Selpercatinib Demonstrates Durable Efficacy and Intracranial Activity in RET+ NSCLC

Alexander Drilon, MD

The RET inhibitor selpercatinib (LOXO-292; Retevmo) was shown to have durable efficacy with mostly low-grade adverse effects (AEs) in patients with RET fusion–positive non–small-cell lung cancer (NSCLC), according to results from the phase 2/2 LIBRETTO-001 trial (NCT03157128) that were published in The New England Journal of Medicine.

Results showed that the agent elicited an objective response rate (ORR) of 64% (95% CI, 54-73) in patients with RET fusion–positive disease who had previously received at least platinum-based chemotherapy per independent review committee (IRC).

Two percent of patients (n = 2) achieved a complete response (CR) with the RET inhibitor and 62% (n = 65) experienced a partial responses (PR). Additionally, 29% (n = 30) of patients were found to have stable disease, while 4% (n = 4) experienced disease progression and another 4% (n = 4) were not evaluable. Notably, responses were observed irrespective of prior treatment with PD-1 or PD-L1 drugs or multitargeted kinase inhibitors.

Moreover, the median duration of response (DOR) per IRC was 17.5 months (95% CI, 12.0–not evaluable [NE]), with 63% (n = 42/67) of responses reported to have persisted at a median follow-up of 12.1 months. The majority of participants, or 66%, were free of progression at 1 year (66%; 95% CI, 55-74) with a median progression-free survival (PFS) of 16.5 months (95% CI, 13.7-NE). Overall, 5% (n = 5) of patients either withdrew from the trial or were lost to follow-up.

“Selpercatinib had substantial antitumor activity in patients with RET fusion–positive lung cancers, including those who received [the agent] as first-line therapy, those who had previously received at least platinum-based chemotherapy, and those with brain metastases,” wrote Alexander Drilon, MD, of Memorial Sloan Kettering, and colleagues, in the paper. “The follow-up of this patient cohort was shorter for patients who received selpercatinib as first-line therapy than for those who had previously received at least platinum-based chemotherapy, but responses continued in the majority of patients more than 1 year after the initiation of treatment.”

While RET fusions are typically diagnosed in approximately 1%-2% of all patients with NSCLC, they are noted to be associated with a higher risk of brain metastases. Experimental models have demonstrated that selpercatinib possesses nanomolar potency against numerous RET alterations—fusions, activating point mutations, and predicted acquired resistance mutations—and spares non-RET kinases. Additionally, selpercatinib was developed to penetrate the central nervous system and preclinical models have illustrated notable antitumor activity with the agent in the brain.

In the phase 1/2 LIBRETTO-001 trial, investigators set out to examine the safety and efficacy of the RET inhibitor in adult and adolescent patients with RET-altered NSCLC and thyroid cancers.

In order to be considered for the study, patients needed to have been 12 years of age or older and have been diagnosed with an advanced or metastatic solid tumor. A RET alteration, either fusion or mutation, needed to have been prospectively identified in patients who reached the second dose level of selpercatinib, where the agent was given at 20 mg twice daily.

Patients also had to have an ECOG performance status of 0 to 2, acceptable organ function, and a corrected QT interval of 470 msec or less in order to participate. Patients were allowed to have received treatment with checkpoint inhibitors, multitargeted kinase inhibitors, and chemotherapy. Notably, patients with previously treated or untreated brain metastases were also eligible for inclusion if they were asymptomatic or had been in a neurologically stable condition for at least 2 weeks.

Both phases of the open-label trial were conducted in 65 centers across 12 countries. Patients received oral selpercatinib as a continuous treatment given in 28-day cycles until either progressive disease, death, intolerable toxicity, or withdrawal of consent. In the phase 1 dose-escalation portion of the trial, patients were given the agent at doses ranging from 20 mg once daily to 240 mg twice daily. For the phase 2 portion of the trial, patients received the recommended 160 mg twice daily dose of the agent.

The primary end point of the trial was ORR as assessed by an IRC in accordance with RECIST v1.1 criteria, while key secondary end points included an objective intracranial response, PFS, DOR, and safety.

A total of 49 patients with RET fusion–positive advanced NSCLC who had received chemotherapy enrolled in the phase 1 dose escalation portion of the trial, while 56 enrolled for phase 2 portion; an additional 39 treatment-naïve patients with advanced RET fusion–positive disease were also enrolled between December 2017 and June 2019.

All patients who received previous treatment with a platinum-based chemotherapy were noted to be heavily pretreated, with 55% having received prior PD-1 or PD-L1 therapies and 48% had received previous multitargeted kinase inhibitors with anti-RET activity. Notably, 36% of participants had brain metastases at baseline per investigator assessment.

Additional data demonstrated that 70% of patients experienced a response while on the trial (95% CI, 60-78) and these responses were observed irrespective of the specific RET fusion partner, according to study authors. Moreover, the median time to response was 1.8 months, with responses ongoing at a median follow-up of 14.8 months.

The median DOR per investigator assessment was 20.3 months (95% CI, 15.6-24.0) and 58% of the responses were still found to be ongoing at a median follow-up of 14.8 months. Notably, 71% of patients who experienced a response continued to be treated. The median DOR was comparable in the overall group of patients who had received previous chemotherapy and in the subgroup of those who had received previous PD-1 or PD-L1 therapy. Sixty-eight percent of patients were free of progression at 1 year per investigator assessment; the median PFS in these patients was 18.4 months (95% CI, 16.4-24.8).

Of the 38 patients who had received previous platinum-based chemotherapy and investigator-assessed central nervous system (CNS) metastases at baseline, 11 had measurable lesions per RECIST v1.1 criteria and IRC. Objective intracranial response was reported in 91% of the 11 patients (95% CI, 59-100) per independent review, and 27% (n = 3) of these patients experienced a CR, 64% (n = 7) had a PR, and 1 patient achieved stable disease. Investigators also found that the median CNS DOR was 10.1 months (95% CI, 6.7-NE).

In terms of safety, the most common grade 3 and 4 AEs associated with selpercatinib included hypertension (14%), increased alanine aminotransferase levels (13%), increased aspartate aminotransferase levels (10%), hyponatremia (6%), and lymphopenia (6%).

Six grade 5 toxicities were also reported and included sepsis (n = 2 patients), cardiac arrest (n = 1), multiple organ dysfunction syndrome (n = 1), pneumonia (n = 1), and respiratory failure (n = 1); however, these toxicities were determined to be unrelated to selpercatinib.

Of all 531 patients who were treated with selpercatinib, 30% (n = 160) required dose reduction because of treatment-related AEs and 2% (n = 12) discontinued treatment. The most commonly reported reasons for discontinuation included an increase in alanine aminotransferase level (n = 2) and drug hypersensitivity (n = 2).

Reference

Drillon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653.