NEW YORK – A case report of a mother and daughter who both carried germline ALK mutations and developed neuroblastoma highlighted the potential benefits of targeted therapy treatments and surveillance for patients with germline mutations in cancer predisposition genes.
The case report, published in JCO Precision Oncology in April, featured the treatment strategies and outcomes for two neuroblastoma patients, a 6-month-old infant and her 36-year-old mother, who both carried a germline ALK R1275Q mutation and received ALK inhibitor treatment.
"What we learned is that these [germline ALK-mutant] patients are exquisitely sensitive and that they respond beautifully to ALK inhibition and their responses are sustained," said Yaël Mossé, first author of the study and professor of pediatrics at Children's Hospital of Philadelphia Cancer Center. "We think we can cure patients who have germline ALK mutations, regardless of whether they have one tumor or they have metastatic disease, only with an ALK inhibitor."
Germline ALK mutations were first identified as a cancer predisposition gene for neuroblastoma in 2008. The researchers, which included Mossé, concluded at that time that heritable ALK mutations were the main cause of familial neuroblastoma.
In other pediatric cancers with somatic ALK fusions, such as certain lymphomas or inflammatory myofibroblastic tumors (IMT), ALK inhibitors have proven to be active and Pfizer's Xalkori (crizotinib) was approved in 2022 for ALK-positive pediatric IMT.
However, neuroblastomas are more likely to have germline ALK mutations, rather than somatic ALK alterations, such as fusions, Mossé said. "For neuroblastoma, where the biology [of ALK] is completely different, we did not really see any activity except for in this patient [in the case report]," she continued.
There have been some small studies of ALK inhibitors in this setting, such as a Phase I trial from Mossé's group evaluating Pfizer's third-generation ALK inhibitor Lorbrena (lorlatinib) in children and adults with relapsed or refractory ALK-driven neuroblastoma. In that study, 30 percent of pediatric patients and 67 percent of adult patients responded to single-agent Lorbrena. When combined with chemotherapy, the response rate rose to 63 percent in the pediatric group and was not yet evaluable for adults in the study.
Shakeel Modak, chief of the neuroblastoma service at Memorial Sloan Kettering Cancer Center who was not involved with the JCO Precision Oncology case report, noted that Lorbrena has become the "drug of choice" for relapsed or refractory neuroblastoma "based on higher reported response rates, pediatric friendly tablets and because it appears to be the most potent and specific of the ALK inhibitors."
He added, however, that response rates to Lorbrena in children with neuroblastoma are much lower than in adults or adolescents.
"Therefore, it is not the ideal ALK inhibitor for neuroblastoma, and exploration of other ALK inhibitors or a better understanding of the mechanism of resistance to lorlatinib in neuroblastoma is warranted," he said.
In the case report, ALK inhibitor treatment proved to have excellent outcomes for these two patients. Patient one first presented with neuroblastoma at 6 months of age. She received chemotherapy and surgery, but six months later, a new mass developed and she had elevated urinary catecholamines, or certain hormones present in urine that can be used to measure stress due to tumor growth. After surgery on the second tumor, her urinary catecholamines remained elevated.
When another mass developed, her clinicians were preparing to deliver a high-dose chemo treatment, which is higher risk for these patients, and ordered germline testing, which showed the ALK R1275Q mutation. Instead of the high-dose chemo, the patient was enrolled in a Phase I trial of the first-generation ALK inhibitor Xalkori. On study, she had an early complete response and ended up receiving Xalkori for a total of five years through a compassionate access program. The patient has remained in remission eight years after stopping therapy.
The second patient in the case report, the 36-year-old mother of patient one, was found to carry the same heterozygous germline ALK R1275Q mutation as her daughter. The researchers noted that genetic counseling was provided and surveillance imaging was recommended but not pursued. During her second pregnancy, she presented with left flank pain and imaging showed bilateral adrenal tumors.
The patient delivered her child early and began treatment with Xalkori five days following delivery. After one month, scans showed stable disease and her urinary catecholamines had normalized. She switched treatment to Genentech's second-generation ALK inhibitor Alecensa (alectinib) due to toxicity on Xalkori and then underwent surgery to remove the bilateral adrenal tumors. She continued on Alecensa for just over two years after achieving a complete response following surgery.
Both patients return for surveillance every six months, including circulating tumor DNA (ctDNA) testing, whole-body magnetic resonance imaging surveillance, and urine catecholamine testing.
Mossé noted that the second patient presented an interesting dilemma for how to monitor adults with a genetic predisposition to neuroblastoma. Currently, the guidelines only recommend surveillance for patients under the age of 10, even with the presence of a germline ALK mutation, because the prevalence of neuroblastoma drops significantly as patients get older.
However, the second patient in the case study developed her cancer at age 36. "We knew the mother had a germline mutation, and we really pondered whether we should screen mom [for cancer]," Mossé said. "Based on the guidance and based on everything we knew about this disease, it seemed unlikely that, in her 30s, she would develop neuroblastoma and, as we wrote, we decided to forego surveillance of the mom."
Mossé said it wasn't clear why the mother developed her cancer later in life, suggesting that pregnancy may have caused changes in her body that spurred the growth of cancer.
Mossé suggested that ctDNA monitoring may be a promising method to more easily monitor adults with germline ALK mutations for neuroblastoma. In the case report, ctDNA was used to monitor these patients alongside imaging.
"My hope is that, one day, ctDNA can replace any type of radiographic surveillance and these patients can just have a blood test," she said.
Modak agreed that surveillance could be increased for adults with germline ALK mutations, but it is currently unclear what age that surveillance should continue until and what value the increased surveillance might add.
"Nevertheless, my practice is to do surveillance with yearly scans," Modak said. "Since the association of germline ALK mutations and neuroblastoma is relatively recent, I have carried out surveillance only in individuals through their 30s and not beyond."
From a therapy perspective, Mossé and her colleagues at the UK nonprofit Cancer Grand Challenges' Knocking Out Oncogenic Drivers and Curing Childhood Cancer (KOODAC) initiative are working with Nurix Therapeutics to develop a new type of ALK therapy for neuroblastoma patients, an ALK protein degrader. They hope to have an ALK protein degrader in clinical trials in 2027, she said.
ALK protein degraders may help prevent treatment resistance to small molecular inhibitors like the currently available ALK targeted treatments, she explained. It's not clear if patients with germline ALK mutations can develop resistance to the small molecular inhibitors. But those with somatic ALK mutations do.
Modak noted that the efficacy of ALK inhibition in germline-associated neuroblastoma remains to be proven in clinical trials.
"The numbers of patients requiring such inhibition is exquisitely small," he said. "To put it in perspective, there are likely less than five patients with germline-associated neuroblastoma diagnosed every year, and some of these could have low-risk tumors that could be treated with surgery alone and not need ALK inhibition."