Impact of immune‐related adverse events on survival outcomes in extensive‐stage small cell lung cancer patients treated with immune checkpoint inhibitors

Abstract Background Immune checkpoint inhibitors have recently become the standard of care in the first‐line treatment of extensive‐stage small cell lung cancer. Although immune‐related adverse events have been reported to influence prognosis in non‐small cell lung cancer patients, few studies have investigated the prognostic value of immune‐related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune‐related adverse events after first‐line treatment with immune checkpoint inhibitor‐based chemotherapy for extensive‐stage small cell lung cancer. Methods We enrolled 90 patients with extensive‐stage small cell lung cancer who received immune checkpoint inhibitor‐based chemotherapy as first‐line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune‐related adverse events. Results There were 23 patients with and 67 without immune‐related adverse events. Seventeen patients had grade 1–2 immune‐related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune‐related adverse event was a skin rash. The median survival time was 22 months in patients with immune‐related adverse events and 9.3 months in patients without immune‐related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19–0.83, p = 0.013). Conclusions The results of this study show that immune‐related adverse events are associated with improved survival outcomes in patients with extensive‐stage small cell lung cancer.


| BACKGROUND
[9][10][11][12][13] However, the prognostic impact of irAE in ES-SCLC patients who received ICI-chemotherapy as first-line treatment is still unclear and needs further investigation.In this study, we retrospectively analyzed the clinical data of ES-SCLC patients who developed irAE after receiving ICI-based chemotherapy and compared their survival outcomes with those who had no irAE.

| Patients and methods
This retrospective study included patients with ES-SCLC who received first-line therapy with ICIs plus chemotherapy between September 2019 and December 2022 at six medical centers in Japan.The chemotherapy regimen consisted of carboplatin (area under the curve: 5 mg/mL per min) and etoposide (100 mg/m 2 ) for up to four cycles.The ICI doses were 1500 mg every 4 weeks for durvalumab and 1200 mg every 3 weeks for atezolizumab.Electronic medical records were used to collect patient information.Patients with insufficient information or missing observation periods were excluded from the study (Figure 1).The patients were divided into two groups based on the presence or absence of irAEs.We compared the two groups' progression-free survival (PFS) and overall survival (OS).

K E Y W O R D S
immune checkpoint inhibitor, immune-related adverse events, small cell lung cancer F I G U R E 1 Study flow chart.ICI, immune checkpoint inhibitor; irAE, immune-related adverse event.

Patients treated with ICI plus Chemotherapy n=93
Excluded cases

Data unavailability n=2
Deviation from observation period n=1

| Diagnostic workup
Patients with pathologically diagnosed small cell lung cancer and distant metastasis were defined as having ES-SCLC.Contrast-enhanced magnetic resonance imaging (MRI) was used to evaluate target lesions in the brain, and contrast-enhanced computed tomography, or positron emission tomography, was used to evaluate target lesions in other organs.The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was applied to assess response and disease control rates.Performance status was assessed using the Eastern Cooperative Oncology Group performance status (ECOG PS).The American Society of Clinical Oncology Clinical Practice Guideline was followed to evaluate immune-related adverse events (irAEs). 14Oncologists diagnosed irAEs after ruling out other possible causes based on the following criteria: (1) pathological evidence of irAEs; (2) a multidisciplinary consensus involving at least two oncologists; and (3) clinical improvement with irAE-specific treatment.

| Patient characteristics and irAE
Ninety-three patients were enrolled in this study, but only 90 met the eligibility criteria (Figure 1).The median age of the entire patient cohort was 72 years (range: 50-93 years).
Of the total patients, 82 were male and 8 were female.
Patients were stratified into two groups based on the presence or absence of immune-related adverse events (irAEs).The irAE group comprised 23 patients, while the non-irAE group comprised 67 (Figure 1).The baseline characteristics of patients in both groups are presented in Table 1.There were no significant differences between the two groups with regard to any of the background factors.
The types and grades of irAEs are detailed in Table 2.The most frequently encountered irAEs were skin rash and hypothyroidism.Three patients experienced more than one irAE.The median time for the onset of irAEs was 75 days (range: 10-1002 days).The treatment was interrupted in three patients due to irAEs (Table 2).

| Survival analysis
In all patient groups, the PFS was 4.9 months (95% confidence interval [CI]: 4.3-5.4months; Figure 2A), and the median OS was 9.7 months (95% CI: 8.7-16.5 months; Figure 2B).In the cohort with irAE, the median PFS was 5.1 months (95% CI: 4.5-5.9months), whereas in the group without irAE, it was 4.5 months (95% CI: 4.1-5.3months; p = 0.941; Figure 3A).The median OS was significantly extended in the irAE group, with a median survival time of 22.8 months (95% CI: 10.3-not assessed months) compared to the group without irAE, which had a median OS of 9.3 months (95% CI: 7.0-11.0months; p = 0.010; Figure 3B).It is noteworthy that the number at risk in the group without irAE at the initiation of PFS and OS is different.This discrepancy can be attributed to patients who did not undergo CT scans at the conclusion of treatment, rendering them ineligible for Response Evaluation Criteria in Solid Tumors (RECIST) evaluation.Consequently, the data for PFS was incomplete.However, as the date and time of death were meticulously documented, the count of events for OS is higher.This incongruity emanates from the inclusion of real-world cases in the study.A landmark analysis was conducted to account for immortal time bias.In the 2-and 3-month landmark T A B L E 2 Immuno-related adverse events.analyses, significant extensions in OS were observed in the irAE group compared to the group without irAE (Figure 4A,B; Table 3).However, the 6-month landmark analysis did not reveal any statistically significant differences (Figure 4C; Table 3).
Survival curves were also analyzed based on the grade of irAEs and prednisolone treatment.However, no significant findings were identified, probably due to the limited number of patients (Figure S1).Swimmer's plots are described in Figure 5A,B

With irAE
Progression-free survival immune checkpoint inhibitor (ICI) treatment.All but one case experienced irAE within 160 days.

| Univariate and multivariate analyses
Univariate and multivariate analyses were performed using the Cox proportional hazards regression.Both univariate and multivariate analyses revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or higher and the absence of irAEs were poor prognostic factors for OS (Table 4).

| DISCUSSION
This study provides novel and important insights into the prognostic role of irAEs in patients with ES-SCLC F I G U R E 4 Kaplan-Meier curves for overall survival with landmark analysis.The survival curves for patients who were alive at 2 months (A), 3 months (B), and 6 months (C) after starting treatment are described.irAE, immune-related adverse event; MST, median survival time.who received first-line treatment with ICIs plus chemotherapy.][9][10][11][12][13][14] However, this is the first study to demonstrate that irAEs are also a favorable prognostic factor for patients with ES-SCLC who received first-line ICI plus chemotherapy, suggesting that irAEs may be a surrogate marker of treatment efficacy and a predictor of long-term survival benefit for this aggressive disease.

With irAE
][9][10][11][12][13][14] Shimozaki et al. found that patients with irAE in solid tumors, including non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, exhibited superior progression-free survival (PFS) and overall survival (OS). 11]13 Recently, Socinski et al. conducted a pooled analysis of patients enrolled in a clinical trial using atezolizumab, analyzing 2503 patients with a landmark analysis to avoid bias. 12Their findings indicated a prognostic impact of irAE, showing a hazard ratio of 0.69 for OS in patients with irAE compared to those without irAE. 12The underlying mechanisms of how irAEs influence prognosis are still unclear.One possible explanation is that ICIs activate exhausted T cells to cross-react with both tumor antigens and self-antigens, resulting in irAEs and enhanced anti-tumor immunity. 18,19Therefore, patients with irAEs may have more tumor cell death and antigen F I G U R E 5 Swimmer plots depicting patients with immune-related adverse events.Individual swimmer's plot for patients with immune-related adverse events (irAE; A) and details of the irAE (B).ICI, immune checkpoint inhibitor.

(A) (B)
activity induced by ICIs, which could lead to durable tumor control and prolonged survival.Another possible explanation is that genomic variants associated with irAEs may modulate both the immune response and the tumor biology, affecting both irAEs and prognosis. 20urther studies are needed to elucidate the molecular and immunological mechanisms of irAEs and their impact on survival outcomes.
Our study also has implications for the optimal use of ICIs in ES-SCLC treatment.The IMPOWER133 trial showed that adding ICIs to carboplatin and etoposide improved survival in patients with ES-SCLC compared to chemotherapy alone. 213][24][25] Thus, it seems that the efficacy of ICIs is mainly observed during the first-line treatment and that subsequent ICI therapy may not be effective for patients who did not respond to first-line ICI plus chemotherapy.Therefore, it is crucial to identify biomarkers that can predict the response to first-line ICI plus chemotherapy and guide the selection of patients who may benefit from this treatment.We propose that irAEs may be a biomarker, as they reflect the immune activation and the tumor sensitivity to ICIs.We also believe that genomic variants associated with irAEs may be another potential biomarker, as they may influence both the immune response and the tumor biology.
Our study has some limitations that should be acknowledged.First, this is a retrospective study that may be subject to selection bias and confounding factors.Second, the number of patients with irAEs is small, which limits the statistical power and generalizability of our findings.Third, some irAEs may occur long after the administration of ICIs, which may lead to a selection bias in favor of patients who survive longer after treatment. 26We performed a landmark analysis to adjust for this bias and found a trend toward a better prognosis in the irAE group, but the long-term follow-up may not be accurate due to the small sample size.Fourth, we could not perform multivariate or subgroup analyses to account for other factors that may influence the prognosis, such as the number and type of irAEs, the use of steroids, and the line of therapy. 10,11,14hese factors may have different effects on the survival outcomes of patients with irAEs.In our report, the incidence of Grade 3 or higher adverse events exceeded that observed in clinical trials.Fujimoto et al. conducted a prospective observational study utilizing real-world data of ES-SCLC with ICI to chemotherapy in Japan. 27Their findings indicated that patients not eligible for inclusion in clinical trials experienced a higher frequency of Grade 3 or higher adverse events. 27Therefore, we attribute the higher occurrence of Grade 3 or higher adverse events in our data to the inclusion of real-world patients, encompassing demographics not typically represented in clinical trials, such as elderly patients and those with poor performance status.
In summary, the present study unveils for the first time that patients afflicted with ES-SCLC who experienced irAEs following ICI as a first-line treatment exhibited significantly improved OS compared to patients without irAEs.This observation underscores the potential of irAEs as a surrogate marker for treatment effectiveness and as a pivotal prognostic factor in this challenging disease.Nevertheless, it is imperative to acknowledge the limitations of our study, including its small sample size, retrospective design, and the absence of genomic analysis.Consequently, our findings warrant validation through larger cohorts, prospective study designs, and comprehensive genomic profiling of irAE-related variants.
. All but two cases completed F I G U R E 2 Kaplan-Meier curves of progression-free survival and overall survival in all patients.Progression-free survival (A) and overall survival (B) are shown.CI, confidence interval; MST, median survival time; PFS, progression-free survival.

3
Kaplan-Meier curves of progression-free survival and overall survival in patients with and without immune-related adverse events.Progression-free survival (A) and overall survival (B) are shown.CI, confidence interval; irAE, immune-related adverse event; MST, median survival time; NA, not assessed; PFS, progression-free survival.

3
Landmark analysis for overall survival.

1.4 | Statistical analysis
Characteristics of the patients.
T A B L E 1Abbreviations: CBDCA, carboplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; irAE, immune-related adverse event.
Univariate and multivariate analyses.
T A B L E 4Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; irAE, immune-related adverse event.