Complete Response Achieved 1 Year after a Single Administration of Nivolumab in a Patient with Lung Adenocarcinoma with Negative Expression of PD-L1
Authors: Takashi Iwata, Aya Yamamoto, Kantaro Hara
Journal: Journal of Thoracic Oncology (2017)

We report a case of durable complete response lasting more than 17 months without any further treatment in a patient with lung adenocarcinoma with 0% expression of programmed death ligand 1 (PD-L1); the response was gradually achieved 1 year after a single administration of nivolumab. A 73-year-old man was transferred to our hospital; he presented with acute nuchal pain. Chest computed tomography (CT) revealed a right apical tumor directly invading the cervical vertebrae (Fig. 1A). His symptoms were mild weakness and paralysis of the bilateral lower extremities due to tumor extension into the spinal canal. Oxycodone and denosumab were immediately administered for the pathological vertebral fracture. CT-guided needle biopsy revealed adenocarcinoma from the apical tumor, but neither EGFR mutation nor ALK receptor tyrosine kinase gene (ALK) rearrangement were discovered. Palliative radiation therapy was given in a dose of 65 Gy to the apical tumor and the spinal invasion. As a result of this treatment, his Eastern Cooperative Oncology Group performance status improved from 4 to 3. Two months after the emergent admission, pemetrexed monotherapy was initiated. The patient’s systemic status gradually improved afterward. However, after 12 courses of pemetrexed, multiple liver metastases and left supraclavicular lymph node metastasis were detected by positron emission tomography (Fig. 2A). The patient experienced frequent anxiety attacks after disclosure of the disease progression. Then, nivolumab was introduced as second-line therapy. But this therapy was discontinued after only the single injection because the patient refused further treatment as a result of his mental instability. Twelve months after the single nivolumab injection and without any other anticancer treatment, the liver metastases gradually shrank and finally disappeared from the CT scan. The apical tumor also shrank, and the destroyed vertebrae were gradually replaced by fibrous and calcified tissue (Fig. 1B). The PET scan did not demonstrate any abnormal accumulation (Fig. 2B). The patient experienced disappearance of the palsy of the bilateral lower extremities. He stopped taking oxycodone and home oxygen therapy. He is well without any symptoms 17 months after the single nivolumab injection. The PD-L1 expression in the biopsy specimen was retrospectively checked with a Dako 22C3 kit (Dako, Carpinteria, CA), and the demonstrated tumor proportional score was 0%.Figure 2(A) Maximum intensity fludeoxyglucose F18 (FDG) positron emission tomography projection reveals high accumulation in the right apical tumor invading the third and fourth vertebrae, mediastinal and left supraclavicular lymph nodes, and multiple liver metastases. (B) Maximum intensity FDG positron emission tomography projection 11 months after the single nivolumab injection demonstrates no FDG accumulation, and otherwise, a background level in the left supraclavicular lymph node.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In patients with NSCLC, expression of PD-L1 is regarded as a biomarker to select good candidates for nivolumab, which is a programmed death-1 immune checkpoint inhibitor antibody.1Ilie M. Hofman V. Dietel M. Soria J.C. Hofman P. Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients.Virchows Arch. 2016; 468: 511-525Crossref PubMed Scopus (197) Google Scholar However, more than 10% of PD-L1–negative patients received benefit from anti–programmed death-1/PD-L1 therapies, suggesting that tumor PD-L1 expression cannot indicate all candidates who could receive survival benefits from immunotherapy.2Aguiar Jr., P.N. Santoro I.L. Tadokoro H. et al.A pooled analysis of nivolumab for the treatment of advanced non-small-cell lung cancer and the role of PD-L1 as a predictive biomarker.Immunotherapy. 2016; 8: 1011-1019Crossref PubMed Scopus (30) Google Scholar The long-term outcome of nivolumab in patients with advanced NSCLC was recently reported.3Brahmer J, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): clinical characteristics of long-term survivors [abstract]. Cancer Res 77:CT077.Google Scholar In this report, PD-L1 expression status was evaluated in 53% of the patients (n = 68). The 5-year survival rates in the subgroups of patients with a PD-L1 expression level less than 1%, 1% or higher, and 50% or higher were 20%, 23%, and 43%, respectively. These results suggest that even among patients with low or absent PD-L1 expression, there would be a certain population for which nivolumab therapy is favorable. Furthermore, in the same report, most 5-year survivors received no subsequent therapy. In our reported case, the effect of nivolumab seemed drastic and durable for 17 months, even though tumor PD-L1 expression was absent. A biomarker more accurate than tumor PD-L1 expression level to select candidates for nivolumab is expected. For now, nivolumab is worth considering as a choice of treatment, even if PD-L1 expression is low or absent in patients with advanced NSCLC. This study was funded by Kansai Rosai Hospital.