ATLANTA (GenomeWeb) – A next-generation TRK inhibitor has yielded promising early results in cancer patients with NTRK gene fusions who had become resistant to other drugs that block the TRK protein.
At the annual meeting of the American Association for Cancer Research this week, David Hyman, chief of the early drug development service at Memorial Sloan Kettering Cancer Center, reported data that showed the next-generation TRK inhibitor is safe and has potential as an option for patients with advanced solid tumors who have stopped responding to another TRK inhibitor. "We are hopeful that LOXO-195 will provide continuum of care for patients," Hyman said at the meeting.
The US Food and Drug Administration approved Bayer and Loxo Oncology's larotrectinib (Vitrakvi) in November last year as a treatment for adult and pediatric patients with advanced solid tumors characterized by an NTRK gene fusion and without other options. The data presented at this meeting on Bayer/Loxo's LOXO-195, intended for patients who develop resistance to larotrectinib and other TRK inhibitors, is from a dose escalation Phase I study and an FDA expanded access program that started while studies for the first-generation drug were ongoing.
The fact that the development timelines for LOXO-195 and larotrectinib overlap is a sign that drug development timelines are narrowing in the era of precision oncology. It is well known by now that most patients treated with a molecularly-targeted drug will eventually become resistant, and researchers working on the studies that led to larotrectinib's approval anticipated this.
"As soon as we saw that happen, we were ready to bring this candidate, LOXO-195, into the clinic," Hyman told GenomeWeb.
The first patients on larotrectinib to develop resistance were treated with LOXO-195 by applying for emergency use of the investigational drug through the FDA. A team led by Hyman published that these patients had "rapid tumor responses and extended the overall duration of disease control" on the next-generation TRK inhibitor, which led to more patients getting expanded access and the Phase I study.Â
The near parallel development of larotrectinib and LOXO-195 also influenced the labeling language and indication of the first-generation drug. The FDA approved indication for larotrectinib specifically states that patients with an acquired resistance mutation should receive the drug.
As of December 2018, 31 adults and children with 15 different types of solid cancers had received the next-generation drug LOXO-195 either through a Phase I study or a compassionate-use access program that Loxo and Bayer supported for patients who couldn't enroll in the study. "I've not seen this [kind of compassionate-use program] for a first-in-human study like this," Hyman said at the conference.
Fourteen patients had their tissue samples sequenced for mutations, 25 had central plasma testing, and 10 had both types of analysis. Of the 29 evaluable patients, a third saw their tumors shrink.
The adverse events to the drug were anticipated. The most common toxicities were dizziness, nausea, anemia, muscle and abdominal pain, and low lymphocytes. Five people had dose limiting toxicities.
Patients can become resistant to TRK-blocking drugs by acquiring new mutations in the NTRK fusion gene that continue to signal the tumor to grow. Patients without signals from NTRK can still become resistant to TRK inhibitors through alterations in other pathways, but sometimes the resistance mechanisms are unknown. Â
According to the data presented at the meeting, all the patients who saw their tumors shrink acquired a new resistance mutation in NTRK. There were 20 such patients and the objective response rate was 45 percent in this subset. One patient who was enrolled on the basis of being intolerant to larotrectinib had a complete response. Researchers observed no responses among patients who were resistant to a prior TRK inhibitor but had no NTRK resistance mutations.
At the meeting, Hyman highlighted the experience of two patients that responded to LOXO-195. One 58-year-old woman with thyroid cancer and multiple prior treatments saw her tumor partially shrink for nine months on larotrectinib before developing resistance. When she came to see Hyman at MSK, he recalled she was so sick she had to be wheeled in on a stretcher. "A day later she went to see a Broadway show in New York," he recounted. "It was quite an amazing experience." She was on LOXO-195 for 8.5 months without progressing.
Another 57-year-old woman treated at MSK with colorectal cancer had only a six-month partial response to larotrectinib before becoming resistant. She got on LOXO-195 through the compassionate-use program and spent 22 months on the drug before she had to discontinue due to progression.
Although the responders in this study were patients who had new NTRK mutations, in a separate abstract presented at the meeting, researchers from MSK, Loxo, and liquid biopsy NGS test provider Guardant Health turned their attention to patients who develop resistance to TRK inhibitors through alterations in other pathways. They identified patients with gastrointestinal cancers who became resistant to TRK inhibitors but then acquired mutations in BRAF and KRAS, and had MET amplification. Researchers created xenograft models with these characteristics and treated them with targeted drugs. The study suggested that GI cancer patients may be more prone to developing resistance through these other mutations and may benefit from combination treatment inhibiting both the TRK and the MAP kinase.
Although the findings on LOXO-195 are from a small cohort and need further validation in more patients, Hyman lauded Bayer and Loxo for advancing two drugs for a subset of patients with a relatively rare tumor marker. NTRK fusions have been observed in 0.31 percent of adult tumors in The Cancer Genome Atlas and in 0.34 percent of pediatric tumors in the St. Jude PeCan database.
"It's pretty remarkable that this drug exists at all because of the commercial viability of TRK [inhibitors] in therapeutics in general," Hyman said. "Given the rarity [of NTRK fusions], the idea that Loxo and Bayer are willing to develop a drug in an orphan indication is remarkable."
He also noted that the speedy development plan for LOXO-195 means that many of the patients treated with first-generation TRK inhibitors will also have access to a second-generation drug in the event of relapse or resistance. "Historically, when you're developing next-generation inhibitors to manage acquired resistance, there is a life cycle where this first-generation drug gets approved, they enter the clinical space, the resistance mechanisms are defined, and a new drug developed and it enters the clinic," he said. "By then several years have elapsed."
For example, the first ALK inhibitor for non-small cell lung cancer patients with ALK rearrangements, Pfizer's crizotinib (Xalkori), was approved in 2011. It was three to four years before patients obtained access to next-generation drugs Novartis' ceritinib (Zykadia) and alectinib (Alecensa). This is considered fast compared to decades-long historical drug development time frames, but the story of larotrectinib and LOXO-195 suggests the pace is picking up even more.Â
"What's unique about this is that we have an opportunity to develop LOXO-195 in almost the same population that led to the approval of larotrectinib and other TRK inhibitors like entrectinib," he said. "They are going to seamlessly transition into LOXO-195. … I don't think that's ever happened before in targeted therapy."
Genentech is developing entrectinib, a first-generation TRK inhibitor. The biotech firm recently submitted the drug for FDA approval as a treatment for adults and kids in NTRK-fusion positive, advanced solid tumors and for advanced ROS1-positive non-small cell lung cancer. At the conference, researchers presented combined data from three studies involving entrectinib and showed that patients with NTRK fusion-positive solid tumors (including NTRK fusion-positive NSCLC) had systemic and intracranial responses to the drug and manageable adverse events.
Other groups at the conference discussed next-generation NTRK inhibitors in preclinical development, including PBI-200 from Pyramid Biosciences and repotrectinib from TP Therapeutics.
As more TRK inhibitors are developed and approved, there is a pressing need to ensure that tests can accurately identify patients with these rare alterations. The FDA's approval of larotrectinib did not come with a concurrent approval of a companion diagnostic. However, agency’s approval letter to Loxo includes a post-marketing commitment to develop a companion diagnostic that can identify which patients have NTRK fusions and are likely to respond to treatment. Loxo has committed to submitting data from analytical and clinical validation of such a test to the FDA by July 2021.
Hyman, however, is not convinced that any one test will be sufficient for identifying best responders for NTRK-fusion guided therapy. "You can imagine someone creating a single-analyte companion diagnostic, but I don't think that would get a lot of use," he said. "The majority of patients who are identified with NTRK fusions will be identified on the basis of broad panel testing that is able to detect these fusions, but that may not be the specific intention of the physician in ordering the test."
He noted that physicians aren't necessarily testing patients to try to identify rare biomarkers like NTRK fusions in their cancer patients. They are testing patients in order to figure out what targeted treatment or immunotherapy they want to give them. As a result, they will likely learn that a patient harbors an NTRK fusion after running a panel that includes a host of markers associated with response to immunotherapies and targeted drugs.
MSK's MSK-IMPACT, Foundation Medicine's FoundationOne CDx, and Caris Life Sciences’ Comprehensive Genomic Profiling Plus are examples of NGS panels that detect NTRK gene fusions. In an abstract presented at the meeting, researchers from Bayer and SeraCare Life Sciences noted that there are differences in commercially available NGS panels in terms of workflow, sensitivity, and bioinformatics.
"In order to achieve precision diagnostics for personalized therapy, testing standardization is needed worldwide," wrote researchers led by Sebastian Bender from Bayer in the abstract, which describes the Seraseq FFPE NTRK Fusion RNA Reference Material to help standardize NGS analysis of NTRK fusions.
The reference material includes 15 fusions in NTRK1, NTRK2, and NTRK3 in a single FFPE sample and challenges labs to detect these alterations across multiple break points for each gene and a dozen amino terminal fusion partners. The researchers noted that the ArcherDx FusionPlex Solid Tumor Assay correctly identified all fusions.
"It's going to be about incrementally improving the ability to detect NTRK fusions in a robust way in the existing large panel tests and also providing dedicated confirmatory testing, such as immunohistochemistry and FISH, and providing off-the-shelf reagents for that," Hyman said.
Physician scientists at MSK have identified around 80 cancer patients with these alterations and are working on a paper describing the landscape of this cancer biomarker. What these cases show, according to Hyman, is that patients with NTRK fusions tend to have less genomically complex tumors, since these fusions don't usually co-occur with other targetable oncogenic mutations.
"It's probably why the drugs work so well," Hyman said. "Because when you find an NTRK fusion in a tumor, it's almost always truly the driver."