Mechanism of action of adapalene for treating EGFR-TKI-induced skin disorder.

BACKGROUND: Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder. METHODS: To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1ß. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR. RESULTS: Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene. CONCLUSION: We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.

Drug-induced interstitial lung disease after chemoimmunotherapy for extensive-stage small cell lung cancer.

Objectives: The combination of chemotherapy and immune checkpoint inhibitors (chemo-ICI) has become the new standard of treatment for extensive-stage small cell lung cancer (ES-SCLC). Recently, slight changes in interstitial shadows, defined as interstitial lung abnormalities (ILA), have been identified. In patients with ES-SCLC who received chemo-ICI, there are limited data on the incidence of drug-induced interstitial lung disease (D-ILD) in daily practice and the association between the development of D-ILD and ILA in the baseline computed tomography (CT). Materials and methods: A multicenter, retrospective study was conducted to investigate the incidence of D-ILD, the risk factors for developing D-ILD, progression-free survival (PFS), and overall survival (OS) in patients with ES-SCLC who received chemo-ICI between August 2019 and November 2021. Results: This study enrolled 70 patients (median age, 71 years; including 58 men) from nine institutions in Japan. There were 62 patients (89%) treated with carboplatin/etoposide/atezolizumab and 8 patients treated with carboplatin or cisplatin/etoposide/durvalumab. Twenty-nine patients (41.4%) were found to have ILA at baseline CT. Eleven patients (15.7%) developed D-ILD. The proportion of patients with ILA was significantly higher in the group who developed D-ILD than in the group who did not (9/11 (81.8%) vs. 20/59 (33.9%), respectively, P = 0.0057). In addition, the frequency of ground glass attenuation (GGA) and reticulation was higher in patients who developed D-ILD. There was no significant difference in PFS and OS between patients who developed D-ILD and those who did not (median PFS, 8.0 (95% confidence interval (CI), 5.5-9.5) months vs. 5.0 (95% CI, 4.5-5.6) months, respectively, P = 0.11 and median OS, not reached (NR) (95% CI, 8.7-NR) vs. 18.2 (95% CI, 13.2-NR) months, respectively, P = 0.20). Conclusion: The incidence of D-ILD in patients with ES-SCLC who received chemo-ICI in clinical practice was higher than that in clinical trials. Patients with pre-existing ILA were more likely to develop D-ILD.

TAPO in first-line osimertinib therapy and continuation of osimertinib.

BACKGROUND: Osimertinib is associated with a relatively high frequency of drug-induced interstitial lung disease (D-ILD), and transient asymptomatic pulmonary opacities (TAPO) have been reported to occur during osimertinib administration. The frequency of TAPO during first-line treatment and the pros and cons of osimertinib continuation is unknown. METHODS: This was a multicenter, retrospective study. The purpose of this study was to research the frequency of TAPO and to evaluate osimertinib continuation in first-line therapy. We also evaluated progression-free survival (PFS) including subgroup analysis. RESULTS: From August 2018 to December 2020, 133 patients were enrolled into the study. The median observation period was 23.2 months (0.3-48.3 months). Thirty patients (22.6%) experienced D-ILD events, including 16 patients (12.1%) with CTCAE grade 1, five patients (3.8%) with grade 2, and nine patients (6.7%) with grade 3 and above D-ILD. Among the patients with grade 1 D-ILD, 11 cases (8.3%) of TAPO were observed, and all patients succeeded in osimertinib continuation. The TAPO images were characterized by localized patchy opacities (73%). The median PFS was 22.6 months (95% confidence interval [CI]: 17.8-28.7 months). Patients with TAPO had a significantly longer PFS than patients with non-TAPO D-ILD in the multivariate analysis. CONCLUSIONS: This study showed that grade 1 D-ILD might include TAPO and that patients with TAPO might have good PFS. We need to consider the possibility of osimertinib continuation when lung opacities appear.

Exacerbation of nontuberculous mycobacterial pulmonary disease in a patient with advanced non-small-cell lung cancer during treatment with PD-1 inhibitor and chemotherapy.

A 69-year-old man visited our hospital due to an abnormal shadow on a chest X-ray. Chest CT showed a mass shadow in his left lower lobe accompanied by an infiltrative shadow in the right upper lobe. Thorough examination led to a diagnosis of pulmonary squamous cell lung carcinoma, stage IIIB (T3N2M0). Combination treatment with chemotherapy and programmed cell death receptor 1 (PD-1) inhibitor was started, leading to a partial response. However, his pre-existing pulmonary infiltrative shadow progressed during the maintenance treatment with PD-1 inhibitor, and sputum culture revealed Mycobacterium abscessus infection. Thus, exacerbation of pre-existing nontuberculous mycobacterial pulmonary disease (NTM-PD) resulting from treatment with PD-1 inhibitor was suspected. Then, treatment with PD-1 inhibitor was discontinued, and he underwent pulmonary resection after antibiotic therapy against Mycobacterium abscessus infection. Recently, special attention has been paid to the association of Mycobacterium tuberculosis (TB) infection and treatment with immune checkpoint inhibitors (ICIs) in TB-endemic areas. This case also emphasizes the importance of realizing the risk of NTM infection when treating patients with ICIs, especially in NTM-endemic areas.