Synchronous occurrence of interstitial lung disease and ICANS after tarlatamab initiation in recurrent small-cell lung cancer

Abstract

Tarlatamab has been approved for patients with recurrent extensive-stage small-cell lung cancer (ES-SCLC). However, it is associated with adverse events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Limited data exist on the concurrent occurrence of ICANS and other treatment-related adverse events. In our case study, we observed the synchronous occurrence of interstitial lung disease (ILD) and ICANS following tarlatamab initiation in recurrent ES-SCLC.

1. Introduction

Small-cell lung cancer (SCLC) is a neoplasm associated with a rapidly progressive pathology. Immune checkpoint inhibitors (ICIs) have improved therapeutic outcomes for patients with extensive-stage SCLC (ES-SCLC) in the first-line treatment [1]. After the recurrence of the initial chemoimmunotherapy, the established standard care remains unclear, except for topoisomerase inhibitors such as topotecan or amrubicin. Tarlatamab, a bispecific delta-like ligand 3-directed T-cell engager immunotherapy, has been approved for standard care of patients with previously treated SCLC [2]. Tarlatamab is associated with specific adverse events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which occurred in 6% (15/262) of treated patients and were mostly grade 1 or 2. One patient (0.3%; 1/262) experienced grade 5 ICANS with synchronous persistent fever, hypoxemia, and hypotension [2]. As treatment-related adverse events (AEs), Interstitial lung disease (ILD) was observed in 1.4% (3/220) [3]. Compared with other immunotherapies, the incidence of lung toxicity related to tarlatamab is relatively rare. Little is known about the concurrent occurrence of ICANS and other treatment-related AEs. We encountered a synchronous occurrence of ILD and ICANS after tarlatamab initiation in recurrent ES-SCLC.

2. Case report

A-82 years old male received carboplatin and etoposide with concurrent thoracic radiotherapy for limited-stage SCLC on 32 months ago. Eight months after chemoradiotherapy (24 month ago), mediastinal lymph node recurrence was detected; therefore, and carboplatin plus etoposide with atezolizumab (IMpower133 regimen) [1] was initiated. The chemoimmunotherapy was performed until 4 cycles, followed by atezolizumab maintenance of 6 cycles, which achieving partial response (PR). However, there was evidence of multiple pulmonary metastases three months after chemotherapy. The patient was rechallenged with IM133 regimen on 12 months ago. The chemoimmunotherapy of 4 cycles was done, followed by 4 cycles with atezolizumab maintenance, which showing PR. During atezolizumab treatment, chest computed tomography (CT) revealed marked growth at the primary site, suggesting progressive disease (Fig. 1A). There was no evidence of brain metastasis and pulmonary lymphangitis carcinomatosis. Tarlatamab was administered as third-line treatment for recurrent disease. On day 11 after the initial tarlatamab administration, he experienced hallucinations and delirium, with an immune effector cell-associated encephalopathy (ICE) score of 0 [2,3]. At the same time, he complained of shortness of breath and decreased oxygen concentration was observed. Chest CT performed on day 12 revealed interstitial opacity in the bilateral lung fields, after the initial tarlatamab administration suggesting lung toxicity related to the drug (Fig. 1B). No evidence of infection, cardiovascular disorders, or other etiologies was observed. Therefore, we diagnosed synchronous occurrence of ICANS (Grade 2) and lung toxicity (Grade 2) associated with tarlatamab treatment. Oxygen and dexamethasone therapies were administered. On day 20 after the initial treatment, there was an obvious improvement in ICANS and ILD scores (Fig. 1C). The patient continued receiving tralatamab monotherapy without adverse events or disease recurrence.

Fig. 1.

Chest CT scan on baseline (A), day 12 after tarlatamab initiation (B), and day 20 after tarlatamab initiation (C).

(A) Chest CT showing multiple nodules indicating the primary site and pulmonary metastasis with consolidation in the left lung field.

(B) Bilateral interstitial opacities appeared on day 12 after administration.

(C) On day 20 after administration of dexamethasone, bilateral interstitial opacities disappeared.

3. Discussion

Our case report demonstrates that bilateral pulmonary infiltrates and hypoxemia developed concurrently with ICANS in a patient with previously treated ES-SCLC. However, immediate steroid therapy was effective in reducing both side effects. In our institution, only one (0.4%) of the 24 patients experienced ICANS, with markedly decreased ICE scores. To our knowledge, this is the first report demonstrating the simultaneous occurrence of ICANS and drug-induced lung toxicity within one cycle of tarlatamab initiation. In the early phase, CRS frequently appears, is mostly grades 1 or 2, and generally responds well to steroid therapy. In the present case, ILD may have been associated with tarlatamab-related CRS. However, whether ICANS triggers pulmonary infiltration remains unclear. We hypothesized that CRS-related cytokines may underlie both ICANS and lung toxicity. Most patients who developed CRS during tarlatamab treatment respond successfully to steroid therapy; therefore immediate administration of dexamethasone should be considered without observation.

Recently, Kushima et al. reported a case of early pseudoprogression mimicking pneumonitis after tarlatamab treatment, suggesting a reversible lung-predominant immune reaction with acute peritumoral infiltration driven by T cells [4]. This case illustrates an immune cell-associated respiratory syndrome arising from a T cell-driven inflammatory reaction in the lungs. In our case, T-cell-mediated neuroinflammation and respiratory reactions occurred concurrently with CRS, and immediate suppression of immune effector cell activation was effective in the treatment of ICANS and ILD.

Physicians should be aware of the potential for the concurrent occurrence of drug-induced lung toxicity when ICANS occurs in patients with ES-SCLC receiving tarlatamab.

CRediT authorship contribution statement

Masakazu Takahara: Writing – original draft, Visualization, Investigation, Data curation, Conceptualization. Atsuto Mouri: Writing – review & editing, Investigation. Ou Yamaguchi: Writing – review & editing. Tatsuhiko Uno: Writing – review & editing, Investigation. Kosuke Hashimoto: Writing – review & editing, Investigation. Hisao Imai: Writing – review & editing. Hiroshi Kagamu: Writing – review & editing, Supervision. Kyoichi Kaira: Writing – review & editing, Supervision, Data curation, Conceptualization.

Funding

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

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.