Targeting exon 20 insertion mutations in lung cancer

Abstract

Purpose of reviewThe application of tyrosine kinase inhibitor (TKI) has successfully changed the standard of care in epidermal growth factor receptor (EGFR) positive non-small cell lung cancer. However, clinical survivals for patients with EGFR exon 20 insertions have failed to improve over the long period and the mutation appeared resistant to EGFR-TKIs. This overview focused on the current treatment strategies, summarized the emerging regimens for patients with EGFR exon 20 insertions, and demonstrated historical challenges and future development.Recent findingCurrent clinical trials suggested that several regimens selectively-targeted EGFR exon 20 insertions presented potent antitumor activity, like mobocertinib and the bispecific anti-EGFR-MET monoclonal antibody amivantamab and were approved by Food and Drug Administration (FDA) in patients progressed beyond first-line treatment. Novel treatments, including DZD9008, CLN-081, revealed modest clinical efficacy as well and clinical trials are underway, which may lead to improvement of survival outcomes.SummaryRecent clinical evidence indicates that targeted therapies could improve survival benefits to some extent. More efforts on drug development are underway to bring higher response rates both extracranial and intracranial, sustained clinical remission, and better survival benefits.

Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations

“…The study of DZD9008 by Yang et al. ( 82 , 83 ) demonstrated that NSCLC patients with EGFR ex20ins had an ORR of > 40%, and the ORR for intravenous amivantamab (JNJ) was > 40%. The study also revealed that the ORR of EGFR ex20ins NSCLC patients treated with 300 mg QD of DZD9008 was 41.9%, whereas those treated with 200 mg QD of DZD9008 had an ORR of 45.9%.…”

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

“…In the follow-up, the company still needs to complete the communication with CDE, submit the new drug marketing application, complete the technical review, on-site verification and other procedures. 167 , 168 …”

“…In the follow-up, the company still needs to complete the communication with CDE, submit the new drug marketing application, complete the technical review, on-site verification and other procedures. 167,168 Rezivertinib (BPI-7711) ( 58) is an orally effective, highly selective and irreversible third-generation EGFR TKI. Rezivertinib shows highly selective inhibitory effects on EGFR Del E746-A750 , EGFR T790M , EGFR L858R/T790M double mutations, including EGFR single mutations, but shows a weak inhibitory effect on WT-EGFR.…”

“…Thus, stabilizing the Max-Max homodimer can prevent Myc-Max transactivation of target genes. 422 To this end, several active small molecules have been identified as promising Max-Max homodimer stabilizers, including NSC13728 (167) and KI-MS2-008 (169). In 2009, Jiang et al reported the development of NSC13728, a symmetrical small molecule that stably inhibits c-Myc-regulated oncogenic transformation, cell growth, and target gene transcription through the stabilization of Max-Max homodimers.…”

A study of high dose furmonertinib in EGFR exon 20 insertion mutation-positive advanced non-small cell lung cancer

“…Among rare mutations, EGFR ex20ins mutation is the most common. The incidence of EGFR ex20ins in EGFR mutated NSCLC patients is 4% -12%, while in NSCLC patients, the incidence is 1.8% -2.3% ( 3 ).…”