Selpercatinib Shows Promise against Lung Cancers with Alterations in RET Gene

The investigational drug selpercatinib may
benefit patients with lung cancer whose tumors have alterations
in the RET gene, according to preliminary results from a clinical trial.

About 2% of patients with non-small cell lung cancer (NSCLC)
have fusions between the RET gene and other DNA segments. These gene fusions
can lead to the production of abnormal RET proteins that spur the growth of
cancer cells.

What is Selpercatinib (LOXO-292)

Selpercatinib (LOXO-292) is a targeted therapy that works by
inhibiting the activity of abnormal RET proteins. The drug is an oral therapy
that patients take as a pill.

In the trial, more patients responded to the drug—that is,
their tumors shrank—than has been seen with older drugs that inhibit RET.
Patients treated with selpercatinib also had fewer side effects.

“This is a new drug that leads to durable responses” in
patients whose lung cancers include RET alterations, said Alexander Drilon,
M.D., of Memorial Sloan Kettering Cancer Center, who presented the trial’s
findings at the World Conference on Lung Cancer in Barcelona on
September 9.

The drug also crossed the blood–brain barrier and shrank
tumors in the brain and other parts of the central nervous system, Dr. Drilon
added, noting that this type of lung cancer frequently spreads to the
brain.

Clinical Trial Results

Alterations in the RET gene are rare, occurring in less than
1% of most types of cancer. But they are more common in lung cancer and occur
in 10% to 20% of thyroid cancers.

No targeted therapies have been approved by the Food and
Drug Administration (FDA) for this form of lung cancer, known as RET
fusion–positive NSCLC.

The results presented in Barcelona primarily cover the first
105 patients with RET fusion–positive NSCLC enrolled in the trial, called
LIBRETTO-001. Loxo Oncology, the maker of selpercatinib, and Eli Lilly
sponsored the trial.

Of this group, 71 of 105 (68%) patients who had prior
treatment with chemotherapy responded to selpercatinib. Among an additional group
of 34 patients who had not been treated previously, 29 (85%) responded to the
drug.

The median duration
of response was 20.3 months, and three patients had complete responses, meaning
that there was no evidence of cancer remaining by imaging, according to Dr.
Drilon.

In the trial, 10 of 11 (91%) patients with brain metastases
responded to the drug.

“This drug looks like
a very effective new therapy for our patients with lung cancer” who have RET
alterations, said Roy S. Herbst, M.D., Ph.D., a lung cancer expert and chief of
medical oncology at the Yale Cancer Center, who was not involved in the trial.

Focusing on RET

Several drugs designed to simultaneously inhibit RET and
other cancer-related proteins have been tested in clinical trials in
recent years, including cabozantinib (Cabometyx) and vandetanib (Caprelsa).

Difference between selpercatinib and older RET inhibitors

The difference between selpercatinib and older RET
inhibitors, Dr. Drilon explained during his presentation, is that the new drug
blocks only RET, which reduces the likelihood of side effects caused by
interactions with multiple drug targets. By contrast, earlier RET inhibitors
were multi-kinase inhibitors that blocked other proteins in addition to RET.

“This drug is much more specific in its targeting than
earlier RET inhibitors,” said Dr. Herbst.

Side effects of selpercatinib

The most common side effects of selpercatinib included dry
mouth, diarrhea, hypertension, and increased blood levels of two liver enzymes.
Most of these were easily managed, according to the researchers.

“What we’re seeing with selpercatinib [in clinical trials]
is very different from what we’ve seen with other [RET-targeted] agents,” Dr.
Drilon said in Barcelona, noting that only 9 of 531 (1.7%) patients in the
trial stopped receiving selpercatinib because of side effects.

Treating Disease in the Central Nervous System

The results presented in Barcelona build on earlier research
that suggested that selpercatinib may be particularly effective against tumors
that have spread to the brain and other parts of the central nervous system.

Earlier this year, for example, Dr. Drilon and his colleagues reported that a patient with RET fusion–positive NSCLC that had spread to the lining of the central nervous system responded to selpercatinib.

The patient, whose disease had progressed on a prior
multi-kinase inhibitor and radiation therapy, had “a brisk and durable ongoing
response” to selpercatinib, the researchers reported.

“We’re seeing meaningful clinical activity in the brain,”
Dr. Drilon said in Barcelona.

Nearly 25% of patients with RET fusion–positive NSCLC have
cancer in the central nervous system at the time of diagnosis, and the disease frequently
spreads to the brain.

Based on the data from the clinical trial, Dr. Drilon said
that selpercatinib appears to have the potential to both treat disease in the
central nervous system and even to prevent the development of brain metastases.

Progress in Treating Lung Cancer

Loxo Oncology has said it plans to submit a New Drug
Application to FDA later this year for approval of selpercatinib for the
treatment of RET fusion–positive NSCLC.

Dr. Herbst predicted that selpercatinib would likely be approved and that doctors would start using the drug for patients whose tumors are found to have RET alterations through a test such as DNA sequencing/RNA sequencing or FISH.

The trial results, he added, “are so good” that a randomized
trial comparing selpercatinib with another treatment, such as chemotherapy,
probably would not be necessary.

Dr. Herbst has been attending the world conference on lung
cancer for more than 2 decades and reflected on progress in the field.

“At a meeting 22 years ago in Dublin,” he recalled, “the
most exciting presentations were about combinations of chemotherapy that
improved survival for patients with lung cancer by a month or two.”

With the current study, “we are hearing about a drug that may improve survival for a year or possibly much more,” he continued. “That’s progress, and it’s been made possible by improvements in our understanding of the biology of lung tumors.”

Selpercatinib Shows Promise against Lung Cancers with Alterations in RET Gene was originally published by the National Cancer Institute.”

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