‘Significant Unmet Needs’ Not Addressed With FDA Approval of Lorbrena

March 31, 2021
Antonia DePace

The FDA recently approved an expanded indication for Lorbrena as a first-line treatment option for a subset of lung cancer that has spread to the brain. Although the drug is effective for some patients, experts debate its widespread use.

The Food and Drug Administration’s (FDA) recent expanded approval of Lorbrena (lorlatinib) for use as a first-line treatment option for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer that has also spread to the brain is a step in the right direction for patients, but experts note there are still significant unmet needs.

“The difficulty we have is that the brain has a blood–brain barrier that protects itself from chemicals,” Dr. Shayma Kazmi, medical director of thoracic oncology at Cancer Treatment Centers of America in Philadelphia, said in an interview with CURE®. “So really, systemic treatments like chemotherapy, which we used to use up until five or six years ago, would not penetrate the brain very well.”

Brain metastases, or the spread of cancer cells from their original site to the brain, occurs in approximately one third of patients with another type of cancer, according to estimates from Johns Hopkins Medicine. In general, research has shown that brain metastases are more common in certain cancers because of the biology of the disease. Lung cancer is one of the more common diseases that can spread to the brain.

Up to 40% of patients with lung cancer, according to Kazmi, develop brain metastases — some of whom already have it present at the time of initial diagnoses. In general, common symptoms patients should be aware of may include headache, nausea, vision changes, clumsiness, forgetfulness and, under more serious circumstances, seizures.

Although it has been difficult to break the blood-brain barrier with conventional chemotherapies, there has been a dramatic amount of progress regarding treatment options for disease that has spread to the brain, says Kazmi. One of which is Lorbrena, which received an expanded approval on March 3. The drug had previously received an accelerated approval in November 2018 for the second- or third-line treatment of ALK-positive metastatic non-small cell lung cancer.

The FDA based its decision to expand the indication of Lorbrena on data from the randomized, multicenter, open-label, active-controlled phase 3 CROWN trial, which was conducted in 296 patients with ALK-positive metastatic non-small cell lung cancer. These patients had not previously received treatment for metastatic disease.

“The (trial) showed that Lorbrena, when compared to cabozantinib (Cabometyx), had tremendous systemic responses as well as almost 98% of patients didn’t have brain metastases at one year,” Kazmi explains.

However, questions remain as to how this drug will affect the treatment of metastatic non-small cell lung cancers that have no genetic mutation such as ALK or EGFR, according to Kazmi. “There’s still a significant unmet need,” she says.

Moreover, Dr. Lecia Sequist, director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital in Boston, questions how Lorbrena compares head-to-head with the other newer drugs such as Alecensa (alectinib) and Alunbrig (brigatinib), which are also showing to be effective. “They are exponentially better for ALK and EGFR in terms of getting into the brain,” she says. “We’ve seen that when compared to older drugs, they are really doing a good job.”

Sequist notes that patients should be aware of a new set of possible side effects associated with Lorbrena use since the drug was specifically designed to get into the brain. She says, “These can cause mental and personality side effects that are a little different than we’ve seen with other ALK drugs, but they are usually well-managed by reducing the dosage and educating people about the types of side effects.” Other symptoms patients should monitor are swelling of the feet and legs, weight gain and changes to the triglycerides in cholesterol.

When it comes to watching and treating brain metastases, in general, Sequist emphasizes the importance of monitoring the brain along with the rest of the body — which can be difficult depending on a patient’s insurance. For those patients not diagnosed with brain metastases, she recommends they get an MRI at least once a year, or every six months if they are on a drug that doesn’t protect the brain as well, to monitor for disease spread.

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