CLN-081 Shows Selective Activity in NSCLC With EGFR Exon 20 Insertions

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CLN-081, a novel agent targeted to non–small cell lung cancer (NSCLC) cells harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations—ie, the addition of nucleotide base pairs in exon 20 of the EGFR gene, a known oncogenic driver event—holds promise, according to the results of a phase I/IIa study presented at the 2022 ASCO Annual Meeting by lead author Helena Yu, MD, of Memorial Sloan Kettering Cancer Center.1 The preliminary data suggest the experimental agent appears to be just as effective as two relatively new competitive agents— amivantamab-­vmjw and mobocertinib­—but with greater selectivity and fewer toxicities.

Helena Yu, MD

Helena Yu, MD

Study Background

CLN-081 is an irreversible, oral EGFR inhibitor with a unique structure and broad-spectrum activity against EGFR mutations, including exon 20 insertion mutations, which are associated with resistance to other EGFR inhibitors. This agent is selective for the inhibition of exon 20 insertion vs wild-type EGFR. It has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration.

“CLN-081 appears to be more EGFR exon 20 insertion mutation–specific, with fewer wild-type EGFR–associated toxicities and what seems to be comparable efficacy. Rash, diarrhea, mucositis, and gastrointestinal upset are less commonly seen with CLN-081,” said Dr. Yu. “These data demonstrate the potential for improvement upon the standard of care with an effective and [apparently] less toxic therapy to treat NSCLC with exon 20 insertion mutations.” 

An estimated 7% to 10% of EGFR-positive NSCLC—and an estimated 2% to 3% of all patients with NSCLC—harbor exon 20 insertion mutations, which is a higher frequency than RET, ROS1, and NTRK fusions. Patients with exon 20 insertions have poorer outcomes than are seen with the more common NSCLC mutations, especially those sensitive to targeted therapies aimed at the individual mutations. 

Methodology and Key Findings

The phase I/IIa study was a safety and dose-escalation study of CLN-081 in patients with recurrent or metastatic NSCLC and documented EGFR exon 20 insertion mutations, according to local laboratory testing. Patients received one of four different doses of CLN-081, ranging from 30 mg to 150 mg, all given twice daily, and treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Seven patients were treated in the phase I dose-expansion phase, with either 100 mg or 65 mg twice daily. In phase IIa, the dose carried forward was 100 mg twice daily. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors, version 1.1. 

A total of 73 patients were enrolled in the trial. In 24 patients (33%), treatment was ongoing at the time of Dr. Yu’s presentation. A total of 49 patients (67%) had discontinued treatment, 30 of them (61%) for progressive disease and 12 (25%) for adverse events. 

“These patients were heavily pretreated. Two-thirds had received two or more prior lines of treatment,” she said. About 36% had prior EGFR tyrosine kinase inhibitor treatment, 55% had prior immunotherapy, and 38% had a history of central nervous system (CNS) metastasis at baseline.

Most adverse events were grades 1 and 2. Dose reductions and discontinuations were rare at doses below 150 mg, and no grade 3 or higher instances of rash or diarrhea were seen at those lower doses. Treatment-related pneumonitis occurred in four patients, but all were asymptomatic (n = 1) or comorbidity-related (n = 3).

The confirmed overall response rate was 38.4% in all 73 patients; the best overall response rate (41%) was observed at the 100-mg dose. At that dose, the clinical benefit rate was 97.4% (ie, partial response and stable disease combined), median duration of response was longer than 21 months, and median progression-free survival was 12 months. The median time on study was 11 months, and the median time to response was 1.5 months.

Although the numbers were small, there was a suggestion that CLN-081 might be active in treating CNS metastasis. Among three patients with CNS lesions at baseline, one achieved a partial response and remains in response at cycle 16, one is continuing treatment with stable intracranial and systemic disease, and one has had disease progression in the brain at cycle 3.

“CLN-081 may have better CNS penetration [than the other two currently approved drugs in this setting], but more research is needed to assess this,” Dr. Yu noted. “Enrollment in phase IIb is planned for later in 2022. A dedicated study in patients with CNS metastasis is planned,” she added. 

Expert Point of View

Commenting on this early study of CLN-081, Rami Manochakian, MD, Associate Professor and Consultant in Thoracic Oncology at Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, commended the investigators and said the preliminary data are encouraging.

“This was a well-designed and well-run phase I/IIa trial,” he noted. “There are two approved drugs for non–small cell lung cancer harboring [epidermal growth factor receptor exon 20 insertion mutations]. While we cannot compare this trial with the trials of the other two drugs directly, the efficacy of CLN-081 seems fairly close to the two approved drugs. It seems the optimal dose of CLN-081 is 100 mg twice daily, which was associated with a longer duration of response and a higher median progression-free survival rate compared with data for the other two drugs. Overall, the toxicity seems acceptable, and there was no grade 3 diarrhea, which is seen with the other two drugs,” Dr. Manochakian said.

“A major question is whether CLN-081 will have central nervous system (CNS) activity. There are plans for an expansion trial in patients with active CNS metastases and in patients whose cancer has progressed on another exon 20 insertion–targeted agent. We will have to see what further studies show,” he added. “Without being definitive—things can change—CLN-081 looks like a promising option, especially at the dose of 100 mg twice daily.”

DISCLOSURE: Dr. Yu has served as a consultant or advisor to AstraZeneca, Black Diamond Therapeutics, Blueprint Medicines, C4 Therapeutics, Cullinan Oncology, Daiichi Sankyo, and Janssen; has received institutional research funding from Astellas Pharma, AstraZeneca, Blueprint Medicines, Cullinan Oncology, Daiichi Sankyo, Erasca, Janssen Oncology, Lilly, Novartis, and Pfizer; and has been reimbursed for travel, accommodations or other expenses from Lilly. Dr. Manochakian has served as an advisor or consultant to AstraZeneca, Guardant Health, Novocure, Turning Points Therapeutics, Janssen, and Takeda.


1. Yu H, Shao-Weng D, Smith EF, et al: Phase 1/2a study of CLN-081 in NSCLC patients with EGFR 20 insertion mutations. 2022 ASCO Annual Meeting. Abstract 9007. Presented June 3, 2022.