Case Report: Outcome of Osimertinib Treatment in Lung Adenocarcinoma Patients With Acquired KRAS Mutations

Abstract

BackgroundOsimertinib belongs to the third-generation epidermal growth factor receptor tyrosine kinase inhibitor that has shown positive effects in treating lung adenocarcinoma cancer. However, the subsequent resistance to Osimertinib has become a clinical challenge.Case PresentationWe present two lung adenocarcinoma cases that developed a resistance to Osimertinib. Among them, one patient attained both KRAS exon 2 and exon 3 mutations and was given paclitaxel (albumin-bound) plus carboplatin. The other patient exhibited a KRAS exon 3 mutation, so the paclitaxel (albumin-bound) plus nivolumab was administered. Eventually, the second patient manifested a better clinical outcome than the first.ConclusionThese results provide supporting evidence that KRAS exon 3 (R68S) mutations may be associated with Osimertinib resistance in lung adenocarcinoma patients. This further reveals the relationship between subtypes of acquired KRAS mutations and the effect of therapeutic approaches. Moreover, the combination of chemotherapy and immune checkpoint inhibitors may generate a satisfying disease control.

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

“…Xiu et al reported a patient with re-biopsy of KRAS G12D and Q61H on osimertinib progression failed to benefit from paclitaxel with carboplatin. In addition, another patient with acquired KRAS R68S responded to nivolumab with chemotherapy [108]. The standard treatment of acquired KRAS mutation after osimertinib still needs more clinical trials to explore.…”

Receptor tyrosine kinase inhibitors in cancer

“…In addition, acquired resistance to both irreversible and reversible EGFR-TKIs, including osimertinib and ge tinib, has been reported in NSCLC and lung adenocarcinoma due to EGFR-dependent and EGFRindependent mechanisms. These include mutations in the EGFR kinase domain duplication (EGFR-KDD) (102) or in the EGFR gene (103), mutations in KRAS exon 3 (R68S) (104), and the involvement of hsa_circ_0005576 via miR-512-5p/IGF1R signaling (105). Acquired drug resistance in EGFR-mutant NSCLC patients is a common reason for the limited long-term e cacy of targeted therapy (106).…”

Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives

“…However, few EGFR-TKI is effective in treating KRAS-mutant NSCLC due to the special resistance ( Pao et al, 2004 ; Kobayashi et al, 2005 ; Linardou et al, 2008 ; Mao et al, 2010 ). In the case reports written by Dr. Xiu’s team, KRAS G12S -mutant NSCLC patients treated with the third-generation EGFR-TKI osimertinib experienced rapid disease progression instead ( Xiu et al, 2021 ). Fortunately, combination treatment with EGFR-TKI and other inhibitors has been found to effectively treat KRAS-mutant NSCLC, as shown in the section below.…”