CLN-081 Granted FDA Breakthrough Therapy Designation Status for EGFR-Mutated NSCLC

The FDA has granted breakthrough therapy designation to CLN-081 for the treatment of patients with locally advanced or metastatic non–small cell lung cancer harboring EGFR exon 20 insertion mutations and who have received prior platinum-based chemotherapy.

The FDA has granted breakthrough therapy designation to CLN-081 (TAS6417) for the treatment of patients with locally advanced or metastatic non–small cell lung cancer harboring EGFR exon 20 insertion mutations and who have received prior platinum-based chemotherapy.1

The novel, oral EGFR inhibitor was designed to have a unique pyrrolopyrimidine scaffold and strong broad-spectrum activity against EGFR mutations, including EGFR exon 20 insertion mutations.2

CLN-081 has been shown to have improved selectivity for the inhibition of EGFR exon 20 insertion mutations compared with EGFR wild-type, which suggests that the agent may have a better safety and risk-benefit profile vs other existing EGFR TKIs in patients with NSCLC. It is known that the product has limited activity against wild-type and exon 20–mutant HER2.

“We are extremely pleased that Cullinan has received breakthrough therapy designation from the FDA for CLN-081, a distinction that underscores the urgent need to bring improved targeted treatments to this patient population and further supports the differentiated clinical profile of CLN-081,” Nadim Ahmed, chief executive officer of Cullinan Oncology, stated in a press release.

Data from a first-in-human phase 1/2a trial (NCT04036682) of CLN-081 were shared during the 2021 ASCO Annual Meeting, and the agent was found to produce high rates of response and encouraging disease control with an acceptable toxicity profile, including reduced frequency and severity of diarrhea vs other EGFR inhibitors in patients with NSCLC harboring EGFR exon 20 insertion mutations.

The trial enrolled patients with EGFR exon 20 insertion–mutated NSCLC who previously received treatment with platinum-based therapy. In the dose-escalation portion of the trial, participants received CLN-081 at any of the following twice-daily dose levels in 21-day treatment cycles: 30 mg, 45 mg, 65 mg, 100 mg, and 150 mg.

In efficacy expansion sets, investigators examined the agent at twice-daily dose levels of 30 mg, 65 mg, and 100 mg. The phase 2 expansion portion of the research was initiated at a twice-daily 100-mg dose after protocol-specified safety and efficacy criteria were met.

At the time of an April 1, 2021 data cutoff, a total of 45 patients were administered at least 1 dose of CLN-081; 42 of these patients were determined to be evaluable. One patient discontinued treatment prior to their first post-baseline assessment, and 2 had not been restaged at the time of the cutoff.

The median age among 44 patients was 64 years (range, 44-82), 51% were female, and 56% were White. Moreover, 66% of patients had an ECOG performance status of 1 and 27% had stable asymptomatic brain metastases at baseline.

The median number of prior systemic therapies received was 2 (range, 1-9), with 27% of patients having received 1 prior therapy, 39% having received 2 prior lines, and 34% having received 3 or more prior lines. Eighteen percent of patients previously received afatinib (Gilotrif) or gefitinib (Iressa), 20% had prior osimertinib (Tagrisso), 9% had prior poziotinib and/or mobocertinib (Exkivity), and 56% previously received immunotherapy.

CLN-081 was found to have activity across all dose levels examined, as well as across a spectrum of EGFRexon 20 insertion mutations. Fifty-two percent of evaluable patients spanning dose levels remained on treatment at data cutoff. Notably, responses were achieved by 44% of those who previously received EGFR TKIs; this included those who previously received mobocertinib and/or poziotinib.

Additionally, 50% of evaluable patients (n = 21/42) were noted to have responded to treatment with CLN-081 across all dose levels. Of these responders, 31% experienced a confirmed objective response. Eight patients experienced unconfirmed objective responses.

When the agent was administered at a twice-daily dose of 100 mg, 54% of patients (n = 7/13) achieved a partial response (PR); this included 6 patients who had a confirmed PR and 1 patient with an unconfirmed PR.

Ninety-eight percent of the 42 patients had stable disease or PR as their best response to treatment. Moreover, the disease control rate reported with the agent was 64% spanning dose levels.

Notably, the agent was found to have rapid activity, with 76% (n = 32/42) of patients experiencing tumor regression at the time of their first post-baseline assessment. Patients experienced rapid symptom improvement in terms of dyspnea, shortness of breath, and cough.

Regarding safety, 98% of 45 patients reported an adverse effect (AE) with the agent; 44% experienced a toxicity that was grade 3 or higher in severity. The most frequently reported toxicities with CLN-081 included rash, anemia, and diarrhea.

Moreover, 98% of the 45 patients reported an AE that was related to study treatment, which included 18% of patients who had a grade 3 or higher event. TRAEs reported in 15% or more patients included rash (76%), diarrhea (22%), paronychia (22%), stomatitis (18%), nausea (18%), anemia (18%), increased aspartate aminotransferase (AST; 16%), and dry skin (16%).

Grade 3 or higher TRAEs reported in all patients included anemia (9%), increased AST (4%), increased alanine aminotransferase (4%), diarrhea (2%), increased amylase (2%), neutropenia (2%), and stomatitis (2%).

Only 1 patient experienced a dose-limiting toxicity in the form of grade 3 diarrhea; this patient had received CLN-081 at a twice-daily dose of 150 mg. Eleven percent of patients required dose reductions and 9% of patients discontinued treatment because of treatment-related toxicity.

The phase 2 expansion cohort of the trial is currently enrolling, and patients will receive the agent at a twice-daily dose of 100 mg.

“The updated data from our ongoing phase 1/2a study in a larger number of patients have demonstrated a high response rate with durable responses and encouraging PFS in heavily pretreated patients,” Ahmed added. “We are also encouraged by the favorable safety profile observed thus far, and we look forward to ongoing, productive regulatory discussions with the FDA, which are further enabled with this designation.”


  1. 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.
  2. 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.