Helena Yu, MD, Discusses Early Findings With CLN-081 in Advanced EGFR exon 20 Ins+ NSCLC


Early findings indicate that CLN-081 may hold promise in patients with advanced EGFR exon 20 insertion mutation–positive non–small cell lung cancer.

The EGFR tyrosine kinase inhibitor CLN-081 appeared to be well tolerated and demonstrated promising antitumor activity in a population of heavily pretreated patients with advanced EGFR exon 20 insertion–positive non–small cell lung cancer, according to Helena Yu, MD, who presented findings from a phase 1/2 trial (NCT04036682) at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

In a population of 70 patients, the confirmed partial response (PR) rate was 36%. Moreover, the stable disease rate was 49% and 4% had progressive disease as a best response. Seven patients had an unconfirmed partial response and 1 was pending confirmatory scan. Within the 100 mg dose group, 39% of patients had a confirmed PR, 47% had stable disease, and 3% progressed. Moreover, 3 patients had an unconfirmed PR and 1 patient was pending a confirmatory scan.

CLN-081 was administered at several dose levels including 30 mg (n = 8), 65 mg (n =14), 100 mg (n = 39), and 150 mg (n = 11). Common any-grade treatment-related adverse effects (AEs) included rash (74%), diarrhea (27%), paronychia (25%), fatigue (19%), anemia (18%), dry skin (18%), and nausea (16%). Grade 3 or higher AEs included anemia (10%), alanine transaminase increase (4%), and aspartate aminotransferase increase (4%).

In an interview with CancerNetwork®, Yu, a medical oncologist and associate attending physician at Memorial Sloan Kettering Cancer Center, highlighted the rationale for assessing CLN-081 and future questions that need to be answered for the successful treatment of patients with EGFR exon 20 insertion mutation–positive NSCLC.

CancerNetwork®: Could you tell me a little bit about the mechanism of action for CLN-081? What were the goals of assessing it in NSCLC?

Yu: CLN-081 is a tyrosine kinase inhibitor that targets EGFR mutations that are common in non–small cell lung cancer. Compared with some of the other in class agents, it specifically targets EGFR exon 20 insertions. We are in the midst of completing the phase 1/2 study of this [agent]. This is the first study assessing this drug in humans. At 2022 ASCO, we presented a cohort of 73 patients who were treated in the phase 1 study. We were looking specifically at what the right dose level would be, so we evaluated escalating dose levels of CLN-081 and looked at toxicity. Then, of course, [we looked at] efficacy with a primary end point of objective response.

Did anything stand out regarding safety?

Thankfully, no. We at MSK have treated a lot of these patients. I’ve mostly been struck with how well tolerated the agent is. We’re seeing fewer adverse effects associated with EGFR wild-type [disease] like rash and diarrhea that affect some of the other drugs in class. And really no sort of standout or kind of unexpected toxicities.

Where do you see future research being focused?

There are 2 approved EGFR exon 20–targeted drugs that do have good efficacy, but they have some toxicity limitations. One of the things that we’ll need to look at is the toxicity profile. Patients are thankfully on these drugs for a long time. If drugs are otherwise equal, finding one that has less impact on patients’ quality of life is important. Another distinguishing factor is going to be central nervous system penetration. About half of patients with EGFR exon 20 insertion mutations will ultimately develop brain metastases. If we can find [a new drug] or if one of these [existing] drugs in class happens to have better CNS penetration, that may be a distinguishing factor that will have more providers use that drug.

The other interesting question is sequencing. For a lot of our other targeted therapies, we use targeted therapy in the first-line setting. But the initial approvals for these drugs were [for use] after chemotherapy. [This begs the question], can we move this up to the first-line setting and use it as first treatment for metastatic cancer? Then second question is, because the mechanism of action is a little bit different—one of the approved drugs is an antibody and the other one is a tyrosine kinase inhibitor—can we sequence these different treatments and can they be effective after each other? Those are the remaining questions.

What do you hope that your colleagues took away from your presentation?

EGFR exon 20 insertion–positive lung cancer is common. It represents an unmet need because we need to find things that are both effective and not so toxic. The preliminary data that we presented at ASCO this year did show good efficacy and reasonable toxicity. It is something that I would hope people look out for in the future.


Yu HA, Shao-Weng Tan W, 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

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