New Hope for Advanced Non-Small Cell Lung Cancer
- Research presented at 2024’s American Society of Clinical Oncology (ASCO) conference indicated that a drug called lorlatinib showed significant progress in treating a type of advanced non-small cell lung cancer known as ALK-positive.
- Lorlatinib is a type of drug known as a tyrosine kinase inhibitor.
- Promising results of the highly-anticipated 5-year follow-up of the phase 3 CROWN study showed that lorlatinib significantly improved progression-free survival (meaning the disease did not progress) for patients with this specific type of advanced lung cancer.
- The study authors commented that this was the longest progression-free survival that has ever been reported in advanced non-small cell lung cancer.
Research presented at this year's American Society of Clinical Oncology (ASCO) annual meeting, a massive conference where professionals present the latest in cancer research, showed lorlatinib, a type of drug known as a tyrosine kinase inhibitor, has shown real promise treating a specific type of non-small cell lung cancer (NCSLC). Research presented at ASCO reported the
highly-anticipated 5-year follow-up of the phase 3 CROWN study . In this trial, patients with a specific type of advanced NSCLC, ALK-positive, were randomized to receive either lorlatinib (i.e. Lorbrena, Pfizer) or crizotinib (Xalkori, Pfizer). ALK is a signaling protein which is inappropriately present on the tumors of about 5% of patients with NCSLC. Lorlatinib and crizotinib are both drugs in a class called tyrosine kinase inhibitors, which target ALK. In approximately 90% of patients with ALK-positive NSCLC, the cancer has already metastasized, or spread to other parts of the body, at the time of diagnosis. The exciting research was simultaneously published in the Journal of Clinical Oncology.
RELATED: There are remarkable new options for treating late-stage lung cancer The control arm treatment in the study, crizotinib, is a Food and Drug Administration (FDA)-approved treatment for adults with ALK-positive metastatic NSCLC. Earlier studies showed that crizotinib was superior to chemotherapy in such patients. The new research aimed to compare lorlatinib — and experts are excited about the results. "It is encouraging that the upfront benefits of lorlatinib over crizotinib continue for several years in more than half the patients. It also is encouraging that patients receiving lorlatinib had much fewer incidences of brain metastasis, which can be devastating,"
Dr. Leslie Busby , oncologist at Rocky Mountain Cancer Centers, told SurvivorNet.
What did the study find?
Lorlatinib was originally approved by the FDA in November 2018 as a second- and third-line drug, meaning that it could be given after a patient’s tumor had already stopped responding to the one or more previous treatment regimens. The CROWN study examined whether lorlatinib was superior in the first-line setting, meaning it was given as the first treatment course after patients were diagnosed. Previous reports of the CROWN study with shorter follow-up time had already shown improved progression-free survival (PFS) and intracranial activity for patients receiving lorlatinib compared to criztonib. PFS refers to time where patients are living and their disease has not progressed or worsened. As a result of these promising earlier reports of the CROWN study, lorlatinib received FDA-approval as a first-line treatment in March 2021. The new, five-year study provides that much more evidence of its effectiveness.
The significance of the 5-year study
In the CROWN study, 149 patients received lorlatinib and 142 received crizotinib as the first treatment after diagnosis with advanced ALK-positive NSCLC. One fourth of the patients had brain metastases, meaning that cancer had already spread to the brain, at the time of diagnosis. As the authors point out in the manuscript, brain metastases are a key clinical challenge in this disease as the prognosis in such patients is unfortunately quite poor. Five-year PFS, or the percentage of patients who lived five years without any evidence of cancer growth or death, was 60% among patients who received lorlatinib as compared to only 8% among patients who received crizotinib — an absolute difference greater than 50%. The study authors commented that this was the longest PFS that has ever been reported in advanced NSCLC. Similarly, the time to intracranial progression was also substantially longer in patients that received lorlatinib. Among the 114 patients assigned to lorlatinib who did not have brain metastases at time of diagnosis, only 4 (3.5%) patients went on to develop brain metastases during the five years of follow-up.
What does this study mean for patients?
The research indicates that patients with this specific type of advanced lung cancer should speak to their doctors about lorlatinib. The overall safety profile of the drug was consistent with previous analyses, and no new concerning safety signals were detected. The rate of adverse events during the study period was higher in patients who received lorlatinib as compared to those who received crizotinib (77% vs. 57%, respectively, for grade 3/4 adverse events). The study authors pointed out that more patients in the lorlatinib group developed high lipid levels (high cholesterol), but the rate of cardiovascular adverse events was similar in both groups at 28%. Even though there were more grade 3/4 adverse events with lorlatinib, the rates of having to stop the treatment due to treatment-related adverse events were similar in the two treatment arms. Most adverse events with lorlatinib were manageable by decreasing the dose of the drug, which did not appear to cause worse outcomes.
Understanding Advanced Lung Cancer
Dr. Busby pointed out that the new research means more tools for doctors to use to treat this specific type of lung cancer. "There are now three ALK inhibitors that have shown benefit over crizotinib in first line ALK positive NSCLC: lorlatinib, alectinib, and brigatinib. Most physicians were moving away from using crizotinib first line prior to this abstract. However, those decision were made before long-term data was widely available and this helps support that decision," he explained. "One issue that is a challenge to determine is with three highly effective drugs, which one is the best — both in terms of efficacy AND toxicity.” He added that there are no direct comparisons of the complication profiles of the three drugs, and comparisons across different trials are known to be problematic.
Will patients live longer?
Also, PFS is frequently used in approval of new cancer drugs, but it is different than the outcome which matters most to patients — overall survival — which is how long the patient will survive after treatment begins. "Due to problems around using PFS as the primary outcome, I am interested to see if this benefit ends up improving overall survival," Dr. Busby added. He also noted that these data raise numerous interesting questions that will hopefully be explored in future studies. “With many patients doing so well for so long, future questions to look at include whether there are patients with such a good response that they can safely stop the drug. Another question is whether adding these drugs to another active therapy such as immunotherapy will deepen the response and allow coming off therapy. Essentially, are there patients we are able to cure?”
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