Figure 3. Comparison of pre- and post-therapy CT scans
(1) Mediastinal lymph node metastases at the beginning of treatment; (2) right adrenal gland metastasis at the beginning of treatment; (3) mediastinal lymph node metastases at the end of the treatment second course; and (4) right adrenal gland metastasis at the end of the second treatement course.
Clinically, the patient’s dyspnea improved because the tumor had shrunk and the tracheal stenosis had resolved. The patient had severe heart failure before the cancer diagnosis, and the echocardiographic evaluation revealed a decreased ejection fraction of 42.9% and decreased wall motion in all circumferential regions, especially from the septum to the anterior wall. On June 12th of same year, his underlying heart failure worsened and he died suddenly. Our request to perform a clinical/pathological autopsy was denied by the patient’s family. Because immune checkpoint inhibitor-associated myocarditis is a rare adverse event, the incidence rate ranges between 0.27% and 1.14%,9 and our patient’s chronic heart failure was severe enough to be the cause of death in this case, we opined that the worsening chronic heart failure was a result of its pre-existing severity and was not directly related to the administration of combination ipilimumab-nivolumab.
Discussion
The present case highlights two clinical issues (3.1 and 3.2) related to combination ipilimumab-nivolumab therapy in a patient with a thoracicSMARCA4 -deficient undifferentiated tumor.
First, in our case, combination ipilimumab-nivolumab successfully showed clinical benefits in the treatment of thoracic SMARCA4 -deficient undifferentiated tumors (3.1). Thoracic SMARCA4 -deficient undifferentiated tumors are unresponsive to chemotherapy and have a poor prognosis, with a median life expectancy of 4–7 months.1,2 Recently, case reports of these tumors responding to immune checkpoint inhibitors both alone (pembrolizumab3,4 or nivolumab6) and in combination with chemotherapy (pembrolizumab plus carboplatin and pemetrexed,10 atezolizumab with bevacizumab, paclitaxel, and carboplatin11) have been published. However, no reports of response to ipilimumab-nivolumab combination exist. Only one case of combination therapy with two immune checkpoint inhibitors has been reported, in which ipilimumab was added some time after the onset of pembrolizumab administration.12 The Checkmate 227 study demonstrated that treatment with combination ipilimumab-nivolumab in patients with non-small cell lung cancer was associated with a significant advantage in OS compared with chemotherapy, regardless of PD-L1 expression. In the same study, 2-year OS tended to be better with combination ipilimumab-nivolumab than that with nivolumab alone in patients with PD-L1 expression ≥1% (22C3) and ≥50%, respectively.7 In our case, the patient was able to receive combination ipilimumab-nivolumab without any apparent adverse events and had a successful response with symptom improvement. Unfortunately, the patient died from worsening chronic heart failure; however, we believe that a long-term positive response might have been possible because the tumor had shrunk and his respiratory distress symptoms and general condition had improved.
The second clinical issue is the good tolerability of combination ipilimumab-nivolumab (3.2). At the time of diagnosis, the patient was at PS2 (could not walk and required oxygenation,) making cytotoxic chemotherapy difficult to administer. In addition, combination ipilimumab-nivolumab was administered on an outpatient basis without any adverse events. The efficacy of PD-1/PD-L1 inhibitor monotherapy in the primary treatment of stage IV non-small cell lung cancer in patients at PS2 is currently unclear, as the KEYNOTE-024 and IMpower110 trials enrolled only patients at PS0–1 as eligibility criteria.13,14 A study on pembrolizumab in patients at PS2 (PePS2 study) reported that pembrolizumab could be safely administered even in patients with PS2.15 Because the patient had a thoracic SMARCA4 -deficient undifferentiated tumor that was not expected to respond to chemotherapy, and his general condition was poor (PS2), we discussed the best supportive care or immunotherapy with him. After an intense discussion, we decided to use both ipilimumab and nivolumab instead of a single agent to achieve a better response. Further studies will be conducted in similar cases to investigate the use of ipilimumab-nivolumab combination.
Conclusion
Combination ipilimumab-nivolumab was successfully administered to a patient with thoracic SMARCA4 -deficient undifferentiated tumor. These findings may be further validated in trials when chemotherapy is not possible owing to patient or tumor factors.