Early Data Show Promise of CLN-081 in Pretreated EGFR Exon 20 Insertion+ NSCLC

Patients with EGFR exon 20 insertion–positive non–small cell lung cancer may have antitumor response with the selective EGFR inhibitor CLN-081 following multiple prior lines of treatment.

Data from the phase 1/2a CLN-081-001 trial (NCT04036682) demonstrated feasibility of the selective EGFR inhibitor CLN-081 to induce responses in heavily pretreated non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, according to data presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Among the 39 patients who received the agent at 100 mg twice daily, the confirmed partial response (PR) rate was 41%, the median duration of response (DOR) was over 21 months (95% CI, 8-not calculated [NC]), and the median progression-free survival (PFS) was 12 months (95% CI, 5-NC).

In the overall population (n = 73), the agent elicited a confirmed PR rate of 38.4%, with a median DOR of 10 months (95% CI, 6-NC), and a median PFS of 10 months (95% CI, 6-12). In the subset of patients who received CLN-081 at a twice-daily dose of 65 mg or less, the confirmed PR rate was 35%, with a median DOR of greater than 19 months (95% CI, 5-NC) and a median PFS of 8 months (95% CI, 5-13). In the 11 patients who received CLN-081 at a twice-daily dose of 150 mg, the confirmed PR rate was 36.4%, the median DOR was 7 months (95% CI, 4-NC), and the median PFS was 8 months (95% CI, 1-10).

“The safety profile of CLN-081 is amenable for long-term treatment [when given] at doses less than 150 mg twice daily,” Helena Alexandra Yu, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, added in a presentation on the data. “Most adverse effects [AEs] were grade 1 or 2. There was no grade 3 rash or diarrhea at doses less than 150 mg twice daily.”

The novel, irreversible, oral EGFR inhibitor possesses a unique pyrrolopyrimidine scaffold. Preclinical data have showcased that the agent has strong, broad-spectrum activity against EGFR mutations, including EGFR exon 20 insertions. The agent also has selectivity against wild-type EGFR, according to Yu.

CLN-081-001 was a phase 1/2a dose-escalation and -expansion trial. The dose-escalation portion of the research utilized an accelerated titration and rolling-six design, Yu said. Moreover, the phase 1 and 2 dose-expansion cohorts enrolled additional patients at dose levels that met predefined thresholds for efficacy and tolerability.

To be eligible for participation, patients were required to have recurrent or metastatic NSCLC harboring EGFR exon 20 insertion mutations that had be confirmed via local laboratory. Patients must have previously received treatment in the recurrent or metastatic setting, including a platinum-based chemotherapy regimen.

In the dose-escalation cohorts, patients were allowed to have previously received an agent that targeted EGFR exon 20 insertion mutations. Notably, those who had untreated central nervous system (CNS) metastases that had been stable for at least 4 weeks before the first day of the first cycle of treatment were permitted.

Study participants received CLN-081 twice daily, at a dose level starting at 30 mg. Investigators evaluated tumor response at 6 weeks and then every 9 weeks thereafter.

At a data cutoff date of May 9, 2022, 73 patients had been enrolled across doses that ranged from 30 mg twice daily to 150 mg twice daily. However, enrollment to the group evaluating the agent at 150 mg twice daily was closed after 11 patients due to toxicity.

Of these 73 patients, 33% continue to receive CLN-081, and 67% have discontinued treatment. The most common reason for discontinuation was disease progression (61%), followed by toxicity (25%), another unspecified reason (8%), and withdrawn consent (6%).

Yu noted that those enrolled to the trial were heavily pretreated, with 44% of patients having received 2 prior lines of systemic anticancer therapy and 22% having received 3 or more prior lines of treatment. Notably, the median prior lines of therapy received was 2, with a range of 1 to 9 prior regimens received.

Thirty-six percent of patients previously received an EGFR TKI in the form of afatinib (Gilotrif) or gefitinib (Iressa; 18%), or osimertinib (Tagrisso; 18%); 4% of patients previously received poziotinib and/or mobocertinib (Exkivity). Moreover, approximately half of patients (55%) had prior immunotherapy. Notably, 38% of patients had a history of CNS involvement at baseline.

Additional data showed that the median time on study was 11 months, and the median time to response with CLN-081 was 1.5 months.

Yu shared additional data on 3 patients who had CNS target lesions at baseline before study entry. One patient was 69 years of age and had initially presented with early-stage disease; this patient had undergone surgical resection and had received adjuvant chemotherapy. One year later, he experienced CNS recurrence. “A large right frontal lobe lesion was resected and radiated,” Yu said. “A separate asymptomatic cerebellar lesion was growing prior to study entry. By cycle 6, there was a decrease from 19 mm to 10 mm and decreased enhancement.”

The second patient, who has received at least 1 year of treatment and continues to receive the agent, achieved stable disease with CLN-081, both intracranially and systemically. The third patient experienced disease progression at cycle 3.

Most toxicities were grade 1 or 2 in severity, and dose reductions and discontinuations were uncommon at doses below 150 mg. Notably, no grade 3 or higher rash or diarrhea was noted in those who received doses of less than 150 mg. Four patients experienced treatment-emergent pneumonitis; this occurred in 1 patient who received the agent at 65 mg twice daily, 2 patients who received it at 100 mg twice daily, and 1 patient who received it at 150 mg twice daily. Notably, however, these cases were noted to be asymptomatic (n = 1) or cofounded by comorbid medical illness (n = 3).

“Enrollment into the phase 2b portion of the study is planned for the second half of this year and there are prespecified cohorts that plan to enroll patients with active untreated CNS metastases and those who have progressed on prior EGFR exon 20 therapies,” Yu concluded.


Yu HA, Tan DSW, Smit EF, et al. Phase (ph) 1/2a study of CLN-081 in patients (pts) with NSCLC with EGFR exon 20 insertion mutations (ins20). J Clin Oncol. 2022;40(suppl 16):9007. doi:10.1200/JCO.2022.40.16_suppl.9007