Primary resistance to crizotinib treatment in a non-small cell lung cancer patient with an EML4-ALK rearrangement: a case report

Abstract

Crizotinib, a small molecular tyrosine kinase inhibitor, manifests dramatic responses in patients with non-small cell lung cancer with echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements. ALK gene point mutation is the primary mechanism of acquired crizotinib resistance; however, the intrinsic mechanism is not fully understood. Here, we report a patient with a low mutant allele fraction (MAF) of EML4-ALK rearrangement, who experienced primary resistance to crizotinib treatment. The patient was a 66-year-old Chinese man, who had a history of metastatic lung cancer and was treated with first- and third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). After 14 months of osimertinib treatment, his disease progressed, and next-generation sequencing was performed from a liquid biopsy of the patient’s blood. An EML4-ALK rearrangement was found and crizotinib was administered. The patient’s lung lesions continued to progress after one month of crizotinib treatment, and pemetrexed-bevacizumab was initiated. After two cycles of chemotherapy, the metastatic cancers shrunk, and the patient maintained stable disease at his last follow-up. EML4-ALK rearrangements can happen in patients with EGFR-positive NSCLC, after acquired resistance to EGFR TKI treatment. The EGFR T790M and C797G mutations occur in cis is a critical mechanism of resistance to osimertinib therapy. The MAF of EML4-ALK rearrangements in cancer cells might be a predictive factor for crizotinib treatment.

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

“…The study found that patients with BIM with missing polymorphisms had shortened PFS and reduced objective response rate, which was an independent predictor of patients treated with crizotinib and was related to primary drug resistance (97). In addition, the low minimum allele frequency (MAF) of the EML4-ALK rearrangement may also be a mechanism of primary resistance to crizotinib (98).…”

The Value of Liquid Biopsies for Guiding Therapy Decisions in Non-small Cell Lung Cancer

“…In majority of cases, ALK translocations do not overlap with other oncogenic mutations found in NSCLC (e.g., EGFR mutations, KRAS mutations, ROS1 gene translocations) ( 69 – 72 ). However, rearrangement of the ALK gene can present as an acquired mutation to EGFR TKI therapy, these fusion mutations and not only the most common resistance mutation T790M should be assessed during EGFR progression ( 33 ). ALK translocations can be detected via liquid biopsy using numerous next-generation sequencing (NGS) methods and targeted real-time PCR assays; however, these methods are unlikely to detect fusions with novel partners.…”

Clinical Relevance of Targeted Therapy and Immune-Checkpoint Inhibition in Lung Cancer

“…Despite the described benefits, a number of LC patients treated with crizotinib developed resistance or relapsed within the following 12-24 months [80]. The resistance to crizotinib is mediated by the onset of secondary mutations which may occur within the TK domain of the ALK gene [80,81]. Several ALK point mutations have been identified and include L1152R, C1156Y, I1171T, L1196M, G1202R, S1206Y, V1180L, and G1269A [82,83].…”