Nivolumab Rechallenge After Immune-related Adverse Events in Patients With Unresectable Advanced or Recurrent Esophageal Cancer

Abstract

Background/Aim

Rechallenge with immune checkpoint inhibitors following immune-related adverse events (irAEs) during the treatment of certain cancers reportedly has good efficacy. However, the subsequent clinical course of esophageal cancer remains unclear. This study investigated the nature of irAEs and the efficacy of a nivolumab rechallenge for patients with esophageal cancer.

Patients and Methods

This study retrospectively analyzed 44 patients with unresectable advanced or recurrent esophageal cancer who were treated with nivolumab as a second-line or later regimen and developed irAEs between February 2020 and May 2022. The cohort was divided into continuation, rechallenge, and discontinuation groups based on nivolumab administration after the occurrence of irAEs. The proportion of each group was investigated according to the type of irAEs. The progression-free and overall survival periods were retrospectively analyzed for each group.

Results

Among patients with skin-related irAEs, 78.6% continued nivolumab administration, 14.3% rechallenged, and 7.1% discontinued nivolumab. Among patients with gastrointestinal disorders, 30.8% continued, 46.2% rechallenged, and 23.1% discontinued nivolumab. Among patients with interstitial pneumonia, none continued, 55.6% rechallenged, and 44.4% discontinued nivolumab. In those with endocrine disorders, 83.3% continued, none rechallenged, and 16.7% discontinued nivolumab. The median progression-free survival after irAE occurrence in the continuation, rechallenge, and discontinuation groups was 210, 333, and 72.5 days, respectively (p=0.022), while the median overall survival after irAE occurrence was 714, 848, and 223 days, respectively (p=0.008).

Conclusion

Rechallenge with nivolumab may be considerably effective, depending on the type and severity of irAEs, and may improve the prognosis of patients with unresectable advanced or recurrent esophageal cancer.

Immune-related adverse events (irAEs) are treatment-specific adverse events associated with immune checkpoint inhibitor (ICI) therapy that require urgent attention. Previous studies have reported the so-called “rechallenge” approach, which involves temporarily interrupting ICI therapy after irAE onset, then resuming after remission of symptoms, as safe and effective (1-4). However, these reports examined only ICI therapy for non-esophageal types of cancer, and the safety and efficacy of rechallenge with ICI for esophageal cancer remain unclear. The present monocentric, retrospective analysis investigated the nature of irAEs that occur during nivolumab therapy as a second-line treatment for unresectable advanced or recurrent esophageal cancer in a real-world clinical setting, with the aim of evaluating the safety and efficacy of nivolumab rechallenge after irAE occurrence.

Patients and Methods

Patients. The present study included 44 of 116 patients who received nivolumab therapy as a second-line or later regimen for unresectable advanced or recurrent esophageal cancer diagnosed at the study center between February 2020 and May 2022, and who developed irAEs during their treatment. The cohort was divided into a continuation group, in which nivolumab administration was continued despite irAE onset; a rechallenge group, in which nivolumab administration was temporarily interrupted and then resumed after improvement of irAEs; and a discontinuation group, in which nivolumab administration was discontinued after irAE onset.

Evaluation. Cancer stage was classified in accordance with the Japanese Classification of Esophageal Cancer 11^th edition (5). Therapeutic efficacy was assessed based on computed tomography, which was conducted every six courses of nivolumab therapy or when deemed necessary at the onset of irAEs in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 criteria. The severity of the irAEs was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0 criteria. The diagnosis and treatment of irAEs were conducted with the cooperation of specialists following the irAE manual guidelines (6).

Treatment. Nivolumab 240 mg was administered every 14 days for the first six courses and thereafter at a dosage of 480 mg every 28 days.

Statistical analyses and ethics. The present study involved a retrospective analysis of the survival period and nature and severity of individual irAEs in the groups. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a modified version of R commander designed to add statistical functions frequently used in biostatistics (The R Foundation for Statistical Computing, Vienna, Austria). A p-value <0.005 was considered to indicate statistical significance. Continuous variables among the three groups were compared using one-way analysis of variance (ANOVA), while survival periods were compared using the log-rank test. The Bonferroni correction was applied to adjust the significance level and perform multiple comparisons between pairs of groups. The Mann-Whitney U-test was used to compare continuous variables between the two groups, and the chi-square test was used to examine the risk ratio. This study was approved by the Institutional Review Board of Tokyo Metropolitan Komagome Hospital and conformed to the provisions of the Declaration of Helsinki in 1995 (as revised in Edinburgh 2000).

Results

Patient population. Table I provides the details of the 44 patients with irAEs associated with nivolumab administration. Of the patients, 36 (81.8%) were male, and the median age was 69.5 years (IQR=63.8-72). All the patients were diagnosed with squamous cell carcinoma. Twenty-four patients had unresectable tumors, and 20 patients had postoperative recurrence. One patient with Stage III cancer was deemed unresectable because of the risks associated with alcoholic liver disease, and the patient received combination therapy with 5-FU and cisplatin prior to nivolumab therapy. Liver, lung, and bone metastases were observed in five, 19, and two patients, respectively. Metastasis to the lymph nodes, including regional lymph nodes, was observed in 40 patients. Regarding the treatments received before nivolumab therapy, 28 patients received one regimen while 16 received two or more regimens. Of the 44 patients, 21 were in the continuation group, 14 were in the rechallenge group, and nine were in the discontinuation group.

Table I. Characteristics of the 44 patients in the present study.

Nature of initial irAE. Table II shows the nature of the initial irAEs in 44 patients. The observed irAEs were, in descending order, skin disorders, gastrointestinal disorders, interstitial pneumonia (IP), and endocrine disorders.

Table II. Details of the initial immune-related adverse events (irAEs) in the 44 patients.

The continuation group had the highest number of skin-related irAEs, followed by endocrine and gastrointestinal irAEs. However, there were no cases of IP. In the rechallenge group, gastrointestinal, IP, and skin disorders were observed in descending order of frequency; however, all cases were grade 2 or lower. In the discontinuation group, IP was the most common adverse event, followed by gastrointestinal disorders, with grade 3 irAEs accounting for more than half of the cases (five cases, 55.6%).

Additional irAEs in the rechallenge group. Table III presents the characteristics of the 14 patients in the rechallenge group. Nine (64.3%) patients experienced additional irAEs. Five (35.7%) patients experienced irAEs that differed from those in the initial case. The same irAEs as the initial irAEs were observed in four patients (28.6%), and two of them were more severe than the initial irAEs. Of the nine patients who experienced an additional irAE, two continued nivolumab therapy, three underwent nivolumab therapy, and four discontinued nivolumab therapy.

Table III. Details of the clinical outcomes in the rechallenge group.

The median duration from the start of nivolumab administration to the onset of the initial irAEs was 72 days (IQR=52-91) in patients with additional irAEs and 103 days (IQR=14-133) in patients without additional irAEs. There was no significant difference between the groups (p=0.894). Furthermore, the median duration from the initial irAE occurrence to the resumption of nivolumab was 28 days (IQR=23-42) in patients with additional irAEs and 34 days (IQR=25-42) in patients without additional irAEs. There was no significant difference between the groups (p=0.739).

When comparing the risk ratio of developing an additional irAE based on the grade of the initial irAE, the cases that experienced grade 2 initial irAE had a risk ratio of 1.5, compared to the cases that experienced grade 1 initial irAE; however, there was no statistically significant difference (p=0.687).

Clinical course after initial irAE occurrence per group. The median progression-free survival (PFS) after initial irAE occurrence in the continuation, rechallenge, and discontinuation groups was 210 days (IQR=108-505), 333 days (IQR=119-447), and 72.5 days (IQR=1-201), respectively (p=0.022) (Figure 1A). There was no significant difference between the continuation group and rechallenge group (p=1.000). However, the rechallenge group had a significantly longer PFS than the discontinuation group (p=0.044), and the continuation group had a longer PFS than the discontinuation group (p=0.068). The median overall survival (OS) after irAE occurrence was 714 (IQR=414-NA), 848 (IQR=528-NA), and 223 days (IQR=77-NA) in the respective group (p=0.008) (Figure 1B). There was no significant difference between the continuation group and rechallenge group (p=1.000). However, both groups had significantly longer OS than the discontinuation group (continuation vs. discontinuation, p=0.048; rechallenge vs. discontinuation, p=0.019).

Figure 1. Kaplan-Meier curves of progression-free survival after nivolumab rechallenge (A) and overall survival after nivolumab rechallenge (B) in the continuation, rechallenge, and discontinuation groups.

Discussion

The present study was conducted to investigate the safety and the efficacy of rechallenge with nivolumab for patients with unresectable advanced or recurrent esophageal cancer. To the best of our knowledge, this is the first report to present the clinical course and the survival outcomes after rechallenge with nivolumab following the initial irAEs in such patients.

irAEs are considered an indicator of ICI treatment efficacy, particularly in cases of non-small cell lung cancer and malignant melanoma (1,7-11). Additionally, some studies have reported the safety and efficacy of ICI rechallenge after irAE remission (1-4). However, in clinical practice, especially in esophageal cancer treatment, uncertainty remains regarding whether rechallenge with ICI after the occurrence of irAEs exacerbates adverse events or contributes to prolonged overall survival. Moreover, it is unclear which types of irAEs tolerate rechallenge. The present retrospective study analyzed 44 patients with unresectable, advanced, or recurrent esophageal cancer receiving nivolumab therapy as second-line or later treatment. The patients were divided into three groups based on their post-irAE nivolumab administration status, and the clinical course, such as PFS and OS after the initial irAE occurrence. The outcomes were investigated in each group to reveal the efficacy of nivolumab rechallenge for esophageal cancer. Furthermore, the nature of the irAEs in each group was retrospectively investigated to determine the types of irAEs that were most suitable for rechallenge. In addition, in cases of rechallenge, the occurrence of additional irAE episodes was investigated to confirm the safety of rechallenge.

Comparisons among the three groups revealed that the PFS and OS in the continuation and rechallenge groups were similar. Both the groups had longer survival than the discontinuation group. This suggests that rechallenge with nivolumab may have a therapeutic effect on esophageal cancer. However, a few previous studies comparing the rechallenge and discontinuation groups in non-small cell lung cancer found no differences in survival outcomes, in contrast to the results of the present study (12,13). This discrepancy may arise because ICI therapy for non-small cell lung cancer is administered as a maintenance therapy, whereas nivolumab therapy for esophageal cancer aims to reduce tumor size. Further evaluation of long-term data is necessary to clarify this discrepancy.

In this study, skin disorders were the most common irAEs. Most patients (78.9%) were able to continue nivolumab therapy, two patients (14.2%) received a rechallenge, and one patient (7.1%) discontinued nivolumab therapy. Moreover, none of the patients in the rechallenge group experienced an exacerbation or recurrence of their initial skin disorders. This finding was consistent with that of a previous cohort study that reported a 4.6% rate of skin disorder recurrence (14). These findings suggest that rechallenge with nivolumab may be considered for patients with well-controlled skin-related irAEs.

Of the patients with gastrointestinal irAEs, such as diarrhea and colitis, 30.8% continued nivolumab therapy, 46.2% received a rechallenge with nivolumab, and 23.1% discontinued treatment. Moreover, among the patients who experienced diarrhea or colitis in the rechallenge group, 33.3% experienced a recurrence of diarrhea or colitis. Abu-Sbeih et al. reported that irAEs, such as colitis or diarrhea, recurred in 34% of the cases with ICI rechallenge (15). Similarly, the previously cited cohort study also reported a high recurrence rate of 38% for colitis (14). The results of the present study are consistent with these findings, highlighting the need to consider the relatively high recurrence rate of approximately 30% in patients with immune-related diarrhea or colitis before administering a rechallenge.

None of the patients with IP continued nivolumab therapy, and two of the five rechallenged patients experienced IP recurrence. In both cases, the grade was higher than that of the initial IP. The ESMO Clinical Practice Guidelines for the management of irAEs suggest that in cases of grade 2 IP, a rechallenge may be considered under careful observation after symptom improvement (6). Additionally, the previously cited cohort study reported that the IP recurrence rate was 27.7% (14). In esophageal cancer treatment, it is important to be cautious of exacerbation of IP when considering rechallenge for the patients with a history immune-related IP.

Among endocrine disorders, hypothyroidism and thyrotoxicosis were manageable, allowing the continuation of nivolumab therapy in all cases. A previously cited cohort study reported that the recurrence rate of hypothyroidism in patients with ICI rechallenge was only 8.5% (14). This result cannot be directly applied to the present study because no patients underwent rechallenge. However, rechallenge with nivolumab may be considered in cases of thyroid-related irAEs under appropriate monitoring, and thyroid function is well restored even if nivolumab therapy is interrupted.

In the rechallenge group of the present study, 64.3% of patients developed additional irAEs after the resumption of nivolumab. Two of these patients had a more severe irAE grade than their initial grade. The same type of irAE was observed in 28.6% of patients. The occurrence of additional irAEs was not affected by the duration from the start of nivolumab administration to the initial irAE occurrence, the duration between the interruption and resumption of nivolumab therapy, or the grade of the initial irAE. Simonaaggio et al. reported that 55% of patients who received ICI therapy, developed irAEs and underwent rechallenge experienced additional irAEs that were not more severe than the initial irAEs. They also reported that a shorter time to the initial irAE was associated with the occurrence of additional irAEs (3). Pollack et al. retrospectively analyzed patients with malignant melanoma who were treated with ICI and reported that recurrent irAEs were observed in 50% of the patients with ICI rechallenge after initial irAEs, and 18% of rechallenged patients experienced the same type of irAE as they had initially (16). Similarly, Santini et al. reported that the rate of additional irAE occurrence was 52% among the patients with non-small cell lung cancer receiving ICI rechallenge after the initial irAE, and 26% of them experienced the same type of irAE as they had initially (2). Furthermore, in a previously cited cohort study, the rate of repeat irAE occurrence after ICI rechallenge was 28.6% (14). Although the patients in the present study included only cases of rechallenge with the same ICI regimen as that before the initial irAE occurrence, the recurrence rate of irAEs and the recurrence rate of the same type of irAEs were similar to those reported in previous studies. However, the results of the present study, which indicate that the duration before the initial irAE did not affect the recurrence rate of irAEs, differ from the results previously reported. Furthermore, the number of patients that experienced more severe grades of additional irAEs was higher in the present study. These discrepancies might arise from differences in the decision-making processes of attending physicians regarding whether to interrupt or rechallenge treatment. In the context of esophageal cancer treatment, nivolumab rechallenge can be safely administered if the type of initial irAE is considered and the irAE has resolved.

Study limitations. This was a retrospective analysis conducted at a single institution. Additionally, there are no clear criteria for rechallenge, resulting in the possibility of bias based on the attending physician’s decision to resume ICI therapy. Therefore, the findings of the present study do not strongly recommend conducting a rechallenge for esophageal cancer. However, considering the limited number of effective regimens for unresectable or recurrent esophageal cancer, nivolumab rechallenge after irAE improvement may contribute to a prolonged prognosis.

Conclusion

Nivolumab rechallenge is feasible for patients with skin- or thyroid-related irAEs. In patients with irAEs, such as diarrhea, colitis, or IP, rechallenge is difficult to conduct, and even if rechallenge is performed, caution is needed to avoid exacerbation of irAEs or the development of other irAEs.

Funding

This study was not supported by any funding sources.

Conflicts of Interest

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

Authors’ Contributions

Kohdai Ueno: Conceptualization; Data curation; Formal analysis; Roles/Writing - original draft. Kunihito Suzuki: Conceptualization; Data curation; Formal analysis; Roles/Writing - review & editing. Katsumasa Saito: Conceptualization; Data curation; Formal analysis; Roles/Writing - review & editing. Hajime Shinohara: Conceptualization; Data curation; Formal analysis; Roles/Writing - review & editing. Akinori Miura: Conceptualization; Data curation; Formal analysis; Roles/Writing - review & editing. All Authors have read and approved the final version of the manuscript.

Acknowledgements

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