Drug Is 'Game Changer'; Screen Cancer Patients for TRK Fusion

Kristin Jenkins

December 11, 2018

The novel drug larotrectinib (Vitrakvi, Bayer/Loxo Oncology) that was approved recently by the Food and Drug Administration is a precision model "game changer," say clinical trial investigators.

The drug achieved overall response rates (ORR) of up to 80% in unique advanced and metastatic pediatric and adult solid tumors that have a genomic TRK fusion, and is the first "tumor-agnostic" agent to be approved for this genomic alteration regardless of cancer type.

Larotrectinib is a first-generation selective tropomyosin receptor kinase (TRK) tyrosine kinase inhibitor (TKI) that targets oncogenic fusions of the neurotrophin receptor tyrosine kinase genes NTRK1, NTRK2, and NTRK3.

These fusions are found in about 90% of rare tumor types that account for 1% of cancers overall, and they are also occasionally found in common cancers.

Some of the patients who are candidates for this drug have exhausted all other treatment options, while some patients face surgery that would result in major morbidity.

"This is a big deal in the pediatric and adult oncology world," said Noah C. Federman, MD, director of the Pediatric Bone and Soft Tissue Sarcoma Program at the Jonsson Comprehensive Cancer Center at the University of California at Los Angeles (UCLA). "In over a decade of experience treating advanced solid tumors in children, adolescents and young adults at UCLA, I have never witnessed the responses seen with larotrectinib."

"As trite as the word 'game-changer' is in oncology this is one of the few times this descriptor is warranted," he told Medscape Medical News.

As trite as the word 'game-changer' is in oncology this is one of the few times this descriptor is warranted. Dr Noah Federman

When asked for his take-home message to pediatric and medical oncologists, Federman said: "Screen your patients for TRK fusions, particularly in advanced or metastatic solid tumors."

Landmark Approval

"This landmark approval represents the first targeted therapy approved for a histology-agnostic indication," said Alexander Drilon, MD, clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York City.

"It definitely provides a model for the continued pursuit of tissue-agnostic drug development in clinical trials such as basket studies," he told Medscape Medical News.

FDA approval was based on a pooled analysis of three phase 1/2 clinical studies in 55 children and adults with 17 unique NTRK fusion-positive cancers. The results were published in the New England Journal of Medicine in February 2018 and reported by Medscape Medical News at the time. They showed a durable ORR of 75% to 80% with no treatment-related grade 3/4 adverse events (AEs).

The report included participants from Loxo Oncology's phase 1 adult trial, the phase 2 basket trial of adults and children (NAVIGATE), and the phase 2/3 pediatric trial (SCOUT). Patients ranged in age from 4 months to 76 years, and had 17 unique NTRK fusion-positive tumor types. These included mammary analogue secretory carcinoma; infantile fibrosarcoma; melanoma; gastrointestinal stromal tumors; and thyroid, colorectal, and lung adenocarcinomas.

The duration of median progression-free survival (PFS) had not been reached by data cut-off, but 55% of patients remained progression-free at one year, and 71% demonstrated an ongoing treatment response. A complete response was seen in seven patients (16%) and a partial response in 64%. Stable disease was seen in seven patients (13%).

Although the oral agent appeared to be well tolerated, investigators emphasized that larotrectinib's safety profile and the duration of benefit will be determined with a longer follow-up in a larger patient population.

Well Tolerated by Most Patients

A somewhat similar drug is under development. Entrectinib (Roche) has demonstrated activity against NTRK1/2/3 fusions as well as cancers positive for the c-ros oncogene 1 (ROS1) and for anaplastic lymphoma kinase (ALK) rearranged cancers. It has completed several small studies, data from which will be submitted to regulatory authorities.

A recent review of larotrectinib and entrectinib concluded that these "first-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumor, on-target adverse events (attributable to TRK inhibition in non-malignant tissues)." The review was published online on October 17 in Nature Reviews/Clinical Oncology.

The authors added that "larotrectinib and entrectinib have a favourable overall safety profile compared with many other TKIs and are, therefore, amenable to chronic dosing."

Grade 1/2 AEs including nausea, diarrhea, constipation, vomiting, and increased serum transaminase levels have been reported in 15% of clinical trial participants treated with either larotrectinib or entrectinib, they said.

Simultaneous Development in Adults & Children

The fact that larotrectinib is both tumor- and age-agnostic is a first, said Federman, who is a SCOUT trial investigator. "The simultaneous development of this targeted therapy in children and adults is a model for drug development worldwide. I can personally say that the responses have been robust and durable. Moreover, larotrectinib is extremely well tolerated with few grade 3 and 4 toxicities."

Updated, integrated data in 120 patients from the SCOUT and NAVIGATE studies continue to demonstrate durable responses to larotrectinib and show that the median duration of response has not yet been reached one year after completion of the trial, said Federman.

The investigator-assessed ORR for these additional patients was consistent with that seen in the first 55 patients. The ORR was 81% with 17% of patients showing a complete response and 65% a partial response, said Federman.

In patients with bone and soft tissue sarcomas, the ORR was more than 93%, he said in a presentation at the annual meeting of the Connective Tissue Oncology Society in Rome, Italy, in November 2018.

These data were also presented in October at the European Society of Medical Oncology 2018 Congress in Munich, Germany, and reported by Medscape Medical News at the time.

Finding Patients Who Could Benefit

For screening children diagnosed with tumors that have a high frequency of TRK alterations, such as infantile fibrosarcoma, secretory carcinoma of the breast, or mammary analogue secretory carcinoma, Federman recommended initial testing with IHC [immunohistochemistry] and FISH [fluorescence in situ hybridization].

In patients with advanced, relapsed, refractory solid tumors, next generation sequencing (NGS) testing that is capable of detecting NTRK fusions should be used, said Federman. NGS testing is also recommended in patients who have tumors with a much lower incidence of NTRK fusions, such as lung and colorectal cancers.

Drilon advised clinicians screening for NTRK fusions in patients with advanced or metastatic solid tumors to "choose your test wisely."

He warned that even the most advanced DNA-based NGS platforms may not identify all NTRK fusions, especially those involving NTRK2 and NTRK3. "You need to make sure that the assay is good at specifically finding an NTRK fusion, and not just other things like mutations or copy number changes."

Drilon added that the best assay is probably a comprehensive hybrid-capture-based NGS panel that includes an interrogation of both DNA and RNA.

FISH and reverse-transcriptase PCR (RT-PCR) have been successfully used in the clinic to detect NTRK fusions and are reasonable alternatives to NGS, Drilon said. However, even though FISH and RT-PCR can be performed relatively quickly and inexpensively, they are limited to detecting a single-driver alteration whereas NGS can detect multiple drivers as well as NTRK fusions, such as those found in lung adenocarcinomas, he pointed out.

Next Generation Agents

In spite of durable disease control in many patients, advanced stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition, Drilon said.

The good news is that when resistance is acquired through NTRK kinase domain mutations, it can be mediated by next-generation TRK inhibitors, he added.

In an on-going, open phase 1/2 study, clinical responses have been observed with the ROS1/TRK/ALK inhibitor repotrectinib (TPX-0005, TP Therapeutics) in patients with ROS1 or NTRK3 fusion-positive cancers who had relapsed on earlier generation TKIs because of resistance.

There is also early evidence of clinical activity in the ongoing open phase 1/2 trial of the next-generation selective TRK inhibitor LOXO-195 (Bayer/Loxo). These results are encouraging and have immediate therapeutic relevance, said Federman.

He added that, in a situation where a solvent-front mutation alters the TRK kinase domain and leads to larotrectinib resistance, "all is not lost." Potentially, LOXO-195 "will allow patients to continue to receive therapeutic benefit from a TRK inhibitor."

Patient subpopulations that are defined by specific molecular alterations may be very small but "some of the molecular features represent excellent drug targets," pointed out W. Michael Korn, MD, chief medical officer of Caris Life Sciences in Irving, Texas, when asked to comment. "NTRK gene fusions exemplify this phenomenon," he told Medscape Medical News.

"I encourage all oncologists to perform comprehensive molecular profiling as soon as possible after the diagnosis of advanced disease is made," said Korn, who is also professor of medicine in the hematology/oncology division at the University of California, San Francisco (UCSF) and founder of the Molecular Oncology Initiative at UCSF's Helen Diller Family Comprehensive Cancer Center.

Commercially available profiling technologies make it possible to analyze a large number of biomarkers from small amounts of tissue in about two weeks, he said.

Korn predicted that in the "very near future," this kind of molecular profiling will become standard in the initial cancer workup, much as imaging studies using PET/CT scans are now. "Since the costs of this diagnostic approach are limited, its worldwide application will be feasible and result in globally improved outcomes," he said.

Drilon reported relationships with TP Therapeutics, Loxo Oncology, Helsinn, AstraZeneca, Roche/Genentech, Pfizer, Takeda/Ariad, Blueprint Medicines, and Beigene. In addition to Caris Life Sciences, Korn disclosed relationships with Oncocyte, Merck, and Lilly. Federman has disclosed no relevant financial relationships.

Nat Rev/Clin Oncol. Published online October 17, 2018. Full text


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