Crizotinib plus erlotinib overcomes osimertinib resistance in a seriously-ill non-small cell lung cancer patient with acquired

摘要

To the Editor: A 59-year-old Chinese man who presented with a severe cough and short of breath was admitted into hospital in October, 2018. Computed tomography scan showed a 4.0 cm × 2.0 cm tumor located on the lower lobe of right lung [Figure ​[Figure1A]1A] and multi-bone lesions, core needle biopsy was performed and adenocarcinoma was confirmed by pathologists. Diagnosis of metastatic lung adenocarcinoma with T4N3M1c in stage IVB was made by oncologists and pathologists. Next generation sequencing (NGS) with the biopsied tumor was done, and epidermal growth factor receptor (EGFR) exon 21 L858R mutation with mutant allele fractions (MAF) of 24.8% was found. Icotinib (Betta Pharmaceuticals Co., Ltd, Hangzhou, China), a first-generation EGFR tyrosine kinase inhibitor (TKI), at a dose of 125 mg orally, three times a day was administered. The patient got a partial response (PR) after 5 months according to the Response Evaluation Criteria in Solid Tumors 1.1 [Figure ​[Figure1B].1B]. He was found multi-brain metastasis on magnetic resonance imaging and the right lung tumor was enlarged [Figure ​[Figure1C]1C] after 9 months of icotinib treatment. NGS was done with the new biopsied progressed lung tissue, which indicated that T790M mutation was negative and the MAF of EGFR exon 21 L858R decreased from 24.8% to 1.83%. Taking into account of the patient's refusal of recommended chemotherapy, osimertinib (80 mg once daily) was administrated to the patient. The lung tumor progressed after 1 month [Figure ​[Figure1D].1D]. Systemic therapy with carboplatin and pemetrexed was performed and a stable disease was reached after 2 months of the treatment. However, disease progressed after 4 months [Figure ​[Figure1E],1E], and the patient's Eastern Cooperative Oncology Group (ECOG) performance status (PS) decreased to grade 4. NGS with serum was done and the MAF of EGFR exon 21 L858R mutation increased to 5.5%; MET amplification with a copy number of 3.1 was also found. Considering the patient's critical ill condition, re-biopsy was unavailable and MET amplification was not re-confirmed by immunohistochemistry or fluorescence in situ hybridization. A combinatorial treatment, consisting of crizotinib (250 mg twice daily) with first-generation EGFR-TKI erlotinib (150 mg once daily), was administrated. The patient's ECOG score improved to 2; and the primary lung tumor decreased by 51% in length [Figure ​[Figure1F].1F]. The patient also obtained significant improvement in symptoms such as cough, dyspnea, and appetite. His disease was under control for 2 months at the last follow-up visit. The side effect was mild acne and anorexia. No diarrhea, pneumonitis, or transaminitis happened.