Combination of Osimertinib and Anlotinib May Overcome the Resistance Mediated by in cis EGFR T790M-C797S in NSCLC: A Case Report

Abstract

The emergence of epidermal growth factor receptor ( EGFR ) exon 20 p.C797S is one of the major resistance mechanisms for osimertinib. However, there are no standard of care for non-small cell lung cancer (NSCLC) patients after acquiring EGFR C797S currently, which brings significant challenges to post-osimertinib clinical management. In the present study, we described a 52-year-old female patient with EGFR -mutated stage IV lung adenocarcinoma, who achieved a partial response (PR) to the treatment of gefitinib and osimertinib after acquiring EGFR exon 20 p.T790M-trans-C797S at osimertinib failure. After progression on the combinatorial treatment, allelic configuration shifted to T790M-cis-C797S. The patient subsequently received a regimen of osimertinib and anlotinib combined with chemotherapy, followed by osimertinib and anlotinib maintenance treatment, and achieved a PR lasting for 9 months. At disease progression, concomitant T790M-C797S mutations both in trans and cis were identified. A combination of chemo- and anti-angiogenic therapies was administrated for two cycles and then discontinued because of the poor physical condition of the patient. She passed away soon with an overall survival of 39 months and a post-osimertinib progression survival of 20 months. Our study provides the first clinical evidence that the osimertinib and anlotinib-based regimen may be an effective therapy in overcoming resistance mediated by T790M-cis-C797S. Our case also highlights the importance of dynamically monitoring the mutation status after osimertinib failure, which may provide patients with increased opportunities for targeted therapy and improve post-osimertinib progression survivals.

Clinical outcomes and safety of osimertinib plus anlotinib for patients with previously treated EGFR T790M‐positive NSCLC: A retrospective study

“…The conclusion indicated that apatinib plus osimertinib might play a synergistic action and improved the clinical outcomes for patients with osimertinib refractory EGFR‐positive NSCLC. Besides, a recent study initiated by Zhou and colleagues reported one patient with cis EGFR T790M‐C797S NSCLC 26 . After the failure of osimertinib therapy, this patient was treated with the combination of anlotinib plus osimertinib as maintenance therapy and achieved PR response of 9 months, which suggested that anlotinib plus osimertinib administration might overcome osimertinib resistance and improve PFS for the patients.…”

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

“…2). Infrequent cases showed triple mutation with C797S in cis may benefit from the combination of osimertinib and anlotinib, the combination of afatinib and apatinib [79,80].…”

Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance

“…Osimertinib plus anlotinib or afatinib plus apatinib achieved a partial response of 9 months and a PFS of more than 10 months in two case reports, respectively. These suggest that combination of EGFR inhibitors and VEGFR inhibitors is a promising therapy for EGFRmutated NSCLC patients with T790M in cis with C797S [116,117]. Recently, an immune checkpoint inhibitor (ICI) combined with platinum-based doublet chemotherapy also exhibited efficacy against T790M-cis-C797S, with a PFS of 8 months, which should be further evaluated in clinical trials [118].…”