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Growing Data on Vitrakvi Demonstrate Enduring Activity Across Variety of NTRK-Positive Tumor Types

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NEW YORK – Adult and pediatric patients with refractory solid tumors characterized by NTRK gene fusions and treated with Bayer's larotrectinib (Vitrakvi), on average, lived for more than three years without their tumors progressing, according to data presented at a cancer conference over the weekend.

Analysis pooled from three trials were presented at the European Society for Medical Oncology's Virtual Congress and confirmed the long-term efficacy of the drug. The data specifically demonstrated larotrectinib's potential to shrink advanced lung and thyroid tumors with TRK fusions, including activity against cancers that have spread to the brain.

Larotrectinib has accelerated approval in the US, Europe, and other regions as a treatment for refractory solid tumor patients with NTRK fusions who are out of treatment options. The US Food and Drug Administration approved the drug for a tissue-agnostic indication in November 2018 based on data on 55 patients who had a variety of tumor types, including melanoma, soft tissue sarcoma, infantile fibrosarcoma, cholangiocarcinoma, as well as salivary gland, thyroid, lung, melanoma, colon, gastrointestinal stromal, appendix, breast, and pancreatic cancers. /regulatory-news/loxos-pan-cancer-drug-garners-fda-approval-patients-ntrk-fusions#.X2NZb2hKg2w

The studies at the time of larotrectinib's US approval reported out an objective response rate of 75 percent. Among responding patients, 22 percent had a complete response and 53 percent had a partial response. The median duration of response had not been reached and progression-free survival data were not available.

At ESMO, the expanded analysis involved 120 additional patients, bringing the total number of larotrectinib-treated patients across three studies to 175, including 116 adult and 59 pediatric patients. NTRK fusions are rare, occurring in .5 percent to one percent of solid tumors. However, such alterations have been seen to date in more than 20 different tumor types and tend to show up more frequently in thyroid cancer, certain lung cancers, sarcomas, mammary analog secretory cancer, infantile fibrosarcoma, and wild-type gastrointestinal stromal tumors.  

In a post-ESMO virtual presentation hosted by Bayer, which holds exclusive rights to develop and sell larotrectinib, Scott Fields, senior VP and head of pharmaceutical development oncology at the drug company, noted the data presented at the meeting represents "the largest dataset and the longest follow up for any agent" against TRK.

At the time of data cutoff on July 15, 2019, the overall response rate among 175 adult and pediatric patients with NTRK fusion-positive cancers was 78 percent, with 19 percent experiencing a complete response and 59 percent having partial responses.

Ray McDermott from St. Vincent's University Hospital and one of the investigators in the larotrectinib trials, noted during the post-ESMO presentation that the updated analysis further confirms that the drug crosses the blood-brain barrier, and patients with central nervous system (CNS) metastases experience tumor shrinkage. The response rate in 14 patients with central nervous system metastases was 71 percent, all having partial responses.

Although the median duration of response is not yet mature, 81 percent of patients were responding at one year. At a median follow-up of 13.8 months, the median progression-free survival was 36.8 months. Median overall survival was not reached at 15.3 months follow up, though 90 percent of patients were alive at one year, and 83 percent were alive at two years.

The data show that "the responses [to larotrectinib] are rapid … and they are durable," said Fields. "When we consider these are solid tumor patients who often don't have alternative treatments, this is a remarkable result."

At data cutoff, 57 percent of patients were still on treatment and 32 patients were continuing on treatment, although their tumors had started growing again. "There is a cohort of patients, and I have some of these [patients] myself, that even when they have limited disease progression on treatment, you can treat that area that's progressing, and … they will continue to benefit," McDermott said.

He highlighted the case of a 32-year-old pregnant woman in Ireland who was in one of the pivotal studies that led to larotrectinib's approval. In January 2018, this patient received an x-ray to investigate the chest symptoms she had been experiencing, and the procedure uncovered a mass. At first, her doctors tried to treat the mass conservatively because she was pregnant, but it grew aggressively over the span of four weeks. Doctors induced labor in early February, delivered her baby, and five days later performed surgery to remove the tumor in her thorax. 

Her cancer turned out to be a rare inflammatory myofibroblastic tumor. However, two months later, she came back to see her doctor with lower back pain, and this time scans showed metastatic cancers in her liver, spleen, and in bones throughout her body. Genomic analysis of a tumor sample identified an NTRK3 gene fusion, and she was able to enroll in one of the larotrectinib trials open in Ireland.

By the time McDermott met her, she was extremely unwell with a high fever, pelvic pain, and anemia. She was admitted to the hospital and on antibiotics. "She started on larotrectinib on the 27th of April and literally it was like turning off a tap," he recalled. "Overnight her symptoms began to improve … [and] she was discharged three days later feeling very well." Scans were already showing signs that her tumors were shrinking.

This patient remained on larotrectinib for more than two years. At some point there was some disease progression in her liver, but doctors resected the tumor and she was able to continue treatment with larotrectinib.

She, like most patients on the drug, tolerated it well. In safety studies to date, larotrectinib has demonstrated limited toxicities, with mostly grade 1 and 2 adverse events, and serious adverse events in 5 percent of patients. "Most patients report very little side effects from being on it," McDermott said.

Activity in lung, thyroid cancers

Additionally, at ESMO, researchers presented data on the activity of larotrectinib in a subset of 14 adult, heavily pretreated, metastatic lung cancer patients with NTRK fusions. The overall response rate in this group was 71 percent, with 7 percent experiencing complete responses and 64 percent having a partial response.

Duration of response, median progression-free survival, and median overall survival were not reached at the time of follow up. However, 69 percent of patients did not see their tumors progress for a year or more, and 91 percent were alive after a year. Three out of seven patients with brain metastases were still on treatment at data cutoff.

Researchers also highlighted larotrectinib's activity in 28 adults and children with locally advanced or metastatic NTRK fusion-positive thyroid cancer. The overall response rate was 75 percent, with complete and partial responses seen in 7 percent and 68 percent of patients, respectively. Two out of seven patients with anaplastic disease, an aggressive form of thyroid cancer, saw their tumors partially reduce in size. Four patients with brain metastases also had a partial response, and three are still on treatment.

Median duration of response and progression-free survival were not mature at the time of follow up. However, researchers estimated that 81 percent of patients did not see their tumors progress at one year. Median overall survival was more than two years in the overall thyroid cancer subgroup and more than a year for those with aggressive thyroid cancer.

Advances in pediatric cancer

During Bayer's post-ESMO call, Theodore Laetsch, a physician at the Children's Hospital of Philadelphia who is also involved in development trials for TRK inhibitors, broke out the activity of larotrectinib in the 59 pediatric patients across the pooled trials.

Currently, approximately 80 percent of children with cancer are cured with standard treatments, but "we haven't been able to extend these survival gains to the remaining 20 percent," said Laetsch. With increasing use of next-generation sequencing, researchers have found potentially targetable genomic alterations in approximately 50 percent of childhood tumors, and yet, precision oncology advances have lagged in pediatric cancers.

Larotrectinib happens to be one of the few precision oncology drugs developed in adults and children simultaneously. It certainly helps from a drug development standpoint that these otherwise exceedingly rare alterations are highly prevalent in certain rare pediatric tumor types. For example, almost all infantile fibrosarcomas harbor NTRK fusions and up to 92 percent of congenital mesoblastic nephromas have them. Further, the drug is available in capsule form and as a liquid oral solution, which makes it easy to give to children with these rare cancers.

The drug was approved in the US based on research involving 12 pediatric patients. Now, the ESMO data includes the experience of 59 patients on larotrectinib, ranging from those as young as one month old up to 18 years old. There were 33 patients with infantile fibrosarcoma. The fact that one-third of the 175-patient dataset is in pediatric patients is "very unusual" in oncology drug development, said Laetsch.

Moreover, 92 percent of pediatric patients saw their tumor shrink with larotrectinib, with 36 percent of patients seeing their tumors completely disappear in scans, and 56 percent experiencing partial responses.

Despite the remarkable benefit seen with larotrectinib, one of the enduring challenges with targeted precision oncology drugs is that although patients with the biomarker of interest experience quick and robust responses, they eventually relapse. In anticipation of that, Bayer has a next-generation TRK inhibitor in the wings, called selitrectinib, Fields noted. That drug is currently entering a Phase I/II safety study enrolling previously treated adult and pediatric patients with NTRK fusion-positive cancers.