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Advanced Test Predicts ALK Inhibitor Success In Lung Cancer
Researchers have developed a test that accurately predicts whether patients with ALK-positive lung cancer will respond to targeted treatments. This could significantly enhance personalised cancer therapies and overcome treatment resistance.
A new study led by researchers at the University of Barcelona has demonstrated that dynamic BH3 profiling (DBP), a novel functional test, can accurately predict the effectiveness of ALK inhibitors in patients with non-small cell lung cancer (NSCLC). This finding could greatly advance personalised cancer treatments for the roughly 5 percent of NSCLC patients with ALK gene alterations.
A functional test for precision treatmentNon-small cell lung cancer accounts for 85 percent of all lung cancer cases, and among these, mutations in the ALK gene lead to unchecked tumour growth in a small but significant subset of patients. Targeted therapies using ALK inhibitors have transformed treatment outcomes for these patients, improving survival and quality of life. However, until now, there has been no reliable way to predict which tumours will respond best to these drugs.
The new research, published in Cell Death and Disease, demonstrates that DBP could fill that gap. Much like an antibiogram helps doctors choose the right antibiotic for a bacterial infection, DBP directly tests how a patient's living tumour cells react to ALK inhibitors, which helps to pinpoint the most effective therapy.
This technique could complement existing genomic tests and sequencing tools, especially in complex cases.
"This technique could complement existing genomic tests and sequencing tools, especially in complex cases," said Professor Joan Montero, who led the study. Montero is a faculty member at the University of Barcelona and a researcher with CIBER-BBN and the Institute for Bioengineering of Catalonia (IBEC).
"These targeted therapies confer the longest survival in non-small cell lung cancer and are better tolerated than cytotoxic agents. The use of ALK inhibitors in the clinic not only increases patient survival, but also improves their quality of life", says Montero
"In this context, dynamic BH3 profiling could complement the application of genomic assays and mass sequencing that routinely guide the use of these targeted therapies in cancer patients, especially in complex cases."
The role of MCL-1 in drug resistanceThe study also highlights a key reason why some tumours eventually stop responding to ALK inhibitors: resistance driven by the protein MCL-1. This anti-apoptotic protein helps cancer cells evade programmed cell death, a central mechanism that many treatments rely on to eliminate tumours.
This anti-apoptotic protein helps cancer cells evade programmed cell death.
"Therapy-resistant cancer cells often adapt by increasing anti-apoptotic defences," explained first author Fernando Martín. "We now know that MCL-1 plays a major role in this resistance mechanism in ALK-positive NSCLC."
Importantly, the team showed that adding BH3 mimetics, drugs that block anti-apoptotic proteins, can restore sensitivity to ALK inhibitors, both in lab experiments and animal models. The findings suggest that combining ALK inhibitors with BH3 mimetics may overcome resistance and prolong treatment effectiveness.
A more personalised approach to lung cancerALK inhibitors are already considered a game-changer for ALK-positive NSCLC. These targeted therapies are more effective and better tolerated than traditional chemotherapy and can even penetrate the blood-brain barrier, which is a crucial benefit, since one-third of patients with advanced NSCLC develop brain metastases.
But despite these advances, treatment resistance remains a challenge.
By using DBP to monitor a tumour's real-time response and swiftly detect emerging resistance, clinicians can proactively tailor treatment combinations, significantly improving patient outcomes.
Next steps in researchThe research team is now investigating how prevalent resistance mechanisms, such as MCL-1 overexpression, are among patients, and evaluating the feasibility of integrating DBP into routine clinical practice. Additionally, they aim to explore whether prolonged drug exposure might trigger other resistance pathways, including therapy-induced senescence.
"Our ultimate goal is to personalise cancer treatment at the functional level," Montero and Martín concluded. "With tools like DBP, we can better predict how each tumour will behave and stay one step ahead of resistance."
Radiation Delay In NSCLC May Aid Outcomes, But Raises Toxicity Risks
Deferring upfront CNS-directed radiation in EGFR-variant and ALK-positive NSCLC may improve outcomes but raises treatment-related toxicity risks.
Deferring upfront CNS-directed radiation in EGFR-variant and ALK-positive NSCLC may improve outcomes but raises treatment-related toxicity risks: © stock.Adobe.Com
For patients with EGFR-variant and ALK-positive non-small cell lung cancer (NSCLC) with brain metastases, deferring up-front central nervous system-directed radiation therapy has been associated with improved outcomes, but with an increase in treatment-related toxicity, according to recent findings.
Dr. Luke R.G. Pike and colleagues published their findings in a recent article from JAMA Oncology. Pike is a radiation oncologist and director of brain radiation oncology at Memorial Sloan Kettering Cancer Center in New York City.
"In the era of [central nervous system]-active [tyrosine kinase inhibitors], the largest multicenter study to date of patients with EGFR-variant and ALK-positive NSCLC found that up-front [stereotactic radiosurgery] was associated with superior local control and time to [central nervous system] progression at the cost of increased treatment-related toxic effects in a minority of patients. Patients with higher-risk [brain metastases], including those with lesions that are large, symptomatic or located in eloquent areas, may benefit more from early [stereotactic radiosurgery]," Pike and his colleagues wrote in the article.
Pike and his colleagues came to their findings after reviewing three multi-institutional cohort studies from the United States and Japan between 2013 to 2022. These studies comprised 591 patients, 52% of whom were male and who had an age range of 35 to 92 years old. Investigators compared central nervous system-active tyrosine kinase inhibitors with or without radiotherapy.
Contemporary practice guidelines, Pike and his colleagues noted, support the deferral of up-front stereotactic radiosurgery for some patients with EGFR-variant and ALK-positive NSCLC who have limited, asymptomatic brain metastases.
Given a lack of clear survival benefit, Pike and his co-authors stated that, "based on clinical factors and patient preferences [specific points] appear reasonable in light of the available evidence." These points include:
Looking forward, Pike and his colleagues stated that randomized clinical trials testing a strategy of using central nervous system-active tyrosine kinase inhibitors with or without stereotactic radiosurgery are warranted.
Brain metastases, as the reseach states, have been shown to be a common cause of morbidity and mortality among patients with EGFR-variant and ALK-positive NSCLC. Stereotactic radiosurgery is the current standard of care for limited brain metastases, and it has shown what Pike and his fellow researchers described as "excellent long-term lesion control rates", although they note that late cerebral radionecrosis, or damage to brain tissue, can be a concern for long-lived and heavily treated patients.
Brain metastases, as explained by the American Lung Association on its website, can occur when cancer cells metastasize, or spread from the original cancer site in the lung, to the brain. Brain metastases may form one or multiple tumors in the brain, and as the metastatic brain tumors grow, they create pressure on parts of brain and they can change the function of surrounding brain tissue, which can cause a range of symptoms.
Reference:"Management of EGFR-Variant and ALK-Positive Non–Small Cell Lung Cancer Brain Metastasis" by Dr. Luke R. G. Pike et al., JAMA Oncology.
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Biomarker Testing Is On The Rise, But Turnaround Time Has Not Improved
Biomarker testing in patients with advanced non-small cell lung cancer (NSCLC) has increased in recent years, but turnaround time for test results has remained roughly the same, a large study suggests.
The study also suggests that longer turnaround times are associated with early use of non-targeted treatment and poor outcomes. These results were presented in a poster at the NCCN Annual Conference 2025.
For this study, researchers analyzed deidentified electronic health records from the Flatiron Health database. The study included 33,945 patients who were diagnosed with advanced NSCLC during 2011-2023 and were tested for at least 1 biomarker, including PD-L1, ALK, BRAF, EGFR, KRAS, MET, RET, and ROS1.
The average number of biomarkers tested per patient increased over time, from 2.0 in 2011 to 6.8 in 2023. In 2023, approximately 80% of patients had ALK/EGFR testing, and approximately 50% of patients underwent testing for all 8 biomarkers evaluated.
Overall, the use of next-generation sequencing (NGS) increased over time, and the use of non-NGS testing methods generally decreased. However, immunohistochemistry remains the predominant testing method for PD-L1.
The researchers also found that turnaround time for biomarker testing results plateaued at about 20 days. Of the 4020 patients with ALK+/EGFR+ advanced NSCLC, 54.8% did not meet the 2-week turnaround time threshold that is recommended in guidelines.
One in 8 patients (12.4%) with ALK+/EGFR+ advanced NSCLC received early non-targeted treatment rather than testing-informed treatment. The use of early non-targeted treatment was associated with longer turnaround time. In fact, the odds of receiving early non-targeted treatment increased 9% with each additional day of turnaround time (odds ratio, 1.09; P <.001).
The researchers noted than 1 in 4 (24.9%) early non-targeted treatment regimens included immunotherapy, which is "known to be ineffective in this patient population."
The team also found that early non-targeted treatment was associated with worse real-world progression-free survival (rwPFS) for the patients with ALK+/EGFR+ advanced NSCLC. The median rwPFS was 11.0 months for patients who received testing-informed treatment and 9.0 months for patients who received early non-targeted treatment (P <.05).
The researchers concluded that slower turnaround time for biomarker testing is associated with early non-targeted treatment in patients with ALK+/EGFR+ advanced NSCLC, a practice that is "common," "suboptimal," and "associated with worse outcomes." Therefore, "future testing needs to balance use of high-throughput methods" with turnaround time.
Disclosures: No disclosures were provided.
This article originally appeared on Cancer Therapy Advisor
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