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.