First-in-Human Trial of CLN-081 in EGFR ex 20+ NSCLC Shows Early Promise


A phase 1 trial of the investigational agent CLN-081 indicates antitumor activity coupled with a tolerable safety profile as treatment of patients with non–small cell lung cancer and EGFR exon 20 insertion mutations.

Systemic therapy with CLN-081 for EGFR exon 20 insertion mutation–positive non–small cell lung cancer (NSCLC) showed early signs of efficacy and safety across a number of different dose levels tested, according to results from a phase 1 trial (TAS6417; NCT04036682) reported at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

These interim data of CLN-081 in this first-in-human trial show the results of dose escalation at 30, 45, 65, 100, and 150 mg twice daily. Doses of 30, 65, and 100 mg twice daily were initiated for efficacy expansion.

EGFR exon 20 insertions are the third most common subtype of EGFR mutations seen in NSCLC and have historically been resistant to first- and second-generation EGFR inhibitors,” Zofia Piotrowska, MD, an instructor at Harvard Medical School, said in her presentation. “Recently, novel targeted therapies have been developed to target these mutations, but they been associated with high rates of toxicities related to inhibition of wild-type EGFR, including rash and diarrhea….CLN-081 is an oral EGFR inhibitor with high selectivity for EGFR exon 20 insertion mutant versus wild-type EGFR in preclinical models.”

At baseline, 6 weeks after CLN-081 administration, and every 9 weeks following, tumor assessments were performed in these patients with a data cutoff of April 1, 2021. Forty-five patients received at least 1 dose of CLN-081 and 42 of these patients were evaluable for response.

For the primary safety end points, 44 of the 45 patients (98%) experienced an adverse event (AE) of any grade and 20 patients (44%) had grade 3 or more. No patients required prophylaxis for gastrointestinal or skin-related toxicity. “We saw that CLN-081 has a favorable safety profile with low-grade rash as the most common toxicity. Diarrhea was uncommon and all AEs were manageable and reversible to date,” Piotrowska said.

Any grade treatment-related AEs (TRAEs) occurred in 98% of patients, and 8 patients (18%) had grade 3 or more. The most common any-grade TRAEs observed in the 45 patients were rash at 76%, diarrhea and paronychia both at 22%, and stomatitis, nausea, and anemia all at 18%. Grade 3 or more TRAEs included anemia at 9%, increased alanine aminotransferase and aspartate aminotransferase both at 4%, and diarrhea, increased amylase, neutropenia, and stomatitis at 2%. Discontinuations due to TRAEs were needed in 4 patients (9%). Dose reductions were needed in 5 patients (11%).

No patients with wild-type EGFR associated TRAEs had grade 3 or more rash. One patient experienced grade 3 treatment-related diarrhea while receiving 150 mg of CLN-081. Due to treatment-related grade 2 pneumonitis, 1 patient discontinued treatment; this patient also had pneumonitis when receiving prior osimertinib (Tagrisso).

Of the 42 response evaluable patients, 21 had a partial response (PR) while receiving CLN-081; 13 had confirmed PR and 8 had unconfirmed PR, 5 of which were pending confirmation at the time of data cutoff according to Piotrowska. Twenty patients had stable disease and only 1 had progressive disease. Altogether, there was a disease control rate of 64% across all dose levels. There were 22 patients (52%) remaining on treatment at the time of data cutoff among all of the dose levels.

In the phase 2 expansion cohort investigating CLN-081 at 100 mg twice daily, which is currently enrolling patients, 7 of the 13 patients (54%) achieved a PR, 6 of which were confirmed and 1 unconfirmed.

Overall, there was some degree of tumor regression in 76% of patients at the 6-week response assessment after baseline evaluation. Patients reported rapid symptom improvement of dyspnea, shortness of breath, and cough, anecdotally.

In the 44 patients reported baseline data, the median number of prior systemic treatments was 2 (range, 1-9), with 12 patients having received 1 prior therapy, 17 patients with 2, and 15 patients with 3 or more prior therapies. Eight patients had prior afatinib (Gilotrif) or gefitnib (Iressa), 9 had prior osimertinib, 4 had prior poziotinib and/or mobocertinib, and 25 had prior immunotherapy.

The median age was 64 years (range, 44-82). There were 20 male patients, 22 female, and 1 patient whose gender was not reported. There were 24 White patients, 15 Asian patients, 2 Black patients, and 2 with race not reported. The ECOG performance status was 0 in 15 patients and 1 in 29 patients. Twelve patients had stable, asymptomatic brain metastases at baseline.

“CLN-081 shows encouraging preliminary anti-tumor activity in this heavily pretreated patient population across the range of dose levels tested to date and across the spectrum of EGFR exon 20 insertions, including patients who had progressed on other EGFR inhibitors. Enrollment to the study is ongoing, [with a phase 2 expansion initiated at 100 mg twice daily],” Piotrowska concluded.


Piotrowska Z, Yu HA, Yang JC-H, et al. Safety and activity of CLN-081 (TAS6417) in NSCLC with EGFR exon 20 insertion mutations (Ins20). Presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021; Virtual. Abstract 9077.

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