Nintedanib allows retreatment with atezolizumab of combined non-small cell lung cancer/idiopathic pulmonary fibrosis after atezolizumab-induced pneumonitis: a case report

The treatment of advanced non-small cell lung cancer (NSCLC) has evolved to include targeted therapy, immune checkpoint inhibitors (ICIs), and chemotherapy for selected patients in the first-line setting. Angiogenesis inhibitors have been used in combination with chemotherapy in the first-line and maintenance settings to provide improved progression-free survival, objective response rate, and overall survival in selected studies. A biologic rationale exists for combining anti-angiogenic agents with immunotherapy and targeted kinase inhibitors [1]. ICIs aid in enhancing antitumor activities, and as a byproduct they can also stimulate the immune system, resulting in immune-related adverse events such as ICI-related pneumonitis. This is contributed to by patients’ smoking history, damage to underlying lung parenchyma, chronic obstructive pulmonary disease, and pulmonary fibrosis [2‐5].

Nintedanib is a tyrosine kinase inhibitor that efficiently slows the progression of idiopathic pulmonary fibrosis (IPF) and has an acceptable tolerability profile [6]. Treatment with nintedanib reduces the risk of acute exacerbations (AEs), and a combined analysis of data from clinical trials of nintedanib shows a trend towards a reduction in mortality [7]. Moreover, a study such as J-SONIC is ongoing to evaluate the efficacy and safety, including AE of IPF (AE-IPF), of nintedanib combined with cytotoxic drugs compared with cytotoxic drugs alone for chemotherapy-naïve patients with IPF combined with NSCLC [8]. However, it is unclear whether nintedanib reduces the risk of ICI-induced pneumonitis of IPF. We herein report a case of NSCLC combined with IPF in which recurrence of ICI-induced pneumonitis may have been prevented with nintedanib therapy.

Our patient developed drug-induced pneumonitis from both pembrolizumab and atezolizumab. However, the use of nintedanib allowed us to re-administer atezolizumab without further recurrence of the drug-induced pneumonitis. We highlight the possibility of using nintedanib to prevent atezolizumab-induced pneumonitis in IPF combined with lung cancer. ICIs such as programmed death 1 (PD-1) and PD ligand 1 inhibitors have shown clinical activity and marked efficacy in the treatment of NSCLC [10]. Pembrolizumab as a PD-1 inhibitor and atezolizumab as a PD ligand 1 inhibitor were used in our patient. Certain ICI-related adverse events have been observed related to the skin, gastrointestinal tract, endocrine system, liver, lungs, and kidneys [11, 12]. Drug-induced pneumonitis has been reported as one of the most common lung-related immunological adverse events with an incidence ranging between 1 and 5% [10]. With nivolumab as a PD-1 inhibitor, the clinical course of most patients with nivolumab-induced pneumonitis was relatively good following the cessation of nivolumab and the initiation of a corticosteroid. It is noteworthy that two thirds of patients with nivolumab-induced pneumonitis were able to restart their nivolumab therapy [13]. However, one third of patients developed recurrent pneumonitis. It is not clear which subgroup among the patients with ICI-related pneumonitis will suffer the recurrence of pneumonitis. However, existing interstitial pneumonia is a known risk factor of ICI-related pneumonitis [2‐5]. Moreover, AE-IPF, as in our case, is a severe and life-threatening complication [14]. AE-IPF is triggered by various causes such as infection, post-procedural/postoperative period, drug toxicity, and aspiration [14]. Although the direct relevance remains unknown, ICIs may be an important trigger in AE-IPF. Our patient developed drug-induced pneumonitis with both pembrolizumab and atezolizumab, and moreover, the atezolizumab-induced pneumonitis occurred immediately. Because of this clinical course and co-existing IPF, we thought our patient was at high risk for recurrence of serious ICI-induced pneumonitis or AE-IPF. Therefore, we hypothesized that nintedanib might allow re-administration of atezolizumab without recurrence of drug-induced pneumonitis.

Nintedanib has a number of clinical benefits in patients with IPF, such as reducing the decline of lung function and extending the time to AE [7]. Nintedanib is an oral angiokinase inhibitor that targets receptors in three proangiogenic pathways: vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptors α/β, and fibroblast growth factor receptors. Therefore, this drug has been expected to have an anti-tumor effect on lung cancer [15]. In fact, combination therapy with nintedanib and docetaxel significantly improved independently assessed progression-free survival compared with placebo/docetaxel in the overall LUME-Lung-1 study population and provided significant, clinically meaningful improvement in overall survival in patients with adenocarcinoma [16]. This study showed that the rates of occurrence of drug-induced pneumonitis did not differ between the nintedanib and placebo groups (1.4 and 0.8%, respectively). However, the J-SONIC trial, a randomized control study for the treatment of NSCLC associated with IPF, showed that nintedanib combined with carboplatin plus nab-paclitaxel prolonged the interval to AE-IPF compared with carboplatin plus nab-paclitaxel alone [8]. That is, nintedanib was thought to be a key drug in the treatment of lung cancer combined with IPF. On the other hand, the excessive autoimmune response of tumor infiltrating lymphocytes can be the one of the reasons of ICI-induced pneumonitis [17]. VEGF can act as an immunosuppressive factor by several mechanisms such as inhibiting dendric cell (DC) function and maturation, enhancing expression of PD-L1 by DCs, promoting into the tumor [18]. Therefore, nintedanib that the target the VEGF pathway may enhance the prevention of ICI-induced pneumonitis. Unfortunately, the combination of nintedanib with atezolizumab showed no anti-tumor effectiveness in our case. However, although there have never been trials of combination treatment of ICIs and nintedanib until now, to the best of our knowledge, this combination therapy may improve the safety and survival of lung cancer associated with IPF.

In conclusion, our case indicates the possibility that ICIs combined with nintedanib might prevent drug-induced pneumonitis or AE-IPF. However, whether anti-fibrotic agents such as nintedanib are actually effective in the prevention of ICI-induced pneumonitis in ILD remains unknown, and additional research is greatly needed to identify effective therapies for ILD combined with lung cancer.