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Osimertinib-induced interstitial lung disease in a patient with non-small cell lung cancer pretreated with nivolumab: A case report.

ABSTRACT: Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for EGFR-T790M-positive non-small cell lung cancer. A high incidence of interstitial lung disease (ILD) during combination treatment with osimertinib and anti-programmed cell death-ligand 1 (PD-L1) inhibitor has been reported. The current study presents a case of ILD development during osimertinib treatment following nivolumab (an anti-PD-1 antibody) treatment. The 59-year-old female was diagnosed with stage IV lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene. Following nivolumab as a sixth-line treatment, an EGFR-T790M-encoding mutation in EGFR exon 20 was identified by re-biopsy. Osimertinib was therefore initiated as a seventh-line treatment. A partial response was subsequently noted; however, 63 days after initiation of the treatment the patient presented with dyspnea with decreased oxygenation in the absence of fever and sputum. A computed tomography scan revealed the emergence of ground-glass opacities with bronchiectasis in both lungs, and a diagnosis of ILD due to osimertinib was made. Following steroid pulse therapy with discontinuation of osimertinib, the patient's chest findings and respiratory condition improved. Therefore, it is considered that anti-PD-1 therapies may be associated with a risk of ILD during subsequent osimertinib treatment.

SUBMITTER: Takakuwa O

PROVIDER: S-EPMC5543261 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Project description:Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the standard treatment for EGFR T790M-positive non-small cell lung cancer (NSCLC). Osimertinib is one of the third-generation EGFR-TKIs and is currently the most advanced in clinical development. Interstitial lung disease (ILD) is a potentially fatal side effect of osimertinib use. Successful rechallenge with the second-generation TKI afatinib following osimertinib-induced ILD has been reported. However, few reports have discussed the safety and efficacy of third-generation TKI rechallenge in this patient population. In this paper, a case of lung adenocarcinoma is retrospectively analyzed, and the relevant literature is reviewed. The patient was initially diagnosed with early lung cancer, for which surgical treatment was performed. The postoperative diagnosis indicated stage IB (pT2N0M0) right lung adenocarcinoma. Genetic testing (amplification-refractory mutation system) revealed EGFR exon 19 deletion. More than 2 years after surgery, multiple metastases occurred in both lungs, so gefitinib (250 mg per day) was administered. However, 6 months after the start of gefitinib treatment, the tumor progressed. Lung tumor biopsy was performed for genetic testing (NGS) and an EGFR T790M mutation was observed. Subsequently, second-line treatment with osimertinib (80 mg per day) was given for 3 months. The evaluated response suggested a partial response (PR) with the occurrence of grade 3 ILD. Pemetrexed plus bevacizumab chemotherapy was subsequently administered, resulting in stable disease. However, following a severe drug reaction after six courses, the patient's chemotherapy was discontinued. Another third-generation TKI, almonertinib (110 mg per day), was rechallenged based on no ILD having been reported in a phase I/II study of this drug. After 4 months of almonertinib administration and 6 months without ILD recurrence, partial remission was attained. This is the first report of successful treatment with almonertinib after osimertinib-induced ILD. The results suggested that almonertinib had a significant effect in patients with EGFR T790M mutation, with fewer side effects and better survival benefits for patients with advanced lung cancer.

Project description:Importance:Nivolumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now the standard-of-care therapies in non-small cell lung cancer (NSCLC). Although EGFR-TKIs are well understood and have well-defined safety profiles, our experience with immune checkpoint inhibitors is still growing, particularly regarding the use of combinations of different classes of antitumor agents, including both the concomitant and sequential use of such agents. Objective:To determine whether nivolumab increases EGFR-TKI-associated interstitial pneumonitis (IP). Design, Setting, and Participants:A database study of 20 516 participants with NSCLC in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, performed between April 2015 and March 2017. Main Outcomes and Measures:We compared the incidence of EGFR-TKI-associated IP in patients receiving and not receiving nivolumab treatment. Results:The mean (SD) age of participants treated with EGFR-TKI, with and without nivolumab, was 64.4 (15.5) and 68.9 (11.8) years, respectively, and the proportion of men was 40.0% and 53.8%, respectively. Of the 20 516 participants with NSCLC, 985 cases (4.80%; 95% CI, 4.51-5.10) developed IP. Of 5777 patients treated with EGFR-TKI, 265 developed IP (4.59%; 95% CI, 4.06-5.16). Of 70 patients treated with both EGFR-TKI and nivolumab, 18 developed IP (25.7%; 95% CI, 16.0-37.6). The adjusted odds ratio for an interaction between EGFR-TKI and nivolumab was 4.31 (95% CI, 2.37-7.86; P < .001), suggesting the existence of an interaction. When we further stratified the patients by treatment with and without nivolumab, the odds ratio of EGFR-TKI-associated IP in cases with and without nivolumab treatment was 5.09 (95% CI, 2.87-9.03) and 1.22 (95% CI, 1.00-1.47), respectively. Conclusions and Relevance:We found a higher proportion of reports of IP for nivolumab in combination with EGFR-TKI vs treatment with either drug alone. Owing to the limitations of this study, the results warrant further confirmation. However, careful consideration should be given to the possibility of an increased risk of IP when EGFR-TKI is administered in combination with nivolumab, including concomitant and sequential use, and careful monitoring for IP is recommended.

Project description:BackgroundAs a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), osimertinib is the standard treatment for patients with EGFR mutations. Diarrhea and rash are the most common side effects, and some rare adverse reactions have started appearing owing to their increased clinical application. Osimertinib-associated myositis was reported to be more common compared with previous studies; however, osimertinib-associated rhabdomyolysis (RM) has not yet been reported. This is the first report of osimertinib-associated RM during the treatment of a lung adenocarcinoma patient with EGFR exon 19 deletion and T790M mutation. Compared to myositis, RM could lead to much more serious consequences, such as acute renal failure (ARF), disseminated intravascular coagulation (DIC) and electrolyte disturbances. Our case exemplifies the symptoms, diagnosis and treatment of osimertinib-associated RM, meanwhile, the potential mechanisms and related therapeutic choices have been fully discussed.Case descriptionHerein, we present a 70-year-old non-smoking woman diagnosed with metastatic lung adenocarcinoma harboring an EGFR exon 19 deletion, who had received afatinib plus bevacizumab as the first-line therapy and almonertinib plus bevacizumab as the second-line therapy. Then the patient underwent osimertinib and bevacizumab as the third-line therapy. After 5-month treatment, the patient developed myalgia, muscular weakness, and tea-colored urine. The muscle strength grade of both the upper and lower limbs was III, and no other abnormalities were found. Serum creatine kinase (CK) and myoglobin (Mb) levels increased to 1,470 IU/L and 616.5 ng/mL. The patient also developed acute renal insufficiency, hyperuricemia, metabolic acidosis, and electrolyte disturbances. All symptoms were improved following the withdrawal of osimertinib. As a result, the patient was diagnosed with osimertinib-associated rhabdomyolysis.ConclusionsThis is the first report of osimertinib-associated RM during the treatment of a lung adenocarcinoma patient. Although osimertinib-associated RM is rare, it is worthy of clinical attention in clinical practice, especially in patients receiving osimertinib plus bevacizumab. Once developed myalgia, muscular weakness and tea-colored urine, laboratory tests including serum creatine kinase (CK) and myoglobin (Mb) levels must be done, also osimertinib should be timely withdrawn to identify the cause.

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Osimertinib-induced interstitial lung disease in a patient with non-small cell lung cancer pretreated with nivolumab: A case report.

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