The discovery of epidermal growth factor receptor (EGFR)-activating mutations in non-small cell lung cancer (NSCLC) and EGFR tyrosine kinase inhibitors (TKIs) have changed the strategy of NSCLC therapy. Recently, EGFR-TKIs, including gefitinib, erlotinib and afatinib, have become the standard therapy for patients with advanced EGFR-mutated NSCLC. However, the majority of the patients progress and second-line therapy is required.

The EGFR T790M point mutation (T790M) is the most common mechanism underlying drug resistance to EGFR-TKIs in EGFR mutation-positive NSCLC patients. Osimertinib (AZD9291) is a third-generation EGFR-TKI approved for the treatment of EGFR-T790M-positive NSCLC (1). Furthermore, immune checkpoint modulation with programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition has also shown promise in changing the strategy of NSCLC therapy. Nivolumab, an anti-PD-1 inhibitor, is a novel drug used in the second-line treatment of NSCLC (2). In both EGFR-TKI and immune checkpoint inhibitors therapy, interstitial lung disease (ILD) is recognized as one of most severe adverse events. These two therapies may be sequentially applied in the same patient, but the effects of the interaction between these two drugs on the risk of ILD remains unclear. A case of ILD that occurred during osimertinib treatment in a patient with a history of previous nivolumab treatment is reported herein.

A 59-year-old female was diagnosed with stage IV (cT3N2M1a) lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene. The patient was treated with platinum-pemetrexed with bevacizumab, followed by maintenance therapy for 6 months. Subsequently, the patient received third-line treatment with afatinib for 6 months, fourth-line S-1 for 5 months, fifth-line docetaxel for 2 months and sixth-line nivolumab for 1 month (administered twice). Eventually, 2.5 years after the initial diagnosis, the patient's disease progressed and a computed tomography (CT)-guided percutaneous needle biopsy for chest wall invasion revealed an EGFR-T790M-encoding mutation in EGFR exon 20. A total of 37 days after the last initiation of nivolumab, oral osimertinib therapy was initiated at a dose of 80 mg per day. Two months later, a chest CT revealed a partial response (Fig. 1A and B) and the patient's performance status (PS) improved from 3 to 1. However, on the 63rd day after osimertinib initiation, the patient presented to the hospital with shortness of breath. The patient had a light cough, without sputum or fever. A chest X-ray revealed ground-glass shadows in the lungs bilaterally and a chest CT showed the emergence of ground-glass opacities and consolidation with bronchiectasis in the right middle and lower lung lobes (Fig. 1C). The patient's peripheral capillary oxygen saturation was 96%, which was lower compared with that at the previous visit, and the laboratory findings revealed increased levels of lactate dehydrogenase (427 IU/l; normal range, 119-229 IU/l) and C-reactive protein (1.43 mg/dl; normal range, <0.30 mg/dl). The patient was hospitalized with a suspected diagnosis of ILD induced by osimertinib, and was treated with steroid pulse therapy, antibiotics (levofloxacin) and discontinuation of osimertinib. Following treatment with steroid pulse therapy, the patient's chest findings and respiratory condition improved and the steroid therapy was switched to prednisolone and the dose was reduced. The serum laboratory tests, including tests for antibodies against atypical pneumonia and immune rheumatic disease, β-D glucan and cytomegalovirus antigen, were all negative. After 10 days of hospitalization, the patient was discharged from the hospital with continuous steroid therapy of 10 mg prednisolone. Subsequently, the ILD remained in remission but the cancer rapidly progressed. Re-treatment with osimertinib and other chemotherapy was not administered; instead, opioid therapy was initiated. Twenty days following hospitalization for ILD, the patient succumbed to cancer progression.

Informed consent was obtained from the patient regarding the publication of the case details and associated images.

For patients with advanced EGFR-mutated NSCLC, treatment with first- or second-generation EGFR-TKIs is associated with response rates of 56-74% (3–6), but the majority of the patients develop disease progression within 1-2 years following treatment initiation (3–6). In ~60% of the patients, the mechanism underlying the acquired resistance is the development of an additional EGFR mutation, encoding EGFR T790M (7).

Osimertinib treatment has demonstrated a response rate of >60%, with durable progression-free survival for NSCLC patients with the EGFR-T790M-resistance mutation (1). The incidence of interstitial pneumonia during osimertinib treatment was reported to be 3%, and grade 5 was observed in 1% of the cases (1). As osimertinib is used in pretreated patients, greater attention must be paid to the incidence of interstitial pneumonia induced by osimertinib compared with other EGFR-TKIs.

It is known that risk factors of ILD in EGFR-TKI treatment include a history of smoking, concomitant interstitial pneumonia and a poor PS (8). In the present study, a poor PS may have been the reason for the incidence of ILD. On the other hand, Ahn et al (9) reported that ILD was observed in 38% of cases receiving combination treatment with osimertinib and durvalumab, a PD-L1 inhibitor, which suggests that treatment with such a drug combination may dramatically increase the risk of ILD. Notably, a similar increased risk of ILD has not been reported for combination treatment with durvalumab and gefitinib (10). These studies suggest that previous treatment with nivolumab may affect the onset of ILD during osimertinib treatment. Durability of the response following discontinuation of nivolumab has been observed (11). As previous treatment with nivolumab may be a critical risk factor for ILD during osimertinib treatment, further verification of this possibility is required.

In sub-group analysis in a previous phase III study (2), it was reported that nivolumab was relatively inferior to docetaxel in patients harboring an EGFR mutation. Furthermore, a meta-analysis reported that immune-checkpoint inhibitors do not improve overall survival over docetaxel in EGFR-mutated advanced NSCLC (12). We consider that nivolumab treatment prior to osimertinib treatment should be considered with caution when devising a treatment strategy for patients with EGFR-mutated advanced NSCLC. The presence of PD-L1 expression has been reported to be a predictive biomarker of the efficacy of anti-PD-1/PD-L1 antibodies, including nivolumab (13). Assessment of tumor PD-L1 expression may aid with decision-making regarding the adoption of nivolumab treatment in patients with EGFR-mutated advanced NSCLC.

In conclusion, the present study reports a case of ILD during osimertinib treatment following treatment with nivolumab. Careful assessment is required prior to commencing osimertinib treatment in patients previously treated with nivolumab. Further studies investigating the risk of ILD during EGFR-TKI treatment following nivolumab pre-treatment are required to reach more definitive conclusions.