RET Inhibitor Demonstrates High Response Rate in RET+ NSCLC, Companion Diagnostic in the Works

Alexander Drilon, MD

Alexander Drilon, MD

Treatment with selpercatinib (LOXO-292) induced responses in 68% of patients withRETfusion—positive non–small cell lung cancer (NSCLC), according to findings from the phase I/II LIBRETTO-001 trial.¹

The data presented at the 2019 World Conference on Lung Cancer (WCLC) add to the growing excitement surrounding the selective RET inhibitor for its potential to treat a specific population of patients with cancer harboringRETalterations.

Further building on excitement for the agent and to ease the identification of patients withRETfusions, Eli Lilly and Thermo Fisher Scientific have entered into an agreement to develop a companion diagnostic for the investigational agent selpercatinib (LOXO-292).²As a result of the deal, the next-generation sequencing (NGS)—based on Thermo Fisher’s Oncomine Dx Target Test, will be used to identifyRETalterations in patients with NSCLC and thyroid cancers.

Currently, the test is approved by the FDA and is indicated as a companion diagnostic for identifyingROS1fusions,BRAFV600E mutations, andEGFRL858R or exon 19 deletion mutations in patients with NSCLC who can be referred for treatment with crizotinib (Xalkori), dabrafenib (Tafinlar) and trametinib (Mekinist), and gefitinib (Iressa), respectively.

RETfusions are found in about 1% to 2% of patients with NSCLC, and although this is a small population of patients, “given the activity of selective RET inhibitors inRETfusion—positive NSCLCs, it is critical to test forRETfusions,” said lead investigator Alexander Drilon, MD, the research director of early drug development at Memorial Sloan Kettering Cancer Center, in an email toTargeted Oncology. “Recognizing that many other actionable drivers are found in lung cancers, the best approach is to do NGS, which looks for all of these alterations, includingRETfusions.”

In addition to in NSCLCs,RETaberrations are also found in about 60% of medullary thyroid cancers and in up to 20% of other thyroid cancers.

Lilly is hoping that the availability of the assay will increase awareness about testing forRETmutations among patients with NSCLC and thyroid cancer that would lead to identifying patients who would benefit from treatment with selpercatinib.

"One of the biggest barriers to realizing the full power of precision medicine in oncology is having access to high-quality testing, such as NGS-based tests, that identify a broad range of clinically actionable alterations, can be performed locally and allow treating institutions to participate in this important step in the evolving treatment paradigm," said Anne White, president of Lilly Oncology, in a statement. "With this agreement, we believe that more patients will gain access to high-quality tumor profiling, identifying those with RETalterations potentially suitable for LOXO-292 therapy, in addition to other alterations suitable for treatment with other therapies."

“With the recent tumor-agnostic approvals of larotrectinib [Vitrakvi] and entrectinib [Rozlytrek] in TRK fusion—positive cancers and the previous approval of pembrolizumab [Keytruda] for microsatellite instability–high cancers, the hope is that payers will eventually cover NGS for every cancer. Lowering the costs of NGS and decreasing turnaround time will also help [increase awareness of genomic testing and its value],” added Drilon, who presented the findings from the LIBRETTO study at WCLC in Barcelona.

LIBRETTO-001 NSCLC Findings

The phase I/II LIBRETTO-001 trial enrolled a total of 531 patients withRET-altered cancers to be treated with selpercatinib. The phase I portion of the trial helped to establish 160 mg twice daily as the recommended phase II dose of the RET inhibitor.

Data presented at the WCLC meeting focused on the patients withRETfusion—positive NSCLC included in the trial.¹The primary analysis set included 105 patients who had received prior platinum-based chemotherapy, but a cohort of 39 untreated patients was also analyzed.

Of the 105 chemotherapy-treated patients, the median age was 61 years and 59% were women. The median number of prior regimens received was 3, which included PD-1/PD-L1 immune checkpoint inhibition in 55% and at least 1 multikinase inhibitor in 48%.

The objective response rate (ORR) neared 70% in this patient population, consisting of complete responses in 2% of patients. An additional 26% of patients achieved stable disease. The median duration of response was 20.3 months and the median progression-free survival was 18.4 months.

Objective intracranial responses were also seen in 10 of 11 patients (91%) with central nervous system involvement and the intracranial disease control rate was 100%.

Thirty-four of the treatment-naïve patients were evaluable for response. The ORR in this patient population was 85% with an additional 9% achieving stable disease. The median duration of response and progression-free survival had not yet been reached in this cohort. 

The most common treatment-emergent adverse events (AEs) noted in the primary analysis group were dry mouth (32%), diarrhea (31%), hypertension (29%), increased aspartate aminotransferase (28%), increased alanine transaminase (26%), fatigue (24%), constipation (22%), headache (20%), nausea (19%), peripheral edema (19%), and increased creatinine (18%). Grade ≥3 treatment-emergent hypertension was observed in 15% of patients.

 

Across the entire study population, similar common treatment-related AEs were observed, and most were only grade 1 or 2. Nine patients (1.7%) discontinued treatment due to treatment-related AEs.

Selpercatinib was granted a breakthrough therapy designation by the FDA in September 2018for the treatment of patients with RETfusion—positive NSCLC orRET-mutant medullary thyroid cancer and data supporting the agent are expected to be submitted to the FDA by the end of the year for review by the FDA for potential approval.

Additionally, a randomized phase III trial is planned to explore the use of selpercatinib in comparison with platinum-pemetrexed chemotherapy plus or minus pembrolizumab in patients with treatment-naïveRETfusion—positive NSCLC.

References:

1. Thermo Fisher Scientific signs agreement with Lilly Oncology for companion diagnostic to be used withRETinhibitor [press release]. Carlsbad, CA: Thermo Fisher Scientific; September 9, 2019. https://bit.ly/2m4utS9. Accessed September 10, 2019.
2. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract PL008.