Research ArticleClinical Studies
Open Access

Association Between Multisystem Immune-related Adverse Events and Progression-free Survivals in PD-1/PD-L1 Inhibitor Monotherapy

ATSUSHI YAMAGUCHI, YOSHITAKA SAITO, KEISUKE OKAMOTO, AYAKO FURUGEN, KATSUYA NARUMI, YOH TAKEKUMA, JUN SAKAKIBARA-KONISHI, YASUSHI SHIMIZU, ICHIRO KINOSHITA, MITSURU SUGAWARA and MASAKI KOBAYASHI
In Vivo November 2024, 38 (6) 2886-2896; DOI: https://doi.org/10.21873/invivo.13770

Abstract

Background/Aim: Immune-related adverse events (irAEs) occur in various organs, and sometimes multiply following treatment with immune checkpoint inhibitors (ICIs). This study aimed to determine the association between the number of irAEs and clinical outcomes. Patients and Methods: This was a retrospective study that included patients with lung cancer, melanoma, and head and neck cancer who were treated with anti-programmed cell death (ligand) 1 (PD-1/PD-L1) monotherapy. We evaluated the association between the number of irAEs and progression-free survival (PFS) in the simple Cox regression analysis. To eliminate the immortal-time bias, an additional landmark analysis was performed. Results: In total, 92, 69, and 37 patients were allocated to the no, single, and multisystem irAEs groups, respectively. The multisystem irAEs were associated with better PFS compared to the no irAE group. In contrast, at the 12-week landmark, multisystem irAEs were associated with poor PFS compared to the no irAEs group. Furthermore, the rate of treatment suspension owing to irAEs in the multisystem irAEs group (62.5%) was higher than that in the single irAE group (17.3%) at the 12-week landmark. Conclusion: The incidence of multisystem irAEs was associated with improved clinical outcomes in patients with lung cancer, melanoma, and head and neck cancer treated with PD-1/PD-L1 inhibitor monotherapy. However, these results may be influenced by a potential immortal-time bias. When accounting for this bias, the early development of multisystem irAEs within 12 weeks was linked to treatment suspension and poorer clinical outcomes.

Key Words:

Immune checkpoint inhibitors (ICIs) inhibit immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and induce anticancer effects by activating the immune system in various cancers (1-3). However, some patients receiving ICIs develop immune-related adverse events (irAEs) due to immune system overstimulation and some guidelines suggest strategies for irAE management (4-7). IrAEs occur in various organs and tissues, sometimes affecting multiple areas, such as the skin, gastrointestinal tract (GI), lungs, thyroid, and liver (8). Although most irAEs are moderate and controllable, severe or fatal irAEs, such as pneumonitis and myocarditis occasionally occur (9). Consequently, adequate management is necessary for patients undergoing ICI treatment.

In contrast, irAEs may reflect T cell activation via immune checkpoint blockade, leading to improved antitumor effects and ICI efficacy (10-15). Although any grade or mild irAEs are associated with improved efficacy, severe irAEs could reduce anticancer effects (16, 17). One reason for this is the suspension of ICI treatment or administration of systemic steroid and/or immunosuppressants for irAEs treatment (10, 18-22). In addition to the severity of irAEs some reports focused on the relationship between ICI efficacy and the number of irAEs and found that patients with multisystem irAEs showed improved ICI efficacy compared with those without irAEs (23-31). However, the association between single and multisystem irAEs is not well understood. Furthermore, the effects of immortal-time or guarantee-time bias have not been fully considered in previous analyses (32). We previously evaluated the factors associated with multisystem irAEs development in lung cancer, melanoma, and head and neck cancer (33). In this study, we conducted a secondary analysis to determine whether multisystem irAEs can improve ICI efficacy compared to single and no irAEs. In addition, we evaluated the immortal-time bias by conducting a landmark analysis.

Patients and Methods

Patients. Patients aged ≥20 years with lung cancer, melanoma, and head and neck cancer who received anti-PD-1 antibodies (nivolumab and pembrolizumab) or anti-PD-L1 antibodies (atezolizumab and durvalumab) monotherapy between April 2016 and August 2021 at Hokkaido University Hospital were retrospectively evaluated. Patients who previously received ICI treatment, experienced persistent adverse effects caused by previous chemotherapeutic treatments, and those without sufficient information were excluded. The patient population in the present study was the same as that in our previous study on the risk factors for multisystem irAE development (33). Patients were divided into three groups: no, single, and multisystem irAEs. Single irAEs were defined as those involving one organ and multisystem irAEs were defined as those involving more than one organ. The present study was approved by the Ethical Review Board for Life Science and Medical Research of the Hokkaido University Hospital (approval number: 023-0100) and was conducted in accordance with the Declaration of Helsinki and the STROBE statement. Given the retrospective nature of this study, the requirement for informed consent was waived by the Ethical Review Board for Life Science and Medical Research of the Hokkaido University Hospital.

Evaluation and classification of irAEs. All the required information was obtained from the patients’ medical records. IrAEs were defined as conditions suggestive of autoimmune disorders appearing during ICI treatment and evaluated by physicians or pharmacists. Systemic steroids and/or immunosuppressants were used to treat irAEs according to their severity at the physician’s discretion.

Outcomes. The primary endpoint of this study was the progression-free survival (PFS) in the no, single, and multisystem irAE groups. Secondary outcomes were overall survival (OS) and disease control rates (DCR). Factors associated with PFS and the suspension rate of ICI treatment owing to irAEs were also evaluated. Tumor response was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), according to the Response Evaluation Criteria in Solid Tumors (version 1.1). PFS was defined as the time from ICIs initiation to PD, death, or the last follow-up. OS was defined as the time from ICI treatment initiation to death or the last follow-up. DCR was defined as the CR, PR, or SD rate.

Statistical analysis. The differences in baseline patient characteristics among the groups were assessed using Fisher’s exact probability test for categorical outcome variables and the Kruskal-Wallis test for continuous parameters; and post-hoc analyses were performed with Holm’s method when statistically significant differences were confirmed. PFS and OS were evaluated in an intention-to-treat manner using the Kaplan-Meier method. Differences in PFS and OS among the three groups were evaluated using the log-rank test with Holm’s method. Univariate and multivariate Cox proportional hazards regression analyses were performed to adjust the PFS results from the number of irAEs and baseline clinical variables, including sex, age, body mass index (BMI), Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking status, cancer type, staging, ICIs type, and prior treatment existence. Variables that had potential associations with PFS, as suggested by the univariate logistic regression analysis (p<0.10), were considered when creating the multivariate model. To avoid immortal-time bias, 6, 12, and 24-week landmark analyses of PFS were performed as previously described (34-36). In this analysis, we included patients who did not experience PD, death, or have a last follow-up by the designated landmark time, and these patients were divided into groups according to the number of irAEs at the landmark time (37). DCR was evaluated using Fisher’s exact probability test with Holm’s method. The treatment suspension rate owing to irAEs in between patients with single and multisystem irAEs was evaluated using Fisher’s exact probability test. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). A p-value <0.05 was considered statistically significant.

Results

Patient characteristics. The total number of study patients was 207, of which 198 were included in the final analysis (Figure 1). Of these patients, 69 (34.8%) and 37 (18.7%) developed single and multisystem irAEs, respectively. Baseline patient characteristics are shown in Table I. Sex, age, BMI, ECOG-PS, smoking status, cancer type, staging, epidermal growth factor receptor (EGFR) mutation, ALK fusion, BRAF mutation, ROS fusion, ICI types, and post treatment status were not significantly different among the three groups. Prior treatment existence was significantly different among the three groups (p<0.01) and was more frequent in the no irAE group than in the multisystem irAE group in post-hoc analysis (p<0.01). The profiles of organ-specific irAEs have been reported previously (33). In summary, skin irAEs were the most common (34.8% of patients), and thyroid (19.7%) and lung irAEs (8.6%) were also common. The most common multisystem irAE patterns in the multisystem group involved the skin and thyroid (37.8%). Skin and lung (16.2%), skin and musculoskeletal (13.5%), and thyroid and lung irAEs (13.5%) were also frequently confirmed.

Figure 1.
Figure 1.

Design of this study.

View this table:
Table I.

Patient characteristics.

Treatment efficacy. The Kaplan-Meier plots of PFS and OS after ICIs treatment initiation are shown in Figure 2. The median PFS of no, single, and multisystem irAE groups were 3.03 [95% confidence interval (CI)=2.16-4.16 months], 15.03 (95%CI=7.39-27.55 months), and 14.55 months (95%CI=11.16-24.90 months), respectively. Patients in the single and multisystem irAE groups had significantly longer PFS than those without irAEs (p<0.01 for both single and multisystem irAEs compared to the no irAE group). However, no significant difference was observed between the single and multisystem irAE groups (p=0.91). Similarly, patients with single and multisystem irAEs demonstrated longer OS compared to the no irAE group, although significant differences between the single and multisystem irAE groups were not observed [median OS: 18.00 months, 95%CI=12.26-26.65 months for no irAEs group, 48.77 months, 95%CI=31.84 months–not achieved (NA) for single irAEs group, and 47.39 months, 95%CI=36.81 months–NA for multisystem irAEs group, respectively; p<0.01 between the no and single irAE groups, p<0.01 between the no and multisystem irAEs groups, and p=0.71 between the single and multisystem irAEs groups, respectively]. The DCR in the single and multisystem irAE groups was significantly higher than that in the no irAE group although no significant difference was observed between the single and multisystem irAE groups (39.1% for the no irAEs group, 68.1% for the single irAEs group, and 73.0% for the multisystem irAEs group, respectively; p<0.01 between the no and single irAE groups, p<0.01 between the no and multisystem irAE groups, and p=0.67 between the single and multisystem irAE groups, respectively).

Figure 2.
Figure 2.

Kaplan-Meier curves of progression-free survival (PFS) (A) and overall survival (OS) (B) in patients.

Association between patient factors and PFS. We also evaluated the impact of patient factors on PFS after PD-1/PD-L1 monotherapy (Table II). Multivariate Cox regression analysis indicated that the number of irAEs was significantly associated with improved PFS [adjusted hazard ratio (aHR)=0.46, 95%CI=0.32-0.66, p<0.01 for the single irAE group vs. no irAE group, and aHR=0.44, 95%CI=0.28-0.68, p<0.01 for the multisystem irAEs group vs. no irAE group, respectively). In addition, patients with lung cancer had improved PFS compared to those with head and neck cancer (aHR=0.68, 95%CI=0.47-0.995; p=0.047). In contrast, poor PS was associated with worse PFS (aHR=3.34, 95%CI=1.67-6.70; p<0.01).

View this table:
Table II.

Cox regression analysis for progression-free survival (PFS).

Subgroup analysis of treatment efficacy in lung cancer patients. Because Cox hazard analysis indicated that cancer types were associated with PFS and our previous report indicated that patients with head and neck cancer had a lower risk of multisystem irAE development (33), we performed a subgroup analysis of PFS for each malignancy (Figure 3). The median PFS of lung cancer in the no, single, and multisystem irAE groups was 3.42 (95%CI=1.97-6.90 months), 27.56 (95%CI=11.60-42.05 months), and 13.39 months (95%CI=9.20-25.07 months), respectively, with significant differences between the no and single irAE groups (p<0.01), and the no and multisystem irAE groups (p=0.049). In contrast, no significant differences were observed between the single and multisystem irAE groups (p=0.31), which was consistent with the results of all patient analyses (Figure 3A). The PFS of melanoma and head and neck cancer were not significantly different among the three groups (p=0.15 between the no and single irAE groups; p=0.06 between the no and multisystem irAE groups; p=0.35 between the single and multisystem irAE groups in melanoma; p=0.12 between the no and single irAE groups; p=0.36 between the no and multisystem irAE groups; p=0.96 between the single and multisystem irAE groups in head and neck cancer, respectively) (Figure 3B and C).

Figure 3.
Figure 3.

Kaplan-Meier curves of progression-free survival (PFS) in lung cancer (A), melanoma (B), and head and neck cancer (C).

Efficacy analysis using a landmark analysis. Generally, a longer ICI administration induces more irAEs (8), which produces an immortal-time bias. Therefore, we conducted landmark analyses at 6, 12, and 24-weeks (Figure 4). Each landmark analysis indicated that the Kaplan-Meier curves were not significantly different among the three groups at any cut-off times (p=0.80 between the no and single irAE groups, p=0.36 between the no and multisystem irAE groups, and p=0.80 between the single and multisystem irAE groups at the 6-week landmark; p=0.59 between the no and single irAE groups, p=0.16 between the no and multisystem irAE groups, and p=0.22 between the single and multisystem irAE groups at the 12-week landmark; p=0.90 between the no and single irAE groups, p=0.58 between the no and multisystem irAE groups, and p=0.58 between the single and multisystem irAE groups at the 24-week landmark, respectively). In addition, multivariate Cox regression analysis in each landmark analysis adjusting for PS, cancer types, and prior treatment existence indicated that multisystem irAEs were associated with poor PFS compared to the no irAE group in the 12-week landmark analysis (Table III) (aHR=2.33, 95%CI=1.09-4.98, p=0.03). The 6-week landmark analysis indicated a poor PFS in the multisystem irAEs group compared to the no irAE group although no significant difference was observed (aHR=1.91, 95%CI=0.94-3.84, p=0.07).

Figure 4.
Figure 4.

Kaplan-Meier curves of progression-free survival (PFS) in 6- (A), 12- (B), and 24-week (C) landmark analyses.

View this table:
Table III.

Cox regression analysis for progression-free survival at each landmark analysis.

Treatment suspension due to irAEs. Finally, we evaluated the rate of treatment suspension due to irAEs (Figure 5); the rate at the 12-week landmark was 17.3% and 62.5% in the single and multisystem irAE groups, respectively, with a significant difference (p=0.01). This difference was maintained in all patient analyses and in the 6- and 24-week landmark analyses (data not shown).

Figure 5.
Figure 5.

Suspension rate of immune checkpoint inhibitor (ICI) treatment due to immune-related adverse events (irAEs) in the 12-week landmark analysis.

Discussion

In this study, we assessed the association between the number of irAEs and clinical outcomes of ICIs. In the simple survival curve and Cox regression model, the development of single and multisystem irAEs was associated with improved PFS and OS compared to the non-development of irAEs, although no difference was observed between the single and multisystem irAE groups (Figure 2 and Table II). Furthermore, a subgroup analysis of patients with lung cancer also indicated improvements in PFS in patients who developed irAEs (Figure 3A). Although no significant differences were observed in the melanoma and head and neck cancer subgroups due to the small sample size, similar trends were observed (Figure 3B and C). Consequently, the irAE incidence, regardless of the number, can be related to improved ICI treatment efficacy. Some studies have demonstrated an association between the number of irAEs and clinical efficacy of ICIs (23-31). Several studies on patients with non-small cell lung cancer (NSCLC) receiving anti PD-(L)1 treatment, showed that patients with single or multisystem irAE development had improved PFS compared to the no irAE group, which is consistent with our lung cancer subgroup results (23-25, 29). In addition, an integrated analysis with various tumors, such as NSCLC, gastric cancer, melanoma, and renal cell carcinoma also indicated that multisystem irAEs were associated with improved ICI efficacy, consistent with our results, although some types of cancer differed between studies (27, 28).

However, most of these studies may have included the immortal-time bias (23-28). Because the incidence of irAEs is generally time-dependent, patients with a longer survival can develop irAEs (32). In fact, most irAEs occur within the first six months of receiving anti-PD-1 treatment but can also occur later, even after discontinuing ICI therapy (8). To overcome this problem, landmark or Cox regression analyses using time-dependent variables were conducted (29, 34-36). We also conducted an additional analysis to eliminate immortal-time bias, using previous reports as a reference (34-36). Landmark analyses in renal cell carcinoma have suggested improved ICI efficacy in patients who develop multisystem irAEs (30, 31), but generalizability to other cancer types is limited. We first evaluated patients with various cancers using 6, 12, and 24-week landmark analysis. The significantly improved PFS in patients with single and multisystem irAEs in the simple Kaplan-Meier analysis was no longer significant (Figure 4), indicating that our simple analysis may have been affected by immortal-time bias. In a time-dependent Cox regression analysis, a previous study on atezolizumab monotherapy in a large population (n=1,548) also indicated that the incidence of single or multisystem irAEs was not associated with PFS (29). Considering these results, the cancer types and statistical methods should be discussed to evaluate the immortal-time bias and the association between the incidence of irAEs and clinical outcomes.

Interestingly, Cox regression analysis of the 12-week landmark demonstrated that multisystem irAE development within 12 weeks was associated with worse PFS compared to patients without irAEs. Similar results were obtained in the 6-week landmark analysis, although the difference was not significant (Table III). These results were consistent with those of previous studies, which indicated that the incidence of irAEs within 12 weeks of treatment initiation was associated with shorter PFS than that of later-onset irAEs (18, 38). In addition, ICI treatment discontinuation results in worse clinical outcomes (18, 19). In our 12-week landmark population, treatment suspension due to irAEs was more common in patients with multisystem irAEs than in those with a single irAE (Figure 5). Consequently, we considered that the early development of multisystem irAEs led to the suspension of ICI treatment, resulting in worse PFS.

Study limitations. First, this was a retrospective analysis with a small sample size. Therefore, clinical trials with larger sample sizes are required. Second, we could not evaluate the severity and grading of irAEs. Third, we included various cancer types and ICI treatments that could affect the efficacy of ICI. Further studies are required to evaluate the efficacy of the same treatment strategy for uniform cancer types. Fourth, we did not consider the PD-L1 expression or concomitant use of steroids, which may influence the immune response to tumors. Fifth, we did not consider the treatment line or the existence of post-treatment. These factors could have affected the PFS and OS. Sixth, the landmark analysis potentially underestimates the events, such as progression disease and death before landmark time, and we could not exclude these impacts on our findings. Finally, this was a secondary analysis of a previously studied population (33). Therefore, our preliminary results should be validated in future studies.

Conclusion

In conclusion, we demonstrated that the development of single and multisystem irAEs was associated with improved PFS and OS in all patient analyses. However, according to our landmark analysis, these results can include an immortal-time bias. Conversely, we first revealed that the early development of multisystem irAEs within 12 weeks results in worse clinical outcomes when the immortal-time bias is considered. Consequently, the appropriate management of multisystem irAEs in the early phases is required to maintain sufficient ICI efficacy.

Acknowledgements

The Authors would like to thank Editage (http://www.editage.jp) for the English language editing.

Footnotes

  • Authors’ Contributions

    AY and YS designed the study. AY and YS conducted the study and analyzed the data. AY, YS, KO, KN, AF, YT, NS, YS, HD, MS, and MK contributed to the writing of the manuscript. All the Authors reviewed the results and approved the final version of the manuscript.

  • Funding

    This study did not receive any specific grants from funding agencies in the public, commercial, or non-profit sectors.

  • Conflicts of Interest

    The Authors declare that there are no competing interests in relation to this study.

  • Received July 29, 2024.
  • Revision received August 20, 2024.
  • Accepted August 25, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Association Between Multisystem Immune-related Adverse Events and Progression-free Survivals in PD-1/PD-L1 Inhibitor Monotherapy
ATSUSHI YAMAGUCHI, YOSHITAKA SAITO, KEISUKE OKAMOTO, AYAKO FURUGEN, KATSUYA NARUMI, YOH TAKEKUMA, JUN SAKAKIBARA-KONISHI, YASUSHI SHIMIZU, ICHIRO KINOSHITA, MITSURU SUGAWARA, MASAKI KOBAYASHI
In Vivo Nov 2024, 38 (6) 2886-2896; DOI: 10.21873/invivo.13770
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