Patients with non-small cell lung cancer and brain metastases often have a poor prognosis. Recent studies investigating the safety and efficacy of targeted and combination therapies provide hope for improved quality of life and extended life for these patients.
NSCLC spreads most frequently to the brain. Of patients with NSCLC, nearly 10% have brain metastases when they are diagnosed, and up to 30% will develop brain metastases over the course of their disease. The incidence of brain metastases is increasing as improved systemic therapies have been developed that predominantly target extracranial disease, thus prolonging life and allowing cancer to spread to the brain.1
From the start of treatment, the median survival of patients with brain metastases is 7 months, while high-risk patients may only live for 3 months.2
In patients with a newly diagnosed solitary brain metastasis, surgical resection and radiation are recommended for increasing lifespan in relatively young patients with good functional status.3
For many years, whole-brain radiation therapy (WBRT) has been the standard of care for patients with multiple NSCLC brain metastases. Radiotherapy is effective; however, radiation is associated with brain edema and changes in blood vessels with the aggravation of intracranial pressure. Neurocognitive toxicity associated with WBRT can complicate matters in 2% to 5% of patients, with these late effects occurring several months to years after treatment.
To avoid these toxicity issues, patients with a limited number of metastases and a better prognosis have been advised to undergo stereotactic radiosurgery alone, which has led to similar survival rates compared with initial treatment with WBRT and stereotactic radiosurgery. Improved local and distant central nervous system control, and decreased risk of death were reported in patients receiving adjuvant WBRT compared with observation only.
Stereotactic radiosurgery alone and surgical resection followed by stereotactic radiosurgery or WBRT are recommended by current National Comprehensive Cancer Network guidelines for treatment of limited brain metastases in selected patients (those with symptomatic metastases or whose tumor tissue is needed for diagnosis).
Usually, CNS metastases are not sensitive to chemotherapy, with an average response rate of brain metastases from solid tumors of 20% to 40%. Cytotoxic chemotherapy has a limited role because of poor blood-brain barrier penetration.
Quality of life and mood can be improved with early use of palliative care in this setting. These improvements are also associated with improved survival. Additional supportive medications, including steroids and antiseizure medications, are also frequently used in patients with brain metastases. Corticosteroids can provide symptom relief by controlling intracranial swelling resulting from the brain metastases, but steroids have considerable adverse effects that should be considered before use.
Anaplastic lymphoma kinase (ALK) rearrangement in NSCLC is a common therapeutic target. ALK tyrosine kinase inhibitors (TKIs) are used to treat patients with the ALK rearrangement.
In patients with ALK-rearranged NSCLC who have been treated with ALK inhibitors, the incidence of CNS metastases is particularly high, from 45% to 70%, indicating that metastasis to the brain is a common defect with ALK inhibitors. The cumulative risk of intracranial metastasis in ALK-positive NSCLC patients was 23.8%, 45.5% and 58.4% at 1, 2 and 3 years from the initial diagnosis.4
Patients with ALK rearrangement can be treated more successfully with ALK inhibitors crizotinib (Xalkori, Pfizer), alectinib (Alecensa, Genentech), ceritinib (Zykadia, Novartis), and brigatinib (Alunbrig, Ariad) than with chemotherapy. To complicate matters, patients typically experience resistance to these drugs.
Metastases from the lungs to the brain.
Patients with ALK-positive NSCLC are often started on crizotinib or ceritinib treatment, with an objective response rate of 57% in previously treated patients. Some patients fail to respond to treatment, and resistance has been reported after an average of 11.3 months.
With crizotinib therapy, the disease control rate in untreated and treated patients with brain metastases was 56% and 62%, respectively.5 The response rate in untreated and treated patients with brain metastases was 18% and 13%.
In a study designed to determine the clinical impact of crizotinib on CNS progression in patients with ALK-positive NSCLC, 81% of patients received crizotinib as first- or second-line treatment for recurrent or advanced disease. Of the 26 patients who had brain metastases, 13 had previously undergone radiotherapy or surgery, whereas 13 patients had untreated brain metastases.
Although the overall response rate was 66%, disease progression was reported in 48 of 59 patients, with 24 patients exhibiting CNS progression. Patients who had untreated brain metastases prior to crizotinib therapy or poor performance status had significantly shorter progression-free survival.
Following crizotinib treatment, the most common site of relapse is the CNS, which is attributable to poor accumulation of the drug because it is readily effluxed from the CNS. Crizotinib has a low blood-brain barrier penetration, which is demonstrated by the low intracranial response rate of 7% in ALK-rearranged NSCLC patients.
Second-line ALK inhibitors, including ceritinib, alectinib, and brigatinib, and the third-generation ALK inhibitor, lorlatinib (PF-06463922, Pfizer), were developed to combat crizotinib resistance.
Alectinib has long-term benefits in patients who have not received ALK inhibitors. In a phase 1/2 study, 25 of 46 patients continued treatment after 3 years, which contributed to a 3-year PFS of 62% and overall survival of 78%. Furthermore, 6 of the 14 patients who had brain metastases at baseline had not progressed after 3 years.
Alectinib is also effective in ALK-positive patients who are resistant to crizotinib. A phase 2 study reported an objective response rate of approximately 50%, with a median PFS of 8.1 months and a median duration of response of 13.5 months.
Importantly, 75% of patients with crizotinib-resistant NSCLC and measurable CNS lesions had an objective response to alectinib, with a CNS objective response rate of 57% reported in a similar subset of patients.
In a phase 3 randomized trial comparing alectinib with crizotinib in treatment-naïve patients with ALK-positive NSCLC, alectinib use was associated with a lower chance of progression, increased 12-month event-free survival, higher response rate, fewer adverse events and a lower rate of CNS progression. The high efficacy of alectinib Is thought to be due to high penetration to the brain and poor efflux from the brain.
Brigatinib is an ALK TKI approved for patients with ALK-positive NSCLC who are intolerant to or have progressed on crizotinib. In the phase 2 ALTA trial, approximately 70% of patients had brain metastases. The overall response rate was approximately 50%, with intracranial response rates of 42% with 90 mg brigatinib and 67% with 180 mg brigatinib.
Unfortunately, as with crizotinib, patients develop acquired resistance to second-generation ALK TKIs. Furthermore, these patients have a higher incidence of on-target mutations than crizotinib-resistant tumors.
Lorlatinib, a third-generation inhibitor, was designed to penetrate the blood-brain barrier and overcome ALK resistance mutations.6
A first-in-human phase 1 study of lorlatinib enrolled 54 patients, including 41 patients with ALK-positive NSCLC and 39 patients with CNS metastases. Of these patients, 19 achieved an objective response, including 11 of 26 patients who had received at least two previous TKIs.
Of the patients with CNS lesions at baseline, 32 had ALK-positive NSCLC, with 10 achieving a complete or partial intracranial response. Of the responders, half had previously received at least two prior ALK TKI therapies and 40% had never received cranial irradiation.
Recently, the FDA granted priority review to lorlatinib for use in patients with ALK-positive metastatic NSCLC who have progressed on ALK TKIs. In a phase 2 trial, the overall response rate was 69%, with an intracranial response rate of 68% in patients who progressed on crizotinib. In patients previously treated with other ALK inhibitors, the response rate was 33% and the intracranial response rate was 42%. Patients who had received two or more ALK inhibitors had an overall response rate of 39% and an intracranial response rate of 48%.
Developments in immunotherapy treatment options for patients with NSCLC have led to increased survival of patients in clinical trials. However, trials evaluating anti–PD1 therapies exclude patients with active or untreated brain metastases.
A retrospective study was designed to investigate the intracerebral efficacy and safety of nivolumab (Opdivo, Bristol-Myers Squibb) in patients with NSCLC and brain metastases. Of the 191 patients, 43 had brain metastases, with 34 receiving prior local therapies.
The intracerebral and extracerebral objective response rates were similar at 9% and 11%, respectively. The safety profile was acceptable, with a 10% overall neurological adverse event rate. These results demonstrate that the intracerebral activity of nivolumab is not inferior to the extracerebral activity, with no major associated safety issues. Further studies are needed to better understand immunotherapy efficacy in patients with brain metastases.
With the development of improved systemic therapies that prolong life but have a limited impact on intracranial disease, cancer is able to spread to the brain, and brain metastases are becoming more common in patients with NSCLC who already have high rates of brain metastases. In patients with ALK-positive NSCLC, ALK TKIs lead to increased intracranial response rates and prolonged survival. Futhermore, immunotherapeutic options have shown initial activity in patients with brain metastases, which may provide additional treatment options for these patients.
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» Immunotherapy Benefits
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