Immune checkpoint inhibitor‐related adverse events in lung cancer: Real‐world incidence and management practices of 1905 patients in China

INTRODUCTION

Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in many types of cancer and are increasingly being used in early disease settings, including advanced lung cancer.1 Response to treatment occurs in a substantial fraction of patients and is frequently durable. The Food and Drug Administration approved the antiprogrammed cell death-1 (PD-1) antibody, pembrolizumab in combination with chemotherapy, as a first-line therapy for metastatic non-small cell lung cancer (NSCLC), irrespective of programmed cell death ligand-1 (PD-L1) status in July 2018 based on the results reported by the Keynote-1892 and Keynote-407 studies.3 Subsequently, pembrolizumab was approved for metastatic NSCLC by the National Medical Products Administration of China on March 28, 2019. Other anti-PD-1/PD-L1 antibodies, including camrelizumab, sintilimab, and tislelizumab, have also been approved in China. Currently, PD-1/ PD-L1 monotherapy or PD-1/PD-L1-combined chemotherapy has become the first-line standard treatment for advanced lung cancer according to the status of PD-L1 expression.

As with other treatments, use of ICIs has been associated with immune-related adverse events (irAEs) that are potentially severe, or even fatal.4, 5 The incidence of irAEs have been reported to vary between 24% and 38% in patients with advanced lung cancer treated with ICI-based therapy.6-11 However, the above reported data were from randomized clinical trials (RCTs), which did not report irAEs in a real-world setting. The special population for ICI treatment includes patients affected by chronic viral infection or with pre-existent autoimmune diseases (AIDs), patients aged over 75 years, or those with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 2–3. Therefore, it is crucial to obtain real-world information about the safety profile of ICIs in patients. Furthermore, irAE management has rarely been reported.

Hence, we conducted this observational study to identify the incidence, spectrum, clinical characteristics, and management practices of irAEs in a real-world setting in Chinese patients with advanced lung cancer.

METHODS Study population

This multicenter observational study aimed to evaluate the safety of ICIs and investigate the status of irAE management practices in a real-world setting in China. We enrolled patients who were (1) >18 years, (2) had pathologically confirmed stage III–IV lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) and (3) treated with ICI monotherapy or ICI-based combination therapy for at least one dose, from 26 hospitals across 10 provinces in China between January 1, 2015, and February 28, 2021.

Data collection and recognition of irAEs

Demographic and clinical characteristics of patients were collected, including age, sex, comorbidities, clinical stage, number of metastatic sites, tumor histology type, ECOG PS status, driving gene mutations, PD-L1 expression status, treatment type, treatment line of ICIs, ICI duration, and disease control rate (DCR). Response assessment was performed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by computed tomography scans every 6 to 8 weeks after the administration of the first dose of ICIs by the investigator.12

The definition of irAEs was based on (1) pathological evidence of irAE, (2) multidisciplinary adjudication including two or more oncologists, or (3) clinical improvement with an irAE-based treatment.13-16 Data was collected on the management practices of irAEs, including use and duration of steroids, and outcome of irAEs. Immune toxicity-related discontinuation of ICIs and rechallenge with ICIs were also collected.

The procedures followed were in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The study was approved by the local ethics committee on human experimentation (Peking Union Medical College Hospital, Internal Review Board protocol number SK-1315, approved on August 31, 2020).

Statistical analysis

Descriptive statistics were used to summarize the cohorts' medical histories and clinical parameters. Counts and percentages were produced for categorical variables, whereas the mean ± standard deviation (SD) or median (interquartile range [IQR]) were computed for continuous variables. The chi-squared and Mann–Whitney U tests were used to compare the demographic characteristics between patients without irAEs and those with irAEs. All statistical analyses were performed using the SPSS software (version 26.0; SPSS). The figures were developed using GraphPad Prism 8.0.

RESULTS Patient characteristics

A total of 1905 patients with advanced lung cancer were enrolled in this study. The median age was 63 years (range 28–87) years. Many of the patients had NSCLC (89.9%, 1712/1905), where 48.0% (915/1712) had adenocarcinoma, and 34.0% (647/1712) had squamous cell carcinoma. A total of 471 patients had a positive driver mutation record, and the leading driving mutations were epidermal growth factor receptor (EGFR) 19/21 (n = 163) and KRAS (n = 132). PD-L1 expression was determined from histological specimens in 441 (23.1%) cases, and 283 (64.2%, 283/441) showed positive PD-L1 results (PD-L1 ≥ 1%). A total of 1488 patients were diagnosed with metastatic disease, with 208 patients developing liver metastases and 330 developing brain metastases. The clinical features of the 1905 patients with advanced lung cancer treated with ICI-based treatment are shown in Table 1.

TABLE 1. Clinical features of the 1905 patients with advanced lung cancer treated with ICI-based treatment Characteristic Total Without irAEs With irAEs p-value N = 1905 N = 1393 N = 512 Age, median (IQR), year 63 (56.25, 68) 63 (56, 68) 64 (58, 69) 0.902 Age 0.902 >75 128 (6.7%) 93 (6.7%) 35 (6.8%) <75 1777 (93.3%) 1300 (93.3%) 477 (93.2%) Sex 0.063 Female 463 (24.3%) 354 (25.4%) 109 (21.3%) Male 1442 (75.7%) 1039 (74.6%) 403 (78.7%) History of Interstitial pneumonitis 1.000 Yes 14 (0.7%) 10 (0.7%) 4 (0.8%) No 1891 (99.3%) 1383 (99.3%) 508 (99.2%) History of autoimmune disease 0.353 Yes 13 (0.7%) 8 (0.6%) 5 (1.0%) No 1892 (99.3%) 1385 (99.4%) 507 (99.0%) History of chronic viral infection 0.819 Yes 35 (1.8%) 25 (1.8%) 10 (2.0%) No 1870 (98.2%) 1368 (98.2%) 502 (98.0%) Clinical stage 0.795 III 417 (21.9%) 307 (22.0%) 110 (21.5%) IV 1488 (78.1%) 1086 (78.0%) 402 (78.5%) Number of metastatic sites >2 324 (17.0%) 254 (18.2%) 70 (13.7%) 0.024* ≤2 1581 (83.0%) 1139 (81.8%) 442 (86.3%) Histologic types 0.076 Non-small cell lung cancer 1709 (89.7%) 1240 (89.0%) 469 (91.6%) Adenocarcinoma 915 (48.0%) 667 (47.9%) 248 (48.4%) Squamous cell carcinoma 647 (34.0%) 464 (33.3%) 183 (35.7%) Large cell carcinoma 34 (1.8%) 20 (1.4%) 14 (2.7%) Other 113 (5.9%) 89 (6.4%) 24 (4.7%) Small cell lung cancer 196 (10.3%) 153 (11.0%) 43 (8.4%) ECOG performance status 0.480 0–1 1755 (92.1%) 1277 (91.7%) 478 (93.4%) 2–3 150 (7.9%) 116 (8.3%) 34 (6.6%) EGFR 19/21 mutation 0.024* Positive 163 (8.6%) 127 (9.1%) 36 (7.0%) Negative 670 (35.2%) 466 (33.5%) 204 (39.8%) Not assessed 1072 (56.3%) 800 (57.4%) 272 (53.1%) KRAS mutation 0.900 Positive 132 (6.9%) 96 (6.9%) 36 (7.0%) Negative 306 (16.1%) 227 (16.3%) 79 (15.4%) Not assessed 1467 (77.0%) 1070 (76.8%) 397 (77.5%) PD-L1 expression status 0.000* Positive 283 (14.9%) 176 (12.6%) 107 (20.9%) Negative 158 (8.3%) 113 (8.1%) 45 (8.8%) Not assessed 1464 (76.9%) 1104 (79.3%) 360 (70.3%) Treatment line of ICI 0.001* First line 1056 (55.4%) 745 (53.5%) 311 (60.7%) Second line 497 (26.1%) 365 (26.2%) 132 (25.8%) Third or more 352 (18.5%) 283 (20.3%) 69 (13.5%) Treatment pattern 0.130 Concurrent with chemotherapy 1162 (61.0%) 864 (62.0%) 298 (58.2%) ICI only 743 (39.0%) 529 (38.0%) 214 (41.8%) ICI duration, median (IQR), cycle 5 (3–10) 5 (2–8) 6 (4–12) 0.000* Best treatment response 0.000* CR/PR/SD 1145 (60.1%) 780 (56.0%) 365 (71.3%) PD 163 (8.6%) 136 (9.8%) 27 (5.3%) NA 597 (31.3%) 477 (34.2%) 120 (23.4%) Abbreviations: ICI, immune checkpoint inhibitor; irAEs, immune-related adverse events; IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; PD-L1, programmed cell death-ligand 1; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. *, means that the p value is statistically significant.

The median number of ICI cycles received was five (IQR, 3–10). The most widely used ICI was pembrolizumab (n = 598), followed by sintilimab (n = 455), nivolumab (n = 273), and camrelizumab (n = 176). The treatment patterns and types of ICIs are shown in Figure 1. The mean treatment course of pembrolizumab was 5.7 months, followed by 4.3 months for sintilimab, 4.1 months for nivolumab, 3.6 months for camrelizumab and 3.9 months for treprizumab. The treatment durations and the mean incidence rate of irAEs per month according to ICIs type are listed in Table 2. A total of 55.4% (1056/1905) of the patients received ICIs as first-line therapy, and 497 (26.1%) patients received ICIs as second-line therapy. More than half of the patients (61.0%, 1162/1905) received ICI-combined chemotherapy, paclitaxel being mostly used as the cytotoxic partner drug (n = 494). Only 23 patients received cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody plus nivolumab or durvalumab.

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Treatment patterns of immune checkpoint inhibitors and incidence of immune-related adverse events according to ICI types. irAEs, immune-related adverse events

TABLE 2. Treatment duration and irAEs incidence per treatment months according to ICI types Number of patients Total duration of ICI exposure (months) Mean duration of ICI exposure (months) Number of patients who developed irAEs Mean incidence of irAEs /months Pembrolizumab 598 3409 5.7 163 4.8% Sintilimab 455 1957 4.3 87 4.4% Nivolumab 273 1119 4.1 73 6.5% Camrelizumab 176 634 3.6 61 9.6% Treprizumab 125 488 3.9 32 6.6% Tisilizumab 81 599 7.4 28 4.7% Atezolizumab 62 329 5.3 23 7.0% Durvalumab 34 211 6.2 11 5.2% Abbreviations: ICI, immune checkpoint inhibitor; irAEs, immune-related adverse events. Treatment response

A total of 1308 patients were available with response assessment records. A total of 518 patients experienced the best overall response of partial response (PR), and 627 patients experienced stable disease (SD).

In patients with squamous NSCLC who received first-line therapy, the objective response rate (ORR) was 54.5% in patients receiving ICI-combined chemotherapy, and 37.3% in patients receiving ICI monotherapy (p = 0.019). The DCRs were 93.6% and 93.2%, respectively (p = 0.908).

As for patients with nonsquamous NSCLC who were not positive for EGFR 19/21 mutation and received first-line treatment, the ORR was 53.4% in patients who received ICI-combined chemotherapy, and 40.2% in patients receiving ICI monotherapy (p = 0.027). The DCRs were 95.2% and 87.6%, respectively (p = 0.013).

In patients with nonsquamous NSCLC who were positive for EGFR 19/21 mutations and failed targeted first-line therapy, the ORR of patients who received ICI-combined chemotherapy was 40.6%, while the ORR of patients who received ICI monotherapy was 27.3% (p = 0.494). The DCR was 100.0% and 54.5%, respectively (p = 0.000).

For patients with SCLC who received first-line ICI-combined chemotherapy (n = 66), the ORR was 74.2% (49 PR, 49/66), and the DCR was 90.9% (49 PR, 11 SD, 60/66). The treatment responses are presented in Table 3.

TABLE 3. Treatment response of 1308 patients Total (n = 1308) Chemo-immunotherapy (n = 785) Immunotherapy only (n = 523) p-value Squamous cell carcinoma N = 455 N = 284 N = 171 First-line N = 279 N = 220 N = 59 ORR 51.6% (144) 54.5% (120) 37.3% (22) 0.019* DCR 94.3% (263) 93.6% (206) 93.2% (55) 0.908 Second-line N = 127 N = 50 N = 77 ORR 33.9% (43) 42.0% (21) 28.6% (22) 0.118 DCR 84.3% (107) 88.0% (44) 81.8% (63) 0.350 Nonsquamous cell carcinoma N = 735 N = 411 N = 324 Without positive EGFR mutation N = 610 N = 329 N = 281 First-line N = 346 N = 249 N = 97 ORR 49.7% (172) 53.4% (133) 40.2% (39) 0.027* DCR 93.1% (332) 95.2% (237) 87.6% (85) 0.013* Second-line N = 167 N = 51 N = 116 ORR 25.7% (43) 31.4% (16) 23.3% (27) 0.270 DCR 86.8% (145) 90.2% (46) 85.3% (99) 0.393 With positive EGFR 19/21 mutation who failed targeted therapy N = 125 N = 82 N = 43 Second-linea N = 43 N = 32 N = 11 ORR 37.3% (16) 40.6% (13) 27.3% (3) 0.494 DCR 65.1% (38) 100% (32) 54.5% (6) 0.000* Abbreviations: ORR, overall response rate; DCR, disease control rate; EGFR, epidermal growth factor receptor; ORR, overall response rate. Incidence and spectrum of irAEs

A total of 671 irAEs were observed in 26.9% of patients (512/1905). The most common overall organ system immune-related toxicities were the endocrine system (8.3%, 159/1905), pulmonary (6.7%, 124/1905), and skin (6.0%, 115/1905). For the subset of patients reported as having endocrine toxicities, the majority were thyroid dysfunction (7.2%, n = 138), including 108 hypothyroidism and 30 hyperthyroidism patients, followed by type I diabetes mellitus (including diabetic ketoacidosis [DKA], n = 12) and hypophysitis (n = 9). All patients who developed pulmonary toxicity were identified as having pneumonitis (6.7%, n = 124). For patients with dermatological toxicities, the majority were rash (n = 52), pruritus (n = 24), or both (n = 8). The incidence of grade 3–5 irAEs was 5.8% (110/1905), with the most common grades 3–5 irAEs being pneumonitis (1.8%, 35/1905), followed by dermatological toxicities (1.2%, 22/1905) and increased alanine aminotransferase (ALT, 0.8%, 16/1905). Eleven irAEs led to death, including nine from pneumonitis, one from liver failure, and one from myocarditis. Other irAEs (n = 17) included thrombocytopenia (n = 3), palpitation (n = 2), anemia (n = 2), hypoproteinemia (n = 1), elevated eosinophils (n = 2), elevated lactic dehydrogenase (n = 2), xerophthalmia (n = 1), cough (n = 1), drug-induced sarcoidosis-like reaction (n = 1), cholangitis (n = 1), and sialadenitis of the submandibular gland (n = 1). The spectrum of irAEs of our study is shown in Figure 2, and the organ distribution of grade 1–2 irAEs and grade 3–5 irAEs is shown in Table 4.

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The organ distribution and spectrum of immune-related adverse events. RCCEP, reactive capillary endothelial proliferation; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; TBIL, total bilirubin; DBIL, direct bilirubin; SCr, serum creatinine; AMY, amylase; LPS, lipase; T1DM, type 1 diabetes; DKA, diabetic ketoacidosis; CNS, central nervous system; cTnI, cardiac troponin I; CK, creatine kinase; CK-MB, creatine kinase isoenzymes

The incidence of irAEs according to the different ICIs is shown in Figure 1. Of the patients who received pembrolizumab (n = 598), 27.3% (n = 163) developed irAEs of any grade; this was followed by 19.1% (n = 87) of the patients who received sintilimab (n = 455), 26.7% (n = 73) of the patients who received nivolumab (n = 273), and 34.7% (n = 61) of the patients who received camrelizumab (n = 176) developed irAEs (Figure 1).

TABLE 4. Organ distribution of grade 1–2 irAEs and grade 3–5 irAEs irAEs All irAEs Grade 1–2 irAEs Grade 3–5 irAEs N = 671 N = 556 N = 115 Thyroid dysfunction 138 136 (98.6%) 2 (1.4%) Pneumonitis

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