941 (0.392–2.260)	0.892
First-line EGFR-TKIs
Osimertinib	41	80.5	Reference		Reference
Afatinib	17	82.4	1.130 (0.261-4.900)	0.869	0.863 (0.192–3.880)	0.848
Erlotinib	38	68.4	0.525 (0.187–1.470)	0.221	0.479 (0.164-1.400)	0.178
Gefitinib	74	51.4	0.256 (0.104–0.627)	0.003	0.282 (0.112–0.711)	0.007
ORR objective response rate; OR odds ratio; CI confidence interval; ECOG PS Eastern Cooperative Oncology Group performance status; ILDs interstitial lung diseases; EGFR epidermal growth factor receptor; PD-L1 TPS programmed cell death ligand-1 tumor proportion score; NA not available; EGFR-TKIs epidermal growth factor receptor tyrosine kinase inhibitors

Predictive factors of PFS

The overall median PFS of first-line EGFR-TKIs was 9.1 months (95% confidence interval [CI]: 7.4–12.4), 8.4 months (95% CI: 5.6–10.3) with gefitinib, 7.4 months (95% CI: 4.0–10.2) with erlotinib, 15.1 months (95% CI: 6.4–21.9) with afatinib, and 17.5 months (95% CI: 6.7–not reached [NR]) with osimertinib (Fig. 1A, C). Univariate analysis indicated that ECOG PS, histologic type, brain metastases, PD-L1 TPS, and type of EGFR-TKIs were associated with median PFS (Table 3). In a multivariate Cox proportional hazard model, ECOG PS of 2 or 3, non-adenocarcinoma, erlotinib, and gefitinib were independent factors associated with poor median PFS.

Table 3

Univariate and multivariate analyses of PFS
Parameter	n	Median PFS (months)	Univariate		Multivariate
Parameter	n	Median PFS (months)	HR (95% CI)	P value	HR (95% CI)	P value
Age (years)
< 75	103	8.5	Reference
≥ 75	67	9.7	1.011 (0.722–1.416)	0.951
Sex
Female	102	9.7	Reference
Male	68	8.2	1.121 (0.797–1.576)	0.513
Smoking history
Never-smoker	109	9.7	Reference
Smoker	61	7.2	1.265 (0.894–1.789)	0.185
ECOG PS
0 or 1	150	9.7	Reference		Reference
2 or 3	20	6.8	2.023 (1.202–3.404)	0.008	1.988 (1.169–3.381)	0.011
Pre-existing respiratory diseases
None	141	8.6	Reference
ILDs	4	17.6	0.798 (0.253–2.516)	0.700
Emphysema	14	3.3	1.599 (0.880–2.908)	0.124
Others	11	17.5	0.469 (0.219–1.008)	0.052
Histologic type
Adenocarcinoma	166	9.5	Reference		Reference
Non-adenocarcinoma	4	3.9	2.804 (1.029–7.641)	0.044	3.684 (1.224–11.080)	0.020
Stage
Ⅳ	154	9.7	Reference
Ⅲ	16	5.5	1.211 (0.696–2.108)	0.497
Brain metastases
None	116	9.7	Reference		Reference
Present	54	8.5	1.463 (1.028–2.083)	0.035	1.258 (0.863–1.832)	0.232
EGFR mutation
Exon 19 deletion	91	9.9	Reference
L858R	72	8.5	1.216 (0.863–1.714)	0.263
Uncommon mutation	7	4.1	2.192 (0.950–5.057)	0.066
PD-L1 TPS
≥ 50%	14	8.4	1.528 (0.699–3.341)	0.289	1.411 (0.609–3.270)	0.422
1–49%	25	17.1	Reference		Reference
< 1%	27	9.7	1.241 (0.643–2.394)	0.519	0.987 (0.492–1.980)	0.971
NA	104	8.4	1.813 (1.077–3.052)	0.025	1.038 (0.547–1.970)	0.910
First-line EGFR-TKIs
Osimertinib	41	17.5	Reference		Reference
Afatinib	17	15.1	1.488 (0.770–2.877)	0.237	1.560 (0.774–3.143)	0.213
Erlotinib	38	7.4	2.811 (1.645–4.805)	< 0.001	2.851 (1.495–5.571)	0.002
Gefitinib	74	8.4	1.976 (1.216–3.210)	0.006	2.052 (1.081–3.896)	0.028
PFS progression-free survival; HR hazard ratio; CI confidence interval; ECOG PS Eastern Cooperative Oncology Group performance status; ILDs interstitial lung diseases; EGFR epidermal growth factor receptor; PD-L1 TPS programmed cell death ligand-1 tumor proportion score; NA not available; EGFR-TKIs epidermal growth factor receptor tyrosine kinase inhibitors

Predictive factors of OS

The overall median OS of first-line EGFR-TKIs was 31.4 months (95% CI: 26.6–44.3), 27.2 months (95% CI: 19.3–43.8) with gefitinib, 27.4 months (95% CI: 22.5–45.2) with erlotinib, 40.8 months (95% CI: 14.7–NR) with afatinib, and NR (95% CI: NR-NR) with osimertinib (Fig. 1B, D). Univariate analysis indicated that sex, ECOG PS, pre-existing respiratory diseases, brain metastases, subtype of EGFR mutation, PD-L1 TPS, type of EGFR-TKIs, use of osimertinib, and treatment after first-line EGFR-TKIs were associated with median OS (Table 4). In a multivariate Cox proportional hazard model, male sex, ECOG PS of 2 or 3, uncommon mutation, and treatment without ICIs were independent factors associated with poor median OS. The median OS from resistance to first-line EGFR-TKIs was longer in patients treated with ICIs than in those treated with chemotherapy excluding ICIs (NR vs 17.3 months, Fig. 2).

Table 4

Univariate and multivariate analyses of OS
Parameter	n	Median OS (months)	Univariate		Multivariate
Parameter	n	Median OS (months)	HR (95% CI)	P value	HR (95% CI)	P value
Age (years)
< 75	103	31.5	Reference
≥ 75	67	31.4	1.201 (0.790–1.824)	0.392
Sex
Female	102	48.3	Reference		Reference
Male	68	24.0	2.035 (1.344–3.081)	0.001	2.236 (1.350–3.704)	0.002
Smoking history
Never-smoker	109	40.8	Reference
Smoker	61	26.2	1.444 (0.950–2.196)	0.086
ECOG PS
0 or 1	150	40.3	Reference		Reference
2 or 3	20	10.8	3.470 (1.967–6.121)	< 0.001	1.964 (1.016–3.798)	0.045
Pre-existing respiratory diseases
None	141	35.5	Reference		Reference
ILDs	4	17.2	2.656 (0.829–8.510)	0.100	1.782 (0.473–6.713)	0.393
Emphysema	14	17.1	2.489 (1.274–4.864)	0.008	1.836 (0.803–4.203)	0.150
Others	11	NR	0.108 (0.015–0.775)	0.027	0.183 (0.025–1.336)	0.094
Histologic type
Adenocarcinoma	166	31.4	Reference
Non-adenocarcinoma	4	21.3	1.984 (0.624–6.304)	0.246
Stage
Ⅲ	16	35.5	Reference
Ⅳ	154	31.2	1.223 (0.565–2.647)	0.610
Brain metastases
None	116	43.8	Reference		Reference
Present	54	27.3	1.724 (1.122–2.650)	0.013	1.676 (0.982–2.860)	0.058
EGFR mutation
Exon 19 deletion	91	43.8	Reference		Reference
L858R	72	29.4	1.304 (0.854–1.990)	0.220	1.213 (0.773–1.905)	0.401
Uncommon mutation	7	9.1	4.817 (2.028–11.440)	< 0.001	3.377 (1.155–9.879)	0.026
PD-L1 TPS
≥ 50%	14	NR	Reference		Reference
1–49%	25	NR	1.446 (0.292–7.172)	0.652	0.803 (0.123–5.231)	0.818
< 1%	27	31.5	4.033 (0.921–17.660)	0.064	2.034 (0.359–11.540)	0.423
NA	104	26.2	4.660 (1.141–19.030)	0.032	1.763 (0.295–10.550)	0.534
First-line EGFR-TKIs
Osimertinib	41	NR	Reference		Reference
Afatinib	17	40.8	1.746 (0.669–4.559)	0.255	0.868 (0.230–3.268)	0.834
Erlotinib	38	27.4	2.480 (1.119–5.497)	0.025	0.612 (0.201–1.869)	0.389
Gefitinib	74	27.2	2.241 (1.047–4.796)	0.038	0.591 (0.198–1.765)	0.346
Osimertinib
First-line or later	66	48.3	Reference		Reference
None	104	26.1	1.824 (1.158–2.872)	0.009	1.417 (0.746–2.693)	0.287
Treatment after first-line
Treatment with ICIs	24	NR	Reference		Reference
Treatment without ICIs	76	27.2	3.139 (1.496–6.587)	0.002	3.394 (1.307–8.817)	0.012
Continuation of first-line EGFR-TKIs	31	NR	< 0.001 (< 0.001-NR)	0.994	< 0.001 (< 0.001-NR)	0.995
Best supportive care	39	15.4	6.417 (2.882–14.290)	< 0.001	7.304 (2.546–20.960)	< 0.001
OS overall survival; HR hazard ratio; CI confidence interval; ECOG PS Eastern Cooperative Oncology Group performance status; ILDs interstitial lung diseases; NR not reached; EGFR epidermal growth factor receptor; PD-L1 TPS programmed cell death ligand-1 tumor proportion score; NA not available; NR not reached; ICIs immune checkpoint inhibitors; EGFR-TKIs epidermal growth factor receptor tyrosine kinase inhibitors

Profile of AEs

Of the 170 patients treated with EGFR-TKIs, 166 (97.6%) developed AEs (Table 5), including 139 (81.8%) with skin toxicity, 83 (48.8%) with diarrhea, 76 (44.7%) with liver injury, 35 (20.6%) with stomatitis, 30 (17.6%) with anorexia or nausea, 16 (9.4%) with renal dysfunction, 14 (8.2%) with taste dysfunction, and 11 (6.5%) with pneumonitis. An AE of grade 5 (pneumonitis) occurred in only one patient, who was treated with gefitinib. AEs of grade ≥ 3 occurred in 40 patients (23.5%), among which liver injury was the most frequent AE. Twenty-six patients (15.3%) required discontinuation of first-line EGFR-TKIs due to AEs, and liver injury (10 patients) and pneumonitis (8 patients) comprised most of them. The patients treated with afatinib most frequently experienced diarrhea and stomatitis (Table 6). Gefitinib, erlotinib, and afatinib caused more liver injury than did osimertinib. In particular, gefitinib caused liver injury of grade ≥ 3 most frequently. The patients treated with osimertinib experienced neutropenia more frequently than the others, but this neutropenia was improved without treatment or discontinuation of osimertinib. Also, they experienced pneumonitis and required treatment discontinuation more frequently. Of the 8 patients experiencing pneumonitis due to osimertinib, only one patient had grade ≥ 3, 2 improved after administration with methylprednisolone, 4 improved only after discontinuation of osimertinib, and 2 improved without discontinuation or additional treatment.

Table 5

Adverse events
Events	All grades	Grade ≥ 3	Grade 5	Discontinuation of first-line EGFR-TKIs
Any adverse events	166 (97.6)	40 (23.5)	1 (0.6)	26 (15.3)
Skin toxicity	139 (81.8)	15 (8.8)	0 (0.0)	4 (2.4)
Diarrhea	83 (48.8)	2 (1.2)	0 (0.0)	0 (0.0)
Liver injury	76 (44.7)	18 (10.6)	0 (0.0)	10 (5.8)
Stomatitis	35 (20.6)	0 (0.0)	0 (0.0)	0 (0.0)
Anorexia or nausea	30 (17.6)	1 (0.6)	0 (0.0)	0 (0.0)
Renal dysfunction	16 (9.4)	2 (1.2)	0 (0.0)	3 (1.8)
Taste dysfunction	14 (8.2)	0 (0.0)	0 (0.0)	0 (0.0)
Pneumonitis	11 (6.5)	2 (1.2)	1 (0.6)	8 (4.7)
Neutropenia	6 (3.5)	2 (1.2)	0 (0.0)	1 (0.6)
Conjunctivitis	4 (2.4)	0 (0.0)	0 (0.0)	1 (0.6)
Anemia	3 (1.8)	1 (0.6)	0 (0.0)	0 (0.0)
Thrombocytopenia	2 (1.2)	1 (0.6)	0 (0.0)	0 (0.0)
Delusion	1 (0.6)	1 (0.6)	0 (0.0)	0 (0.0)
Visual abnormality	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)
Rhabdomyolysis	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)
Data are presented as n (%) EGFR-TKIs epidermal growth factor receptor tyrosine kinase inhibitors

Table 6

Adverse events for each first-line epidermal growth factor receptor tyrosine kinase inhibitor
	Gefitinib	Erlotinib	Afatinib	Osimertinib	P value
Events	n = 74	n = 38	n = 17	n = 41
Any adverse events	72 (97.3)	37 (97.4)	17 (100.0)	40 (97.6)	1.000
Grade ≥ 3	16 (21.6)	10 (26.3)	4 (23.5)	10 (24.4)	0.959
Discontinuation	9 (12.2)	6 (15.8)	2 (11.8)	9 (22.0)	0.549
Skin toxicity	56 (75.7)	35 (92.1)	16 (94.1)	32 (78.0)	0.081
Grade ≥ 3	3 (4.1)	6 (15.8)	3 (17.6)	3 (7.3)	0.078
Discontinuation	2 (2.7)	2 (5.3)	0 (0.0)	0 (0.0)	0.466
Diarrhea	32 (43.2)	15 (39.5)	16 (94.1)	20 (48.8)	< 0.001
Grade ≥ 3	1 (1.4)	0 (0.0)	1 (5.9)	0 (0.0)	0.297
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Liver injury	44 (59.5)	15 (39.5)	8 (47.1)	9 (22.0)	0.001
Grade ≥ 3	14 (18.9)	3 (7.9)	0 (0.0)	1 (2.4)	0.017
Discontinuation	7 (9.5))	2 (5.3)	0 (0.0)	1 (2.4)	0.394
Stomatitis	7 (9.5)	9 (23.7)	9 (52.9)	10 (24.4)	0.001
Grade ≥ 3	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Anorexia or nausea	15 (20.3)	7 (18.4)	3 (17.6)	5 (12.2)	0.757
Grade ≥ 3	0 (0.0)	0 (0.0)	1 (5.9)	0 (0.0)	0.100
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Renal dysfunction	5 (6.8)	3 (7.9)	1 (5.9)	7 (17.1)	0.346
Grade ≥ 3	0 (0.0)	1 (2.6)	0 (0.0)	1 (2.4)	0.405
Discontinuation	0 (0.0)	1 (2.6)	0 (0.0)	2 4.9)	0.190
Taste dysfunction	5 (6.8)	7 (18.4)	2 (11.8)	2 (4.9)	0.104
Grade ≥ 3	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Pneumonitis	2 (2.7)	0 (0.0)	1 (5.9)	8 (19.5)	0.002
Grade ≥ 3	1 (1.4)	0 (0.0)	0 (0.0)	1 (2.4)	1.000
Discontinuation	1 (1.4)	0 (0.0)	1 (5.9)	6 (14.6)	0.007
Neutropenia	0 (0.0)	0 (0.0)	1 (5.9)	5 (12.2)	0.001
Grade ≥ 3	0 (0.0)	0 (0.0)	1 (5.9)	1 (2.4)	0.103
Discontinuation	0 (0.0)	0 (0.0)	1 (5.9)	0 (0.0)	0.100
Conjunctivitis	0 (0.0)	4 (10.5)	0 (0.0)	0 (0.0)	0.005
Grade ≥ 3	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Discontinuation	0 (0.0)	1 (2.6)	0 (0.0)	0 (0.0)	0.324
Anemia	2 (2.7)	0 (0.0)	0 (0.0)	1 (2.4)	0.857
Grade ≥ 3	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.4)	0.565
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Thrombocytopenia	0 (0.0)	0 (0.0)	0 (0.0)	2 (4.9)	0.209
Grade ≥ 3	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.4)	0.565
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Delusion	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.4)	0.565
Grade ≥ 3	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.4)	0.565
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Visual abnormality	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)	1.000
Grade ≥ 3	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Rhabdomyolysis	0 (0.0)	1 (2.6)	0 (0.0)	0 (0.0)	0.324
Grade ≥ 3	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Discontinuation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	NA
Data are presented as n (%)

Clinical outcomes of ICIs

In the 24 patients treated with ICIs, the ORR was 25.0%, median PFS was 2.3 months (95% CI: 1.4–5.6), and median OS was NR (95% CI: 14.8–NR) (Fig. 3A, B). In the patients with PD-L1 TPS ≥ 50%, 1–49%, and < 1%, the ORRs were 66.7%, 12.5%, and 0.0%, respectively. The median lengths of PFS and OS in patients with PD-L1 TPS ≥ 50% were longer than those with PD-L1 TPS 1–49% or < 1% (PFS: 14.3 [95% CI: 1.4–NR] vs. 3.4 [95% CI: 1.8–NR] vs. 1.2 months [95% CI: 0.9–NR] and OS: NR [95% CI: NR–NR] vs. NR [95% CI: 19.1–NR] vs. 14.8 months [95% CI: 1.9–NR], respectively) (Fig. 3C, D). Immune-related AEs occurred in 9 patients including 3 patients with skin toxicity, 2 with liver injury, 1 with diarrhea, 1 with hypothyroidism, 1 with myositis, and 1 with pneumonitis. Immune-related AEs of grade ≥ 3 occurred in two patients including 1 with skin toxicity and 1 with diarrhea, but there were no immune-related AEs of grade 5.

In this study, we revealed predictive factors for outcome of first-line EGFR-TKIs, differences between EGFR-TKIs, and the efficacy of ICIs in patients with EGFR-mutated NSCLC in a clinical setting. Non-adenocarcinoma and poor ECOG-PS were predictive factors for poor median PFS, whereas male sex, uncommon EGFR mutation, poor ECOG-PS, and treatment without ICIs were predictive factors for poor median OS. Although patients treated with osimertinib experienced a significant tumor response, there was no significant difference in prognosis among the different first-line EGFR-TKIs. The patients treated with osimertinib experienced less diarrhea, stomatitis, and liver injury but more frequently experienced pneumonitis and neutropenia than patients treated with the other EGFR-TKIs. The patients with PD-L1 TPS ≥ 50% who received ICIs had better tumor response and prognosis than those with PD-L1 TPS < 50%.

Previously, several predictive factors of clinical outcome in patients with EGFR-mutated NSCLC were reported. Several studies showed that poor ECOG PS (Gijtenbeek et al. 2020; Ng et al. 2021; Okamoto et al. 2018), uncommon mutation (Okamoto et al. 2018), and male sex (Gijtenbeek et al. 2020; Ng et al. 2021) were associated with prognosis in these patients. In general, patients with EGFR-mutated non-adenocarcinoma are less common and experience lower efficacy with EGFR-TKIs than do patients with EGFR-mutated adenocarcinoma. Kobayashi et al. (2020) reported that 3.1% of non-adenocarcinoma patients have an EGFR mutation. The LUX-Lung 8 trial, which enrolled patients with squamous NSCLC, showed that the median PFS with afatinib was 2.4 months and that with erlotinib was 1.9 months (Soria et al. 2015).

In clinical trials, osimertinib and afatinib were superior to first-generation EGFR-TKIs including gefitinib and erlotinib (Park et al. 2016; Ramalingam et al. 2020; Soria et al. 2018). Although no clinical trial has compared osimertinib and afatinib, a network meta-analysis of clinical trials evaluating EGFR-TKIs showed that osimertinib achieved longer median PFS and median OS and caused fewer AEs of grade ≥ 3 than gefitinib, erlotinib, and afatinib (Zhao et al. 2019). However, Kishikawa et al. (2020) studied 56 patients treated with osimertinib and showed that neutropenia occurred in 7.1% of the patients, with grade ≥ 3 in 3.6%. Several cases of pancytopenia and aplastic anemia occurring during osimertinib treatment were reported, but these AEs were not noted during gefitinib, erlotinib, and afatinib therapy (Di Marino et al. 2022; Ogata et al. 2017; Sala et al. 2020). Our literature search could find no reports on the pathogenesis of hematological AEs induced by osimertinib. In addition, osimertinib causes pneumonitis more frequently than the others (3.9% vs. 1.1%), particularly in Japanese patients (12.3%) (Ohe et al. 2019; Soria et al. 2018; Suh et al. 2018). Recently, several studies reported that pneumonitis during osimertinib treatment included transient asymptomatic pulmonary opacities (TAPOs). TAPOs are asymptomatic, localized, and resolve spontaneously despite continuance of osimertinib (Lee et al. 2018; Noonan et al. 2016). Sato et al. (2022) studied 452 patients treated with osimertinib and showed that 80 (17.7%) experienced pneumonitis, of whom 37 (46.3%) were identified as having TAPOs. The present study revealed that osimertinib achieved better median PFS than gefitinib or erlotinib, but there was no difference in the median OS among the EGFR-TKIs. This finding may be associated with the administration of osimertinib in several patients after first-line EGFR-TKIs. Osimertinib caused diarrhea, stomatitis, and liver injury less frequently than the other EGFR-TKIs. Although neutropenia and pneumonitis were more frequent, most of the incidences were not severe. All incidences of neutropenia improved without treatment or discontinuation of osimertinib, and almost all incidences of pneumonitis also improved without treatment. Two incidences of pneumonitis that improved without discontinuation of osimertinib might have been TAPOs.

Generally, EGFR-mutated NSCLC shows lower efficacy of ICIs than NSCLC without driver mutation. Hastings et al. (2019) and Mazieres et al. (2019) investigated 171 and 125 patients, respectively, with EGFR-mutated NSCLC treated with ICIs. They reported that the respective ORR was 10.3% and 12.8%, median PFS was 1.8 and 2.1 months, and median OS was 9.4 and 10.0 months. Additionally, in the WJOG8515L trial involving NSCLC developing resistance to first-line EGFR-TKIs, nivolumab showed shorter median PFS than carboplatin plus pemetrexed (1.7 vs. 5.6 months) (Hayashi et al. 2022). In contrast, subgroup analyses of the IMpower150 trial revealed that the addition of atezolizumab to bevacizumab plus carboplatin plus paclitaxel may improve median PFS and median OS (Nogami et al. 2022; Reck et al. 2019). Moreover, several studies reported the efficacy of ICIs for EGFR-mutated NSCLC in patients with PD-L1 TPS ≥ 50%. Masuda et al. (2021) studied 17 patients with EGFR-mutated NSCLC and PD-L1 TPS ≥ 50% and 18 with PD-L1 TPS < 50% who received programmed cell death-1 (PD-1) inhibitor monotherapy. They reported that the patients with PD-L1 TPS ≥ 50% had better ORR, median PFS, and median OS than those with PD-L1 TPS < 50% (29.4 vs. 0.0%, 5.3 vs. 1.6 months, and 26.4 vs. 12.7 months, respectively). Isomoto et al. (2020) investigated 9 patients with EGFR-mutated NSCLC with PD-L1 TPS ≥ 50% and 18 with PD-L1 TPS < 50% who received PD-1 inhibitor monotherapy. They reported that the patients with PD-L1 TPS ≥ 50% had longer median lengths of PFS and OS than those with PD-L1 TPS < 50% (7.1 vs. 1.7 months and NR vs. 20.3 months, respectively). Our study showed that the patients treated with ICIs had a better prognosis. However, half of the patients treated with ICIs received either osimertinib or afatinib, and most of the patients treated with chemotherapy excluding ICIs received either gefitinib or erlotinib. So, we evaluated the median OS from resistance to first-line EGFR-TKIs and found that patients treated with ICIs had longer median OS. In particular, the patients with PD-L1 TPS ≥ 50% had higher efficacy than those with PD-L1 TPS < 50% as in previous studies. Therefore, we consider treatment with ICIs to be a reasonable treatment option because it may improve prognosis.

This study has several limitations. First, because it was retrospective, some patient characteristics were not available. Second, it was performed at a single hospital and only Japanese patients were treated. Third, the sample size was small. Finally, the observation period differed between each of the EGFR-TKIs administered. In particular, patients treated with gefitinib or erlotinib included older patients.

In summary, predictive factors for clinical outcome of first-line EGFR-TKIs were similar to those of previous reports. Osimertinib achieved more efficacy and safety than did the others. According to previous studies, patients with EGFR-mutated NSCLC had lower efficacy than those without driver mutation, but this study showed that patients treated with ICIs had better prognosis, and particularly, those with PD-L1 TPS ≥ 50% experienced more effectiveness with ICIs. At least one round of therapy using ICIs should be considered when treating patients with EGFR-mutated NSCLC.

Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Taisuke Isono. The first draft of the manuscript was written by Taisuke Isono and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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

Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflict of interest The authors declare that they have no conflict of interest.

Ethics approval This study was approved by the institutional review board of Saitama Cardiovascular and Respiratory Center (No. 2021022).

Consent to participate Informed consent was obtained from all individual participants included in the study.

Consent to publish This manuscript contains no individual person’s data.

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No competing interests reported.

Outcomes of EGFR tyrosine kinase inhibitors and immune checkpoint inhibitors for advanced EGFR-mutated non-small cell lung cancer

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Subjects

Study design

Statistical analysis

Results

Patient characteristics

Predictive factors of ORR

Predictive factors of PFS

Predictive factors of OS

Profile of AEs

Clinical outcomes of ICIs

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1