To the Editor:
Immunotherapies harnessing preexisting anticancer immune responses by targeting the
immune checkpoint pathways, particularly the programmed death 1 (PD-1) pathway, have
shown remarkable clinical activity across several tumor types, including NSCLC. Several
drugs targeting the PD-1 pathway are currently in clinical development, and two of
these agents (nivolumab and pembrolizumab) are U.S. Food and Drug Agency–approved
for use in advanced-stage NSCLC. In clinical trials with the anti–PD-1 agents, immune-mediated
pneumonitis was seen in nearly 10% of patients.
1
Patients with interstitial lung disease (ILD) were not eligible to participate in
trials with these agents out of concern for adverse outcomes. There are no reports
in the literature on the safety of anti–PD-1 immunotherapy in patients with preexisting
ILD.
We report the case of a patient with NSCLC with concomitant idiopathic pulmonary fibrosis
(IPF) treated with nivolumab. A 67-year-old man with a diagnosis of IPF for nearly
a decade was first found to have a left lower lobe nodule in 2012; it was followed
up with serial imaging with computed tomography and found to be progressively increasing
in size (22 × 18 × 22 mm) and fludeoxyglucose F 18–avid (maximum standardized uptake
value 13.7). Some fludeoxyglucose F 18–avid hilar and mediastinal lymphadenopathy
was found on a positron emission tomography/computed tomography in 2014. Bronchoscopy
with endobronchial ultrasonography revealed no hilar or mediastinal lymph node involvement.
Transbronchial biopsy confirmed a moderately differentiated squamous cell carcinoma
of the left lower lobe (T1aN0M0, stage 1A). In consideration of the patient's poor
pulmonary functional status, he underwent a video-assisted nodulectomy in early 2015,
with negative margins and an uneventful postoperative course. Pathologic examination
revealed a 1.5-cm moderately differentiated squamous cell carcinoma with clear margins.
The background lung showed emphysema and severe pulmonary fibrosis with a patchwork
pattern and fibroblast foci, as well as foci of parenchymal scarring and microscopic
honeycomb change consistent with a diagnosis of combined IPF and emphysema. No adjuvant
chemotherapy was recommended, and surveillance was conducted with imaging. Follow-up
scans at 4 months showed development of a new peripheral nodule measuring 1.3 cm in
the lingula, additional peribronchial nodular opacities measuring up to 5 mm in the left
upper lobe, and left hilar lymphadenopathy. Bronchoscopy with a transbronchial biopsy
confirmed squamous cell carcinoma with necrosis in the left hilar lymph node. Because
of the patient's underlying severe ILD, concurrent chemoradiation was not considered
safe and systemic therapy with carboplatin and docetaxel was initiated. He had poor
tolerance of chemotherapy, with severe fatigue and skin reactions to docetaxel, and
after two cycles of chemotherapy he had mild progression of disease. The left lower
lobe tumor was tested for programmed death ligand 1 (PD-L1) (E1L3N). The patient had
1% tumor PD-L1 positivity; in addition, he had PD-L1 positivity in the tumor-associated
macrophages.
He began receiving nivolumab in September 2015. Before initiation of nivolumab, he
had pulmonary function tests that showed a diffusion capacity of lung for carbon monoxide
of 27% and he was given 2 to 3 liters oxygen by nasal cannula. He tolerated nivolumab
without any significant toxicities or significant adverse events. He had mild shrinkage
of his tumor, stable response in his tumor per the Response Evaluations Criteria in
Solid Tumors (Fig. 1
A), improved exercise tolerance, and stable to slightly improved oxygen requirements.
Interestingly, his positron emission tomography scan after 5 months of treatment with
nivolumab showed a modest improvement compared with his pretreatment baseline scan
(Fig. 1
B). He had tolerated nivolumab well with good disease control for 8 months, at which
time he presented to the hospital with progressive shortness of breath, cough, and
fever. He was found to have new bilateral infiltrates. He had a bronchoscopy for further
evaluation and work-up revealed infection with coronavirus infection. His oxygen requirements
had increased to 6 liters of oxygen by nasal cannula. He had prolonged hospitalization
for 2 weeks, with respiratory and supportive care with improvement of symptoms. However,
in consideration of his severe deconditioning and decline in performance status, nivolumab
was discontinued; he was transitioned to hospice and died 4 months later.
Figure 1
(A) Chest computed tomography images at baseline before nivolumab treatment (left)
and after 5 months of nivolumab therapy (right) in a patient with NSCLC with underlying
pulmonary fibrosis that reveal a decrease in size of the dominant left hilar mass.
(B) Pulmonary function tests before and after treatment with nivolumab. FEV1, forced
expiratory volume in 1 second; FVC, forced vital capacity; Dlco, diffusion capacity
of lung for carbon monoxide.
IPF is a progressive and excessive remodeling of the pulmonary alveolar hyperplasia
associated with deposition of extracellular matrix. IPF results from an inflammatory
process characterized by chronic inflammation and alveolar epithelial hyperplasia,
resulting in the clinical and physiologic derangements characteristic of IPF.
2
There are striking similarities in the pathobiology and dire clinical outcomes of
both IPF and lung cancer. PD-1 plays a role in controlling inflammatory response to
injury in the normal lung tissues and could be critical in the pathogenesis of both
IPF and lung cancer.
3
Risk factors such as smoking and occupational and environmental exposures result in
stimulus producing episodes of acute lung injury followed by pathological wound healing
predisposing to genetic mutations, including atypia, dysplasia, and ultimately development
of IPF and lung cancer.
2
Anti–PD-1 agents are an important class of agents for treating patients with NSCLC.
These drugs are well tolerated, with fewer adverse events compared with cytotoxic
chemotherapy; however, they can cause a unique class of side effects called immune-related
toxicities.
4
Pulmonary toxicity with anti–PD-1 agents is more common in patients with NSCLC that
in patients with other tumor types, which is possibly due to impaired immune tolerance
resulting from smoking-induced changes in the normal lungs. Clinical trials with anti–PD-1
and anti–PD-L1 agents excluded patients with underlying ILD. Patients with IPF have
an increased risk for lung cancer.2, 5 Patients with advanced-stage NSCLC have limited
treatment options, and it is important to consider treatment anti–PD-1 agents when
appropriate.
To our knowledge this is the first case of NSCLC with concomitant diagnosis of ILD
treated with nivolumab with good disease control and a safe outcome without exacerbation
of the ILD. However, more studies are needed to establish the safety of agents targeting
the PD-1/PD-L1 pathway in patients with interstitial lung disease.