Meeting NewsPerspective

Selpercatinib induces deep, durable responses in RET fusion-positive lung cancer

BARCELONA — The investigational drug selpercatinib induced deep antitumor responses among patients with RET fusion-positive non-small cell lung cancer, according to updated data from the phase 1/phase 2 LIBRETTO-001 trial presented during the presential symposium at International Association for the Study of Lung Cancer World Conference on Lung Cancer.

The selective RET inhibitor also appeared well-tolerated, results showed.

“We know that RET fusions are bona fide drivers of lung cancer. These share many features with ALK fusions or ROS1 fusions,” Alexander Drilon, MD, research director of early drug development at Memorial Sloan Kettering Cancer Center, said during a press conference. “This is an underserved population of patients. We’ve really tried hard over the last couple of years to develop drugs for these patients, but those clinical trials have been fraught with issues. The difference between selpercatinib and those drugs is that it is a selective RET inhibitor. It’s a cleaner drug.”

As many as 2% of patients with NSCLC have RET fusion-positive disease, for which no targeted treatments have been approved. Additionally, up to half of patients with advanced disease have brain metastases.

Selpercatinib (LOXO-292, Loxo Oncology) is a potent, highly selective, investigational drug under development for the treatment of RET abnormalities, including fusions and activating point mutations. The FDA granted the drug breakthrough therapy designation in August 2018 based on early results from LIBRETTO-001.

The study — conducted at 87 sites in 15 countries — included patients with advanced RET-altered solid tumors, such as RET fusion-positive NSCLC. The researchers administered oral selpercatinib to patients in 28-day cycles. Phase 1 determined the maximum tolerated dose and recommended a phase 2 dose of 160 mg twice daily.

For phase 2, researchers assigned patients to one of six cohorts according to tumor type, RET alteration and prior treatment. Objective response rate per RECIST 1.1 criteria served as the primary endpoint. Duration of response, central nervous system ORR and duration of response, PFS, OS, safety and pharmacokinetics served as secondary outcomes.

A total of 247 patients with RET fusion-positive NSCLC had been treated as of June 17. Drilon presented data from the primary analysis set, designed in cooperation with the FDA, which included the first 105 consecutively enrolled patients with RET fusion-positive NSCLC previously treated with platinum-based chemotherapy. Fifty-four of these patients (51%) previously received immune checkpoint inhibitors.

The researchers followed most responders in the primary analysis set for 6 months or more after initial response.

Among these patients, researchers observed an ORR of 68% (95% CI, 58-76) with no differences in response based on fusion partner or the type or number of previous treatments, including chemotherapy, immune checkpoint inhibitors and multikinase inhibitors with anti-RET capacity.

Patients with measurable brain metastases at baseline (n = 11) demonstrated an intercranial ORR of 91% (95% CI, 59-100).

Median duration of response was 20.3 months (95% CI, 13.8-24), with a median follow-up of 8 months. Median PFS was 18.4 months (95% CI, 12.9-24.9), with a median follow-up of 9.6 months.

Among 34 evaluable treatment-naive patients, Drilon reported an ORR of 85% (95% CI, 69-95).

Safety data for all 247 patients with RET fusion-positive NSCLC showed five treatment-related adverse events among at least 15% of patients; these included dry mouth, elevated aspartate aminotransferase, diarrhea, elevated alanine aminotransferase and hypertension. Most adverse events were grade 1 or grade 2.

Only three of the 247 patients stopped selpercatinib due to treatment-related adverse events.

The data will serve as the basis of a new drug application submission to the FDA later this year, according to researchers.

“The drug was designed to meaningfully penetrate the blood-brain barrier, and here we’re seeing meaningful clinical intracranial activity,” Drilon said. “That not only means you can use this drug for patients who already have existing disease intracranially, but also as we’ve seen with other agents, you can use selpercatinib to potentially prevent the acquisition of brain metastases, which, of course, spares patients a lot of morbidity.” – by Jennifer Byrne

Reference:

Drilon A, et al. Abstract PL02.08. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.

Disclosures: Drilon reports research grants from Foundation Medicine, GlaxoSmithKline and Teva/Taiho/PharmaMar. Please see the abstract for all other authors’ relevant financial disclosures.

BARCELONA — The investigational drug selpercatinib induced deep antitumor responses among patients with RET fusion-positive non-small cell lung cancer, according to updated data from the phase 1/phase 2 LIBRETTO-001 trial presented during the presential symposium at International Association for the Study of Lung Cancer World Conference on Lung Cancer.

The selective RET inhibitor also appeared well-tolerated, results showed.

“We know that RET fusions are bona fide drivers of lung cancer. These share many features with ALK fusions or ROS1 fusions,” Alexander Drilon, MD, research director of early drug development at Memorial Sloan Kettering Cancer Center, said during a press conference. “This is an underserved population of patients. We’ve really tried hard over the last couple of years to develop drugs for these patients, but those clinical trials have been fraught with issues. The difference between selpercatinib and those drugs is that it is a selective RET inhibitor. It’s a cleaner drug.”

As many as 2% of patients with NSCLC have RET fusion-positive disease, for which no targeted treatments have been approved. Additionally, up to half of patients with advanced disease have brain metastases.

Selpercatinib (LOXO-292, Loxo Oncology) is a potent, highly selective, investigational drug under development for the treatment of RET abnormalities, including fusions and activating point mutations. The FDA granted the drug breakthrough therapy designation in August 2018 based on early results from LIBRETTO-001.

The study — conducted at 87 sites in 15 countries — included patients with advanced RET-altered solid tumors, such as RET fusion-positive NSCLC. The researchers administered oral selpercatinib to patients in 28-day cycles. Phase 1 determined the maximum tolerated dose and recommended a phase 2 dose of 160 mg twice daily.

For phase 2, researchers assigned patients to one of six cohorts according to tumor type, RET alteration and prior treatment. Objective response rate per RECIST 1.1 criteria served as the primary endpoint. Duration of response, central nervous system ORR and duration of response, PFS, OS, safety and pharmacokinetics served as secondary outcomes.

A total of 247 patients with RET fusion-positive NSCLC had been treated as of June 17. Drilon presented data from the primary analysis set, designed in cooperation with the FDA, which included the first 105 consecutively enrolled patients with RET fusion-positive NSCLC previously treated with platinum-based chemotherapy. Fifty-four of these patients (51%) previously received immune checkpoint inhibitors.

The researchers followed most responders in the primary analysis set for 6 months or more after initial response.

Among these patients, researchers observed an ORR of 68% (95% CI, 58-76) with no differences in response based on fusion partner or the type or number of previous treatments, including chemotherapy, immune checkpoint inhibitors and multikinase inhibitors with anti-RET capacity.

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Patients with measurable brain metastases at baseline (n = 11) demonstrated an intercranial ORR of 91% (95% CI, 59-100).

Median duration of response was 20.3 months (95% CI, 13.8-24), with a median follow-up of 8 months. Median PFS was 18.4 months (95% CI, 12.9-24.9), with a median follow-up of 9.6 months.

Among 34 evaluable treatment-naive patients, Drilon reported an ORR of 85% (95% CI, 69-95).

Safety data for all 247 patients with RET fusion-positive NSCLC showed five treatment-related adverse events among at least 15% of patients; these included dry mouth, elevated aspartate aminotransferase, diarrhea, elevated alanine aminotransferase and hypertension. Most adverse events were grade 1 or grade 2.

Only three of the 247 patients stopped selpercatinib due to treatment-related adverse events.

The data will serve as the basis of a new drug application submission to the FDA later this year, according to researchers.

“The drug was designed to meaningfully penetrate the blood-brain barrier, and here we’re seeing meaningful clinical intracranial activity,” Drilon said. “That not only means you can use this drug for patients who already have existing disease intracranially, but also as we’ve seen with other agents, you can use selpercatinib to potentially prevent the acquisition of brain metastases, which, of course, spares patients a lot of morbidity.” – by Jennifer Byrne

Reference:

Drilon A, et al. Abstract PL02.08. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.

Disclosures: Drilon reports research grants from Foundation Medicine, GlaxoSmithKline and Teva/Taiho/PharmaMar. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective
    Robert C. Doebele

    Robert C. Doebele

    The registration results of the phase 1/phase 2 LIBRETTO-001 study of LOXO-292, now known as selpercatinib, are very exciting. The response rate of 68% is what we would expect of a good, targeted oncology agent in NSCLC. Median PFS was approximately 18 months, although that data is immature and may change somewhat.

    The study also demonstrated that this drug has activity against brain metastases. This means that, hopefully, we will soon have the first targeted agent for patients with RET gene fusions. Currently, none has been FDA approved; we hope, based on the company’s statement that it intends to file late this year, that next year we will see an approval, which means a lot for these patients. We’ve been trying for years with several drugs that aren’t very active and none of which has been worthy of pursuit for approval.

    There is also another competitor molecule, BLU-667 (Blueprint Medicines), which appears to have very similar effects, so I think it’s likely we are going to have very good options for our RET fusion-positive patients in the near future.

    • Robert C. Doebele, MD, PhD
    • University of Colorado Cancer Center

    Disclosures: Doebele reports consultant/advisory board roles with AstraZeneca, Bayer, F. Hoffmann-LaRoche, Genentech, Rain Therapeutics and Takeda; ownership or stock interest in Rain Therapeutics; a patent license with Abbott Molecular and licensing fees for biologic materials from Black Diamond, Foundation Medicine and Genentech.

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