Robust Antitumor Activity Observed in Advanced RET Fusion+ NSCLC With Selpercatinib

Durable efficacy and a manageable safety profile were observed with selpercatinib for Chinese patients with advanced, RET fusion–positive non–small cell lung cancer.

Durable efficacy and a manageable safety profile were observed with selpercatinib (Retevmo) for Chinese patients with advanced, RET fusion–positive non–small cell lung cancer (NSCLC), according to results from the phase 2 LIBRETTO-321 trial (NCT04280081) presented during the 2021 World Conference on Lung Cancer.

Among a subset of patients with central lab–confirmed RET-fusion status (PAS; n = 26), the Independent Review Committee (IRC)–assessed overall response rate (ORR) observed with selpercatinib was 69.2% (95% CI, 48.2%-85.7%), with 94.4% of responses ongoing at a median follow-up of 9.7 months. In all patients with NSCLC (n = 47), the IRC-assessed ORR achieved with the agent was 66.0% (95% CI, 50.7%-79.1%), with 96.8% of responses ongoing at a median follow-up of 10.3 months.

“These findings were consistent with previous data in global and East Asian populations from [the phase 1/2] LIBRETTO-001 trial [NCT03157128], suggesting that selpercatinib is a promising treatment option for Chinese patients with RET fusion–positive NSCLC,” Shun Lu, MD, PhD, lead study author, professor at Shanghai Chest Hospital, Jiao Tong University, and chief of the Shanghai Lung Cancer Center, said during a presentation on the data.

The ongoing, open-label, multicenter, phase 2 LIBRETTO-321 trial is being conducted in China and is examining the safety and efficacy of selpercatinib in patients aged 18 years or older with treatment-naïve or pretreated locally advanced or metastatic tumors.

A total of 77 patients were enrolled to the study and were divided into 3 cohorts. Cohort 1 (n = 30) was comprised of patients with advanced RET fusion–positive solid tumors who had progressed on or were intolerant to 1 or more prior standard first-line therapies or those who had declined or were not suitable to receive standard frontline therapy. Cohort 2 (n = 26) enrolled patients with advanced RET-mutant medullary thyroid cancer who had or had not received previous systemic therapy.

Lastly, those enrolled to cohort 3 (n = 21) had advanced RET-altered solid tumors that met the requirements for cohorts 1 or 2 but did not have measurable disease, those with a RET-altered solid tumors or a RET alteration/activation that did not meet the criteria for cohorts 1 or 2, and those who were circulating tumor DNA positive for a RET alteration that was not known to be present in their tumor.

The primary efficacy analysis set included 47 patients with NSCLC and a subset of 26 patients who had NSCLC that was confirmed via a central laboratory to have RET fusion status.

Study participants received oral selpercatinib at a twice-daily dose of 160 mg, administered in 28-day cycles until. Treatment was administered until either disease progression, intolerable toxicity, withdrawn consent, or death. Notably, patients could continue the study regimen beyond progression if continued benefit was observed.

The primary end point of the study was ORR per RECIST v1.1 criteria and IRC assessment. Secondary end points comprised ORR per RECIST v1.1 criteria and investigator assessment, duration of response (DOR), central nervous system (CNS) ORR, CNS DOR, clinical benefit rate (CBR), time to relapse (TTR), time to best response (TTBR), progression-free survival (PFS), overall survival (OS), pharmacokinetics, and safety.

Across the 2 groups, patients had a median age of 53 years (range, 26-72), and the majority were female (55.9%) and had an ECOG performance status of 1 (86.8%). The median number of prior treatments received was 2 (range, 0-9), and most patients had previously undergone treatment with platinum-based chemotherapy (68.9%). Additionally, 33.5% of patients were treatment naïve, 33.5% had CNS metastases, and 91.5% had measurable disease.

Additional data showed that in the PAS subset, selpercatinib elicited an ORR of 61.1% (95% CI, 35.7%-82.7%) in those who were pretreated (n = 18) vs 87.5% (95% CI, 47.3%-99.7%) in those who were treatment naïve (n = 8). In the all-NSCLC group, the ORRs experienced with the agent in those who were pretreated (n = 36) and treatment naïve (n = 11) were 58.3% (95% CI, 40.8%-74.5%) and 90.9% (95% CI, 58.7%-99.8%), respectively.

In the PAS subset, 1 patient achieved a complete response (CR) to treatment (3.8%), and 17 achieved a partial response (PR; 65.4%); the stable disease rate was 26.9% (n = 7). In the all-NSCLC population, 3 patients achieved a CR (6.4%), and 28 achieved a PR (59.6%); here, the stable disease rate was 29.8% (n = 14).

Additionally, 80% of patients with measurable CNS lesions at the time of enrollment achieved an IRC-assessed confirmed intracranial response at a median follow-up of 9.3 months.

The median TTR for both groups was 1.8 months, and the median DOR had not yet been reached in either group. At data cutoff, 94.4% of responding patients in the PAS subgroup continued to respond to treatment vs 96.8% in the all-NSCLC population.

In a safety population comprised of 77 patients, 97.4% experienced at least 1 treatment-emergent adverse effect (TEAE) of any grade, and 97.4% reported a treatment-related AE (TRAE) of any grade. The most common grade 3 or higher TEAEs that were experienced with selpercatinib included hypertension (19.5%), increased alanine aminotransferase (ALT; 15.6%), and increased aspartate aminotransferase (AST; 15.6%). Frequently reported grade 3 or higher TRAEs included hypertension and increased ALT and AST (15.6% each).

TEAEs resulted in treatment discontinuation in 5.2% of patients (n = 4), with 3.9% (n = 3) considered to be related to selpercatinib. Moreover, 32.5% (n = 25) of patients required dose reductions. Additionally, 1 patient died because of grade 5 acute pancreatitis, although this effect was not considered to be related to treatment with selpercatinib.

Selpercatinib is currently being examined as initial treatment in patients with advanced or metastatic RET fusion–positive NSCLC as part of the phase 3 LIBRETTO-431 trial (NCT04194944).


Lu S, Cheng Y, Huang D, et al. Efficacy and safety of selpercatinib in Chinese patients with RET fusion-positive non-small cell lung cancer: a phase 2 trial. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. Abstract MA02.01.

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