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Can Newly Approved “Tissue Agnostic” Drugs Benefit Pediatric High-grade Glioma Patients?

Recently, the U.S. Food and Drug Administration (FDA) granted accelerated approval* to the drug Rozlytrek (entrectinib, Genentech/Roche**) as a treatment for patients, 12 years or older, whose tumors have a specific genetic defect known as an “NTRK gene fusion.”***

This is now the second drug that the FDA has approved to treat patients with this type of genetic mutation, regardless of where their tumor is located. Just last fall, NBTS highlighted the FDA’s approval of Vitrakvi (larotrectinib, Bayer/Loxo^) for adult and pediatric patients with advanced solid tumors (all cancers that are not blood-based like leukemia, lymphoma, and myeloma) that harbor the NTRK gene fusion. Because brain cancers are solid tumors, theoretically, Vitrakvi could be used to treat tumors in the brain with these fusions****.

While these fusions are extremely rare in adult brain tumor patients, they have been identified as occurring more frequently in pediatric high-grade glioma patients. In fact, a major study of pediatric high-grade gliomas had previously identified NTRK gene fusions in 4% of tumor samples from DIPG patients and 10% of patients with non-brainstem pediatric high-grade glioma (NBS-HGG). Further, amongst NBS-HGG patients younger than 3 years-old these fusions were identified in 40% of the cases. 

Although both the Vitrakvi and Rozlytrek approvals were based on trials that didn’t specifically report data on the benefit of these drugs in patients with brain tumors, recent scientific reports and presentations have provided some initial information on the potential effectiveness of these so-called “TRK inhibitors” for patients with tumors in their brain. 

Rozlytrek in Brain Cancer

At the 2019 American Society of Clinical Oncology conference, Dr. Giles Robinson of St. Jude Children’s Research Hospital reported results from a trial of Rozlytrek in pediatric cancer patients with recurrent solid tumors, including brain tumors. Six patients in the trial — called STARTRK-NG — had primary brain tumors (all high-grade tumors with gene fusions that hadn’t responded to previous treatment attempts) trial.

Dr. Robinson called the response of brain cancer patients with very advanced disease to Rozlytrek in this trial, “striking, rapid, and durable,” and that the data “support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3…especially in high-grade [brain tumors].”

Vitravki in Brain Cancer 

At the same conference, Dr. Alexander Drilon of Memorial Sloan Kettering Cancer Center presented data from three separate clinical trials of Vitravki that included 24 adult and pediatric patients with brain cancer. Six were patients with brain metastases (or secondary brain tumors; tumors that spread to the brain from a different, original site) and 18 were patients with primary malignant brain tumors, all gliomas. 

In both of these populations, a significant proportion of patients saw their tumors stop growing or shrink. Notably, nearly half (45%) of all pediatric patients in this group had some type of response (complete tumor shrinkage, partial tumor shrinkage, or stable disease). 

Importance of Molecular Testing for Brain Cancer Patients

While rare, some brain cancer patients do have tumors driven by NTRK gene fusions, particularly pediatric high-grade glioma patients. And because both Vitrakvi and Rozlytrek are approved for ALL solid tumor patients with these mutations, any brain cancer patient with such fusions should likely be able to receive treatment with either of the drugs****. However, in order to identify if an individual patient’s tumor is positive for these fusions, molecular tumor testing is required at the time of diagnosis. Consistent with the updates the World Health Organization made to brain tumor classifications in 2016, NBTS has always recommended patients have their tumors sequenced when able, and these new drugs that appear to provide significant benefits to nearly half of all patients that try them offer further support for molecular testing as a routine practice at diagnosis. 

“Although the target fusions are rare and the chances of finding the fusion may be low, clinicians should be looking for these gene aberrations because the impact of therapy is very promising — especially when alternative treatment options are limited,” Dr. Robinson told HemOnc Today

Most patients that might benefit from TRK inhibitors will be able to have these fusions identified by broad genomic testing, but many companies are also developing tests specifically for the NTRK gene fusions. 

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue-agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” FDA Acting Commissioner Ned Sharpless, MD, said in a press release.

Takeaways for Patients & Families

As we move further into the era of precision medicine — with TRK inhibitors and other emerging targeted treatments — it’s becoming increasingly important for patients and families facing a brain cancer diagnosis to ask the right questions at diagnosis and during treatment, including after a potential recurrence. (The hyperlinks in the previous sentence provide lists of specific questions NBTS recommends at each respective stage of the diagnosis and treatment process). Again, as it relates to TRK inhibitors, additional questions to consider include:

  • Can I/my loved one receive molecular testing of the tumor, and will the tests that your center uses detect NTRK gene fusions?
  • In addition to brain tumor-specific treatments, are there any potential “tissue agnostic” treatment options that could be available to me/my loved one?

Visit https://braintumor.org/brain-tumor-information/theexperience/ to view all our resources for navigating the brain tumor treatment experience. 


*The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image or other measures that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval. Drug companies are still required to conduct studies (known as Phase 4 trials) to confirm the anticipated clinical benefit. If the confirmatory Phase 4 trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug.  If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market. [Source: FDA].
**Rozlytrek was developed by Ignyta which was acquired by Roche in late 2017. Rozlytrek was approved in Japan earlier in 2019.
***The approval language reads as: “Adults and pediatric patients 12 years of age of older with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy.” (I.e. second-line use or where no standard therapy is available in frontline uses.)
****The FDA does not regulate the practice of medicine in the U.S., so technically any doctor can prescribe any treatment for any condition or patient if they believe it will benefit that individual, whether the treatment is FDA approved for that condition or not. This is called “off-label” use. However, most health insurers, including Medicare and Medicaid, require scientific evidence – typically confirmed through FDA approval – that a medicine works for specific conditions for them to cover the treatment. Thus, often it can often be the case when receiving a medicine off-label that insurance will deny reimbursing that treatment.
^After Eli Lilly bought Loxo, Bayer kept control of Vitrakvi under a special provision. 

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