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Pfizer's Lorbrena Produces Longest Progression-Free Survival Seen in ALK-Positive NSCLC Patients

NEW YORK – Pfizer's third-generation ALK inhibitor Lorbrena (lorlatinib) not only beat out its first-generation ALK inhibitor Xalkori (crizotinib) as a frontline treatment for ALK-positive advanced non-small cell lung cancer in the Phase III CROWN trial but also performed far better than newer competitors in its drug class.

The results, presented at the American Society of Clinical Oncology's annual meeting on Friday, showed that treatment with Lorbrena led to longer progression-free survival and better control and prevention of brain metastases compared to Xalkori. The CROWN trial included nearly 300 participants with ALK-positive advanced NSCLC who were randomly assigned to receive either Lorbrena or Xalkori.

At a press conference on Wednesday before the annual meeting, Benjamin Solomon, a medical oncologist at the Peter MacCallum Cancer Center in Australia, noted while presenting data from the CROWN trial that the progression-free periods patients experienced in this study are some of the longest ever reported in ALK-positive NSCLC. These are also the longest progression-free survival times observed with "any targeted therapy in lung cancer to date, to our knowledge, and speaks to the progress made in this area," Solomon added.

At a median follow-up of 60.2 months in the Lorbrena arm, the median progression-free survival was not reached. In the Xalkori arm, the median progression-free survival was 9.1 months at a median follow-up of 55.1 months. Sixty percent of patients on Lorbrena were alive without their cancers progressing at five years, while only 8 percent were alive without progression in the Xalkori arm.

In 2021, based on an earlier readout from the CROWN trial, the US Food and Drug Administration granted accelerated approval to Lorbrena as a first-line treatment for ALK-positive NSCLC based on a 72 percent reduction in the risk of disease progression or death versus patients on Xalkori. The updated results from this study lend further support behind Lorbrena's long-term benefit.

David Spigel, CSO at the Sarah Cannon Research Institute, who was not involved with the CROWN study and discussed the results at the press conference, said these are the "best results" he has seen so far for an ALK inhibitor in the first-line setting.

"We have not seen anything close to this," he said, adding that other drugs in this class, including second- and third-generation ALK inhibitors like Genentech's Alecensa (alectinib) and Takeda's Alunbrig (brigatinib), "have not reported … durable progression-free survival events of this magnitude."

However, Spigel noted that the comparison to Xalkori is a potential limitation in the CROWN study, because this older drug is not prescribed much in the US since newer ALK inhibitors have entered the market.

Still, based on cross-trial comparisons, which Solomon said should be made cautiously due to the differences in study design and patient cohorts, Lorbrena appears to best other drugs in its class. Median progression-free survival seen in previous studies of Alecensa and Alunbrig were 34.8 months and 30 months, respectively, Solomon noted. "This median progression-free survival in excess of 60 months [on Lorbrena] is something quite different," he said.

Solomon noted that about a quarter of ALK-positive NSCLC patients will have brain metastases at diagnosis and that involvement of the central nervous system "remains a major concern for these patients."

In the CROWN study, about a quarter of participants had baseline brain metastases. In this group, the five-year progression-free survival rate was 53 percent, and median progression-free survival was not reached at 60 months of follow-up.

Researchers also assessed the time it took patients to experience intracranial progression in the study by performing serial MRI scans of their brains every eight weeks. Among those who had baseline brain metastases, 83 percent had no intracranial progression on Lorbrena at five years, while all patients on Xalkori had experienced intracranial progression.

Among patients without baseline brain metastases, nearly all patients (96 percent) had not experienced intracranial progression at five years on Lorbrena versus 27 percent in the Xalkori arm. Only four of 114 patients developed disease progression in the brain on Lorbrena, Solomon said, all within the first 16 months of treatment. In the Xalkori arm, 39 of 109 patients developed brain metastases.

"In contrast to the rapid progression in the brain with crizotinib, time-to-intracranial progression was improved … with lorlatinib," Solomon said. "These results speak to the ability of lorlatinib not only to prevent progression of the existing brain metastases but to prevent or delay progression of new brain metastases."

In an exploratory analysis of circulating tumor DNA in 31 patients, the researchers noted that emerging new ALK mutations were not detected in samples collected at the end of treatment with Lorbrena. Solomon noted that this further supports the use of Lorbrena in this setting because acquired resistance can be an issue in ALK-positive NSCLC.

The treatment landscape for ALK-positive NSCLC has become increasingly crowded since Xalkori, the first ALK inhibitor, entered the US market in 2011. Novartis' Zykadia (ceritinib) entered the scene next in 2014, followed by Alecensa in 2015, Alunbrig in 2017, and Lorbrena in 2018 as options for advanced ALK-positive NSCLC patients who had progressed on Xalkori.

More recently, these drugs have been moving into earlier lines of treatment. Zykadia and Alecensa became a first-line option in advanced ALK-positive NSCLC in 2017, followed by Alunbrig in 2020 and Lorbrena in 2021.

When it comes to choosing which ALK inhibitor to prescribe a patient, Spigel noted that it should depend on a treating physician's comfort with each drug. Lorbrena's toxicity profile, for example, requires different management from other ALK inhibitors.

Spigel specifically noted Lorbrena's known toxicities that affect cholesterol and cognitive function. In earlier results from the CROWN trial, researchers found that 21 percent of patients in the trial reported cognitive effects, such as memory impairment, disturbance in attention, amnesia, cognitive disorder, and delirium. Also in the study, 16 percent of patients experienced mood effects on Lorbrena, including anxiety, depression, affect lability, affective disorder, agitation, irritability, and altered mood. He added that other ALK inhibitors largely don’t have these effects on cholesterol or cognitive function.

"There's an idea that I'll start with drug A and then switch to drug B at progression, and I'll get the benefits of both," Spigel said. "But we know in all cancer, not just lung cancer, that patients don't always make it to the next line of therapy, so you should use your best drug first. When you have a patient in front of you, you want to give the best drug you can give upfront that can be managed the best."