Investigators Seek New Standard in RET Fusion–Positive NSCLC

Geoffrey R. Oxnard, MD

Investigators hope selpercatinib (LOXO-292), a highly selective RET inhibitor, will demonstrate potential as a new standard of care (SOC) for patients with advanced or metastatic treatment-naïve RET fusion—positive non–small cell lung cancer (NSCLC) in the phase III LIBRETTO-431 (NCT04194944) trial.¹

In the 3-arm study, investigators will compare selpercatinib with platinum-based chemotherapy to determine whether the investigational agent can confer a greater survival benefit. Approximately 400 patients with nonsquamous histology will be randomized to receive selpercatinib as monotherapy or pemetrexed plus the investigator’s choice of carboplatin or cisplatin with or without pembrolizumab (Keytruda).

RET fusions and mutations affect approximately 2% of NSCLC cases, specifically, and are known to occur in 10% to 20% of papillary and other thyroid cancers as well as a subset of other cancers.¹

“In lung cancer, we have a wide range of targetable mutations that we test for, and we know that we are improving treatment options by connecting genomic targets with precision therapy. But in order to offer these drugs to patients in an informed fashion, we need to know how good the outcomes are with targeted approaches and how they compare with outcomes from standard treatments,” said Geoffrey R. Oxnard, MD, principal investigator of LIBRETTO-431’s site at the Dana-Farber Cancer Institute in Boston, Massachusetts.

Based on earlier findings, investigators believe that LIBRETTO-431 will have a positive outcome. “This trial is being launched to show that selpercatinib is superior to standard chemotherapy in order to change the SOC in the upfront treatment of RET fusion—positive lung cancer,” said Oxnard, an expert in NSCLC and associate professor of medicine at Harvard Medical School, also in Boston.

Genomic aberrations in the RET kinase, such as fusions and activating point mutations, prompt overactive RET signaling and malignant cell growth. RET fusion—positive cancers and RET-mutant medullary thyroid cancer (MTC) depend on single RET kinase activation to survive and metastasize. This reliance, known as oncogenic addiction, renders these tumors susceptible to small-molecule RET inhibitors such as selpercatinib.¹

Figure. Selpercatinib in Metastatic RET Fusion—Positive NSCLC (Click to Enlarge)

Due to the modest activity of the available treatment options, it is essential to expand the armamentarium for RET-positive NSCLC, Oxnard said. Chemotherapy has some efficacy in RET fusion—positive NSCLC and, although data are limited, immunotherapy “doesn’t tend to work in these genotype-driven cancers,” he added. Moreover, multikinase inhibitors used off label, such as cabozantinib (Cabometyx) and vandetanib (Caprelsa), come with toxicity and work only occasionally. “There are no good, reliable, approved RET inhibitors for these patients,” he added.

LIBRETTO-431 is not yet recruiting but will accrue patients across 158 sites globally. To be eligible to participate in LIBRETTO-431, patients must have histologically confirmed stage IIIb to stage IIIc or stage IV nonsquamous, RET fusion—positive NSCLC that is not suitable for radical surgery or radiation therapy (Figure). The primary end point is progression-free survival (PFS). Secondary end points include overall survival, overall response rate (ORR), duration of response (DOR), and intracranial ORR. Crossover will be permitted for patients randomized to the control arm.

A Promising Clinical Foundation

The rationale for LIBRETTO-431 is supported by early results from the ongoing phase I/II LIBRETTO-001 trial (NCT03157128) of selpercatinib in 531 patients with advanced solid tumors including RET-mutant MTC, RET fusion—positive solid tumors, and other tumors with RET activation. In this study, which is notably the largest trial reported in patients with RET-mutant cancer, selpercatinib has demonstrated safety and efficacy in patients with the rare alteration.

The LIBRETTO-001 study comprised 2 phases. In the dose-escalation phase, investigators identified 160 mg twice daily as the selpercatinib dose for the expansion phase of the trial.²

Data from a primary analysis set (PAS) of 105 patients with RET fusion—positive NSCLC who received prior platinum-based chemotherapy were presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer in September 2019. The findings showed that selpercatinib not only demonstrated robust antitumor activity in these patients but also led to high response rates, investigators said. The ORR in the PAS cohort was 68% (95% CI, 58%-76%), which included complete responses in 2% and partial responses in 66% of patients.²

Moreover, 26% of patients had stable disease, translating to a disease control rate (DCR) of 94%. The median DOR and PFS rates were 20.3 months (95% CI, 13.8- 24.0) and 18.4 months (95% CI, 12.9-24.9), respectively. Follow-up for each end point was <10 months.² Patients in the PAS received a median of 3 prior systemic therapies.²

Patients with central nervous system (CNS) involvement (35% of PAS population) also did well with selpercatinib. In the 11 patients with CNS involvement, the DCR was 100% and the ORR was 91% (95% CI, 59%-100%).² Selpercatinib’s developer, Eli Lilly and Company, reported in September 2019 that the agent was the first and only RET inhibitor to demonstrate such a robust CNS ORR.¹ Up to 50% of RET fusion—positive NSCLCs metastasize to the brain.

In a separate analysis of selpercatinib therapy in 34 patients with treatment-naïve disease, selpercatinib was found to elicit an ORR of 85% (95% CI, 69%-95%). A fraction of these patients (9%) had stable disease, resulting in a DCR of 94%. Neither the median DOR nor the median PFS had been reached after a median follow-up of 4.8 months and 3.7 months, respectively.²

A safety analysis of selpercatinib showed that the agent was well tolerated by the trial’s full patient cohort of 531 patients. Only 9 patients (1.7%) discontinued selpercatinib therapy due to treatment-related toxicity, according to the trial update at IASLC. “As with other potent precision therapies, there is the potential for dramatic responses with very few side effects,” Oxnard said. In LIBRETTO-001, most AEs have been low grade and unrelated to selpercatinib, investigators said. At the time of the presentation, the 3 most common treatment- emergent AEs were dry mouth (32%), diarrhea (31%), and hypertension (29%). Hypertension was also the most prevalent grade 3 treatment-emergent AE.²

These early findings from LIBRETTO-001 led the FDA to award selpercatinib breakthrough therapy designations for each of the 3 main indications explored in the study in September and October of 2018.¹

Specifically, selpercatinib’s breakthrough designations cover patients with metastatic RET fusion—positive NSCLC who require systemic therapy and have progressed following platinum-based chemotherapy and anti–PD-1/PD-L1 therapy, and patients with either RET-mutant MTC or advanced RET fusion—positive thyroid cancer who require systemic therapy, have progressed following prior treatment, and have no acceptable alternative treatment options.¹

Setting a New Precedent

Oxnard and other LIBRETTO-431 investigators hope to advance the RET fusion—positive NSCLC treatment paradigm with selpercatinib, but Oxnard noted that broader adoption of genotyping in addition to the introduction of more effective therapies, is also necessary to achieve better outcomes for patients with this disease.

“We cannot be satisfied with the guessing game of giving patients chemoimmunotherapy and crossing our fingers, because in the patients who have a driver mutation, the best treatment is an oral targeted therapy. We can’t rely on partial genotyping, so we need to be experts at getting our patients genotyped,” Oxnard said.

“If you want to find the RET-positive patients, you need to test for RET, and if you aren’t seeing RET and ROS and these other rare genotypes in your clinic, it’s possible that you’re not looking hard enough for them. Through persistence and conscious testing of all our patients, we can find the RET-positive patients and treat them with the best possible therapies,” Oxnard added.

References

1. Lilly announces positive results for selpercatinib (LOXO-292), demonstrating a 68 percent objective response rate and sustained durability in heavily pretreated RET fusion-positive non-small cell lung cancer [news release]. Indianapolis, IN: Eli Lilly and Company; September 9, 2019. prnewswire.com/ news-releases/lilly-announces-positive-results-for-selpercatinib- loxo-292-demonstrating-a-68-percent-objective-response- rate-and-sustained-durability-in-heavily-pretreatedret- fusion-positive-non-small-cell-lung-cancer-300913590. html. Accessed January 3, 2020.
2. Drilon A, Oxnard G, Wirth L, et al. Registrational results of the LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. Paper presented at: International Association for the Study Lung Cancer 20th World Conference on Lung Cancer; September 7-10; Barcelona, Spain. Abstract PL02.08.

Developed to inhibit native RET signaling with minimal off-target effects, selpercatinib can potentially induce “a dramatic effect” on tumor activity without excess toxicity, Oxnard said. “Selpercatinib is like other smart designer drugs that we use, such as osimertinib (Tagrisso) for EGFR and alectinib (Alecensa) and brigatinib (Alunbrig) for ALK, agents that precisely inhibit the protein of interest without off-target toxicity, thereby leading to efficacy with minimal adverse events [AEs],” Oxnard said.