LIBRETTO-001 Trial Shows Promise for Selpercatinib in NSCLC Marked by RET Gene Fusions


Results from this trial observed in patients with RET-altered lung and thyroid cancers also led to the approval of selpercatinib by the FDA in May for this indication.

Results from phase 1/2 LIBRETTO-001 trial, published in The New England Journal of Medicine, suggested that selpercatinib (Retevmo) was well tolerated and achieved durable objective responses in patients with non-small cell lung cancer (NSCLC) marked by RET gene fusions.1

Notably, data from this trial observed in patients with RET-altered lung and thyroid cancers also led to the approval of selpercatinib by the FDA in May 2020 for this indication.

“Genome-guided precision oncology has altered the landscape of multiple kinase-driven tumors, with lung cancer being the poster child. However, we previously did not have any drug approved specifically for RET-fusion positive non-small cell lung cancer,” senior author Vivek Subbiah, MD, associate professor of Investigational Cancer Therapeutics at MD Anderson Cancer Center, said in a press release.2 “Moving from the first-in-human Phase I trial to FDA approval in less than three years is a testament to the fact that patients benefited a great deal from this treatment and had no effective options.”

The study cohort consisted of patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. The primary end point was an objective response as determined by an independent review committee. Key secondary end points included the duration of response, progression-free survival (PFS), and safety.

Of the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the objective response rate (ORR) was 64% (95% CI, 54-73). This included 2% with a complete response (CR), 62% with a partial response (PR), and 29% with stable disease (SD). Moreover, the median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Median PFS was 16.5 months.

Among a separate cohort of 39 previously untreated patients, the ORR was 85% (95% CI, 70-94), and 90% of the responses were ongoing at 6 months. This included 85% with a PR and 10% with SD. However, neither median duration of response nor median PFS had been reached at the time of analysis.

Of 11 patients with measurable central nervous system (CNS) metastasis at enrollment, the objective intracranial response rate was 91% (95% CI, 59-100), including 3 CRs. The median duration of CNS response was 10.1 months.

The most common adverse events (AEs) of grade 3 or higher were hypertension (14%), an increased alanine aminotransferase level (12%), an increased aspartate aminotransferase level (10%), hyponatremia (6%), and lymphopenia (6%). Only 2% (12 of 531) discontinued selpercatinib due to a drug-related AE.

“The data show these patients benefit from this treatment and it is safe compared with multi-kinase inhibitors and chemotherapy,” Subbiah said in the release. “The continued implementation of a robust molecular screening strategy in frontline lung and thyroid cancers with the ability to detect RET and other gene fusions will be critical for identifying patients who may benefit from specifically targeted therapies like selpercatinib.”

In additional cohorts of LIBRETTO-001, also published in The New England Journal of Medicine, selpercatinib demonstrated activity in RET-altered thyroid cancers, including medullary thyroid cancer (MTC) with RET mutations and papillary/anaplastic thyroid cancers with RET fusions, with a similar safety profile observed.3

Among patients with MTC, there was a 73% ORR in previously untreated patients and 69% ORR in those receiving prior targeted therapies. In patients with previously treated papillary/anaplastic thyroid cancer, the ORR was 79%.


1. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. The New England Journal of Medicine. doi: 10.1056/NEJMoa2005653

2. Lung cancer trial of RET inhibitor selpercatinib achieves durable responses in majority of patients with RET gene fusions [news release]. MD Anderson. Published August 26, 2020. Accessed August 27, 2020.

3. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. The New England Journal of Medicine. doi: 10.1056/NEJMoa2005651

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