CLN-081 Continues to Elicit Encouraging, Durable Responses in EGFR Exon 20 Insertion+ NSCLC


CLN-081 continued to produce encouraging, durable responses with favorable safety and tolerability in patients with non–small cell lung cancer whose tumors harbor EGFR exon 20 insertion mutations and who have progressed on or after prior therapy.

lung cancer

CLN-081 (TAS6417) continued to produce encouraging, durable responses with favorable safety and tolerability in patients with non–small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 20 insertion mutations and who have progressed on or after prior therapy, according to updated data from a phase 1/2a trial (NCT04036682).1,2

Results indicated that the best response to treatment with CLN-081 in the overall population (n = 70) was a confirmed partial response (PR) in 36% of patients, an unconfirmed PR in 10% of patients, and stable disease in 49% of patients. Four percent of patients experienced disease progression.

Among the 36 evaluable patients who received CLN-081 at the recommended phase 2 dose (RP2D) of 100 mg twice daily, 39% achieved a confirmed PR and 1 additional patient (3%) had a PR that was pending confirmation at the time of data cutoff, which was December 1, 2021. Moreover, 8% of patients experienced an unconfirmed PR, 47% had stable disease, and 3% had progressive disease.

In the cohort of 11 patients who received CLN-081 at a twice-daily dose of 150 mg, the confirmed PR rate was 27%, the unconfirmed PR rate was 18%, the stable disease rate was 45%, and 9% of patients experienced disease progression.

“The updated data from our ongoing phase 1/2a study in a larger number of patients further reinforce CLN-081’s differentiated clinical profile. CLN-081 has demonstrated both a high response rate and durable responses in heavily pre-treated patients,” Nadim Ahmed, chief executive officer of Cullinan Oncology, stated in the press release. “For many [patients with] lung cancer currently receiving EGFR inhibitors, treatment-related adverse effects [AEs] can significantly impact their daily lives. In this regard, we are encouraged by CLN-081's favorable safety profile at the 100-mg, twice-daily dose.”

The open-label, multicenter, first-in-human trial enrolled patients with histologically or cytologically confirmed, recurrent, metastatic NSCLC who had documented EGFR exon 20 insertion mutation positivity. In the dose-escalation portion of the trial, participants received CLN-081 at any of the following twice-daily dose levels as part of 21-day cycles: 30 mg, 45 mg, 65 mg, 100 mg, and 150 mg.

In expansion sets, investigators evaluated the drug at the following twice-daily dose levels: 65 mg (n = 7), 100 mg (n = 6), and 150 mg (n = 4).

Among all 73 patients enrolled to the trial, the median age was 64 years (range, 36-82). Thirty-eight percent of patients had brain metastases at baseline. Notably, the population was heavily pretreated, with 30% of patients having received 1 prior systemic anticancer regimen, 44% having received 2 prior lines, and 22% having received 3 or more prior lines. The median number of prior lines of treatment was 2 (range, 0-9).

Regarding prior treatment, 37% of patients received a prior EGFR TKI (non–exon 20), 5% received poziotinib and/or mobocertinib (Exkivity), and 53% received checkpoint inhibitor therapy.

Prior data from the trial showed that CLN-081 elicited a response in 50% of evaluable patients (n = 21/42) across all dose levels evaluated. Among these responders, 31% of patients achieved a confirmed objective response and 8 patients had unconfirmed responses.3

Updated data showed that the responses achieved by patients who received the agent at the twice-daily, 100-mg dose were durable and extended stable disease was observed. Moreover, antitumor activity was noted across the spectrum of EGFR exon 20 insertion mutational subtypes.

Tumor regression was reported in 92% of patients (n = 33/36). The agent was also found to act rapidly, with regression experienced by 86% of patients at the time of the first assessment. Notably, patients who previously received EGFR TKIs or checkpoint inhibitors still responded to CLN-081.

In the initial cohort of phase 1 patients (n = 13), the median duration of response with the agent was longer than 15 months, the median progression-free survival was 12 months, and the disease control rate (DCR) was 92%. In 4 patients who had central nervous system (CNS) disease history at baseline, the DCR was 100%; this rate was 89% in those without this history (n = 9).

The RP2D continued to demonstrate a favorable safety and tolerability profile. The most commonly reported treatment-related AEs of interest included skin rash (grade 1, 54%; grade 2, 18%), diarrhea (grade 1, 26%; grade 2, 8%), elevated alanine/aspartate aminotransferase (grade 1, 5%; grade 2, 5%; grade 3, 5%), and anemia (grade 1, 8%; grade 2, 3%; grade 3, 3%). Thirteen percent of these patients required a dose reduction and 3% discontinued treatment.

“We are pleased with CLN-081's safety and efficacy to date. CLN-081 has demonstrated antitumor activity among heavily pre-treated patients, including patients treated previously with other EGFR inhibitors or immunotherapy, and across a spectrum of exon 20 mutational sub-types,” Jon Wigginton, MD, chairman of the scientific advisory board and senior advisor at Cullinan Oncology, added in the release. “We are similarly encouraged by the emerging durability data shown in this update, which we believe could also reflect the benefit of the drug’s favorable safety and tolerability profile. Our goal now is to review these results and potential future clinical development with the FDA and to move CLN-081 as expeditiously as possible into late-stage development.”

On January 4, 2022, the FDA granted breakthrough therapy designation to CLN-081 for the treatment of locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations and who have received prior platinum-based chemotherapy.4


  1. Cullinan oncology announces updated phase 1/2a data for CLN-081 in NSCLC EGFR exon 20 patients. News release. Cullinan Oncology; December 16, 2021. Accessed December 17, 2021.
  2. Mining for tomorrow’s cures: CLN-081 clinical update. News release. Cullinan Oncology; December 16, 2021. Accessed December 17, 2021.
  3. 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). J Clin Oncol. 2021;39(suppl 15):9077. doi:10.1200/JCO.2021.39.15_suppl.9077
  4. FDA grants breakthrough therapy designation for Cullinan Oncology’s CLN-081 in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer. News release. Cullinan Oncology, Inc.; January 4, 2022. Accessed January 4, 2022.
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