Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management ...
Opinion: Osimertinib Plus Chemo May Enhance Outcomes In Metastatic EGFR-Mutated Lung Cancer
Oncology nurses play a vital role in informing patients about the importance of molecular testing and brain imaging in EGFR-mutated lung cancer.
Amanda Brink, DNP, APRN, FNP-BC, AOCNP
In the United States, lung cancer holds the unfortunate distinction of being the second most frequently diagnosed cancer among both men and women, following prostate cancer for men and breast cancer for women. Projections for 2024 indicate that there will be over 230,000 new cases of lung cancer, with more than 125,000 individuals succumbing to the disease.1
Targeted therapies guided by molecular diagnostics have become a standard approach in treating patients with non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC harboring an epidermal growth factor receptor (EGFR) mutation can be treated with a class of medications known as tyrosine kinase inhibitors (TKIs), some of which specifically target EGFR.2 These TKIs have been shown to have superior effectiveness compared to first-line platinum-based chemotherapy in patients with advanced NSCLC with an EGFR mutation.3
EGRF-positive lung cancer represents about 10-15% of lung cancer diagnoses in the United States.4 It is more common in patients of Asian descent2 and those with little to no smoking history.4
First-generation TKIs targeting EGFR include gefitinib and erlotinib, while afatinib is a second-generation TKI targeting EGFR. Despite a notably high objective response rate (ORR) of 60–70%, most patients treated with these agents ultimately develop resistance, with progression-free survival (PFS) averaging 9 to 15 months. Resistance commonly arises from the T790M mutation in EGFR exon 20. Third-generation TKIs, including osimertinib (Tagrisso), target both the EGFR mutations and the T790M-resistance mutation.3
Unfortunately, patients with lung cancer harboring an EGFR or anaplastic lymphoma kinase (ALK) mutation are more commonly diagnosed with brain metastasis than other patients with NSCLC, with estimates as high as 70%.5 Therefore, it is crucial for EGFR TKIs to effectively treat a patient's brain metastasis along with other areas of systemic disease.
Central Nervous System Efficacy of Osimertinib in EGFR-Mutated NSCLC
In a clinical trial involving patients with untreated EGFR-mutated advanced NSCLC and baseline central nervous system (CNS) metastases, osimertinib demonstrated a 52% reduction in the risk of CNS progression or death compared to erlotinib (Tarceva) and gefitinib (Iressa). Despite the known benefit of osimertinib therapy, questions persist regarding whether adding chemotherapy to osimertinib may further enhance outcomes compared with osimertinib monotherapy, especially in patients with baseline CNS metastases.6
Jänne et al.6 conducted a phase 3, international open-label, randomized clinical trial in untreated patients with EGFR-mutated advanced NSCLC. Eligible patients were randomly assigned 1:1 to receive either osimertinib plus platinum-pemetrexed chemotherapy or osimertinib monotherapy.
A total of 557 patients participated in the study, all of whom underwent baseline brain imaging before starting treatment. Baseline characteristics were balanced between the groups. Of the 222 patients with baseline CNS disease, the combination of osimertinib and chemotherapy yielded a 24-month CNS PFS rate of 74% compared to 54% with chemotherapy alone. However, the observed difference did not reach statistical significance (HR, 0.58; 95% CI, 0.33-1.01). Interestingly, the number of patients who achieved a complete response in the CNS was higher in the combination arm (59%) compared to the monotherapy arm (43%).
Notably, among the limited number of patients with baseline leptomeningeal metastases, 8 out of 13 patients in the combination treatment group remained alive and free from CNS progression, compared to none in the monotherapy arm.
Findings across the entire study population, including those with and without CNS disease, were also favorable for combination therapy, with a trend towards enhanced overall survival.
Nursing Considerations
After receiving a cancer diagnosis, patients are understandably eager to commence anti-cancer treatment promptly. However, in the case of patients newly diagnosed with lung cancer, it is crucial to wait until biomarker testing results are available before determining the most suitable treatment approach. When patients inquire about the timing of treatment initiation with their oncology care team, oncology nurses can provide education regarding the treatment implications associated with obtaining biomarker results.
Patients may also experience difficulty tolerating a brain MRI due to claustrophobia. Therefore, it is crucial to effectively communicate to patients the significance of undergoing brain imaging to monitor for brain metastasis in specific cancer types, such as EGFR-mutated NSCLC. When patients know the rationale behind these tests, they are often more inclined to have them done.
In conclusion, lung cancer remains a significant health concern in the United States, with a high incidence and mortality rate projected for 2024. Targeted therapies guided by molecular diagnostics, particularly for EGFR-mutated NSCLC, have revolutionized treatment approaches and improved outcomes for patients. Oncology nurses play a crucial role in patient education and support throughout the treatment journey, emphasizing the importance of biomarker testing and brain imaging for comprehensive disease management. By continuing to develop next-generation therapies and exploring combination approaches, we can aim for improved outcomes in patients with EGFR-mutated NSCLC and CNS metastases.
References
Alectinib Significantly Improves Disease-Free Survival In ALK-Positive NSCLC
Seeking more data on adjuvant alectinib in patients who have resectable ALK-positive non–small cell lung cancer (NSCLC), investigators compared outcomes vs chemotherapy.
At 2 years in the ALINA trial, patients on alectinib had a 76$ reduced risk of death or disease recurrenceImage Credit: PeakStock - stock.Adobe.Com
Disease-free survival (DFS) among patients living with resectable ALK-positive non–small cell lung cancer (NSCLC) showed significant improvement following adjuvant treatment with the kinase inhibitor, alectinib, compared with platinum-based chemotherapy, according to a new primary data analysis published in The New England Journal of Medicine.
ALK-positive disease accounts for 4% to 5% of all NSCLC cases. Patients with this cancer subtype also tend to be younger, nonsmokers, and diagnosed at a more advanced stage compared with individuals who receive a diagnosis of ALK-negative NSCLC.
In the global phase 3 open-label ALINA trial (NCT03456076), between 4 and 12 weeks after surgical rection for their cancer (lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy, patients were randomized 1:1 to treatment with either 600-mg twice-daily oral alectinib (n = 130) or intravenous chemotherapy (n = 127) for four 21-day cycles, which is the current standard of care for ALK-positive NSCLC. All patients included had completely resected ALK-positive NSCLC stage 1B, II, or IIIA. DFS, the primary end point, was investigated hierarchically in patients with stage II or IIIA disease and an intention-to-treat (ITT) cohort. Secondary end points were central nervous system (CNS) DFS, overall survival, and safety.
"Although the treatment landscape for early-stage NSCLC is rapidly evolving with the approval of cancer immunotherapy and targeted therapy regimens," the authors wrote, "adjuvant targeted therapy in patients with resectable NSCLC harboring a rearrangement in the ALK gene (ALK-positive NSCLC) warrants evaluation."
For patients with stage II or IIIA disease—116 patients receiving alectinib and 115 receiving chemotherapy—there was a 76% reduction in risk of disease recurrence or death with alectinib vs chemotherapy (HR, 0.24; 95% CI, 0.13-0.45; P < .001), in that 93.8% of patients who received treatment with alectinib had DFS at 2 years compared with 63.0% treated with chemotherapy; at 3 years, the numbers were 88.3% and 53.3%, respectively. A similar trend was seen for the ITT population: 93.6% vs 63.7%, for another 76% reduced risk (HR, 0.24; 95% CI, 0.13-0.43; P < .001) at 2 years, and 3 years, 88.7% and 54.0%, respectively.
In addition for the ITT cohort, there was a clinically meaningful benefit for CNS DFS, at a 78% reduction in risk of disease recurrence or death with alectinib vs chemotherapy (HR, 0.22; 95% CI, 0.08-0.58).
Alectinib was administered for 2 years or the first of disease recurrence, unacceptable toxicity, or consent withdrawal. Chemotherapy could be cisplatin 75 mg/m2 and vinorelbine 25 mg/m2 on days 1 and 8, gemcitabine 1250 mg/m2 on days 1 and 8, or pemetrexed 500 mg/m2 on day 1. Carboplatin at an area under the curve of 5 or 6 mg/mL/min could be substituted for cisplatin if patients could not tolerate the latter.
Female patients comprised more of the alectinib cohort vs the chemotherapy cohort (57.7% vs 46.5%), as well as those without a smoking history (64.6% vs 55.1%). No patients overall received radiotherapy.
Median follow-up for the ALINA trial was 27.8 months overall, and slightly longer in the chemotherapy vs the alectinib group: 28.4 vs 27.8 months. By data cutoff, 3 times more patients with stage II or IIIA disease in the chemotherapy group had died or experienced disease recurrent vs the alectinib group: 45 vs 14. In the ITT analysis, these patient totals were 50 and 15, respectively. The most common site of disease recurrence was the brain.
In the safety analysis of 248 patients, median duration of alectinib treatment was 23.9 months, and chemotherapy, 2.1 months. Most patients in each group reported at least 1 adverse event (AE); no fatal AEs were reported. The most common AEs were increased creatine kinase, constipation, nausea, and decreased appetite.
The investigators highlighted that alectinib's DFS benefit was consistent, even when evaluating outcomes by disease stage, race, sex, and smoking status, and that the few cases of brain metastases they saw—3.1% of the alectinib group and 11.0% of the chemotherapy group—indicate alectinib's potential to prevent or delay CNS recurrence.
They concluded by emphasizing the importance of biomarker testing for ALK alteration in all stages of NSCLC.
"Currently, biomarker testing for ALK alterations in resectable NSCLC is mainly performed to exclude patients from receiving immunotherapy," they wrote, "but routine ALK testing should also support identification of patients who are likely to benefit from adjuvant alectinib."
Reference
Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in eesected ALK-positive non–small-cell lung cancer. N Engl J Med. 2024;390(14):1265-1276. Doi:10.1056/NEJMoa2310532
Roche Wins FDA OK For Alecensa In Early Lung Cancer
The Food and Drug Administration has made a medicine from Roche the first specifically available for early treatment of lung tumors driven by a well-known cancer gene.
On Thursday, the agency cleared use of the drug, Alecensa, after surgical removal of a tumor in patients whose non-small cell lung cancer is positive for mutations in a gene called ALK. The approval makes Alecensa the first targeted treatment in that so-called adjuvant setting, during which patients typically receive chemotherapy.
The approval is the latest step in treatment for the most common form of lung cancer and one of the leading causes of cancer-related deaths. An estimated 125,000 people in the U.S. Die each year from lung cancer, and 80% to 85% of lung tumors are of the "non-small cell" variety, according to the American Cancer Society.
Over the last decade, drugs that harness the immune system have become standard options for the disease. Some are available earlier in treatment, either before or after a tumor is surgically removed.
Several medicines targeting genetic drivers of certain lung tumors, like ALK and EGFR, have also emerged and become widely used. So have medicines for people whose cancers have so-called RET fusions or are what's known as ROS1-positive. Drugs aimed at another lung cancer target, TROP2, are in advanced testing and one, from AstraZeneca and Daiichi Sankyo, could be approved by the end of the year.
Roche's drug is for the estimated 5% of lung cancer patients with ALK mutations. Alecensa is already available for those with metastatic disease, as are Pfizer's Xalkori and Takeda's Alunbrig. But until Thursday, none had been available right after surgery and before a tumor spreads elsewhere. Cancers recur in about half of patients whose lung tumors are surgically removed, according to Roche.
Additionally, those with ALK mutations are typically diagnosed "at a younger age, often face recurrence and have a higher risk of developing brain metastases" than people with other types of non-small cell lung cancer, said Ken Culver, head of research and clinical affairs at the patient advocacy group ALK Positive, in a statement provided by Roche.
In testing, Alecensa reduced the risk of disease progression or death by 76% compared to chemotherapy in a study of 257 patients. Median disease-free survival, a measure of disease recurrence, was just over 41 months for people who received chemotherapy, but wasn't reached in those who received Alecensa. Similar results were seen in the subgroup of patients with Stage 2 or 3A disease.
Liver damage, constipation, muscle pain, COVID-19 and fatigue were among the most common adverse events in patients who received treatment in the study.
The application was approved one month ahead of the FDA's decision deadline as part of the "real-time oncology review" program, which allows the agency to begin evaluating an application before it is completed.
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