NSCLC with EGFR exon 20 insertion mutations

NSCLC with EGFR exon 20 insertion mutations

Phase I/IIa study of CLN-081 in patients with NSCLC with EGFR exon 20 insertion mutations demonstrating the therapeutic potential (Abstract # 9007)

CLN-081 is an orally administered, irreversible EGFR inhibitor that selectively targets cells exhibiting exon 20 insertion mutations of the epidermal growth factor (EGFR) while protecting cells expressing wild-type EGFR. CLN-081 was given Breakthrough Therapy Designation by the US Food and Drug Administration (FDA) in January 2022 for the treatment of patients with locally advanced or metastatic NSCLC who have EGFR exon 20 insertion mutations and have previously received platinum-based systemic chemotherapy. The company presented findings from their ongoing Phase I/IIa (NCT04036682) open-label, multi-center study. At the cutoff date of May 2022, 73 patients have been treated across doses ranging from 30 to 150 mg twice daily (BID).

The median progression-free survival (PFS) was 12 months in this subgroup. CLN-081 had a confirmed partial response (PR) rate of 38.4%, with a median duration of response (DOR) of 10 months, among a total of 73 patients.

  • The findings revealed a confirmed PR rate of 41% (n= 16), with a median DOR of more than 21 months, among the 39 patients who received the drug at a dose of 100 mg twice daily. The median PFS in this subgroup was 10 months.
  • Furthermore, the confirmed PR rate in patients who received CLN-081 at a 65 mg or less twice-daily dosage was 35%, with a median DOR of more than 19 months and a median PFS of 8 months.
  • The confirmed PR rate was 36.4% in the 11 patients who received CLN-081 at a twice-daily dosage of 150 mg, the median DOR was 7 months, and the median PFS was 8 months.

CLN-081 seems to have a favorable safety profile for long-term treatment at doses less than 150 mg twice a day.

“We believe CLN-081 has the potential to be a best-in-class treatment option for patients with NSCLC whose tumors harbor EGFR exon 20 insertion mutations with persisting unmet need. With an established high response rate and favorable safety and tolerability profile, we are encouraged to now see an updated durability of response profile that continues to improve”–Expert Opinion.

“We do have approved agents here (amivantamab, mobocertinib) but certainly room for more”-–Expert Opinion.


EGFR Ex20ins mutations are among the most prevalent subtypes of EGFR mutations, accounting for approximately 10% of EGFR-NSCLC. EGFR ins20-mutant NSCLC has historically been challenging to treat. Previously, there were few advances in the EGFR ins20 NSCLC space, but the approval of amivantamab-vmjw (Rybrevant, Janssen Biotech) has changed the narrative. However, numerous challenges remain, such as understanding the biology of individual EGFR ins20 variations and the causes of resistance to each of the various medicines being developed. With the development of several novel targeted medicines for this patient population, the complexity of clinical decision-making over choosing the appropriate therapy at the right time for these patients will continue to rise. CLN-081 is a new EGFR tyrosine kinase inhibitor that the FDA has designated as a Breakthrough Therapy for treating patients with EGFR ins20 NSCLC. Recent findings indicate the possibility that this drug can change the standard of care for EGFR ins20 NSCLC.