Novel Tumor-Agnostic Agent: 80% RR, but Target Is Rare

Kristin Jenkins

February 22, 2018

The investigational tumor-agnostic drug larotrectinib (LOXO-101, Loxo Oncology) has shown a 75% to 8O% response rate in children and adults with unresectable or metastatic solid tumors that harbor tropomyosin receptor kinase (TRK) fusions.

The latest data on this drug "suggest larotrectinib is likely to be the most effective treatment option for any patient with an advanced solid tumor harboring a TRK fusion," principal investigator David M. Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News.

"Further follow-up will determine the exact duration of this benefit, although it is already in a very clinically meaningful range," he added.

As previously reported by Medscape Medical News, larotrectinib has shown unprecedented high response rates in all 17 unique tumor types in which it has been tested.

More details have now been published in the February 22 issue of the New England Journal of Medicine.

In a pooled analysis of a phase 1/2 clinical trial program conducted in 55 patients (age range, 4 months to 76 years), the response rate was 75% to 80%, as determined on the basis of independent radiologic review and investigator assessment.

A complete response was seen in seven patients (13%), and a partial response in 34 (64%). Stable disease was seen in seven patients (13%).

At 1 year, 71% of the patients had an ongoing response, and 55% remained progression free after this "age- and tumor-agnostic therapy," note Hyman and colleagues.

"Magic Bullet" for Infantile Fibrosarcoma

In two pediatric patients with locally advanced infantile fibrosarcoma, larotrectinib therapy shrunk the tumor enough to allow curative, limb-sparing surgery. Negative margins were confirmed, and at 4.8 months and 6.0 months' follow-up after treatment, the patients remained progression free.

This is truly a magic bullet for our patients with TRK-positive cancer. Dr Leo Mascarenhas

"This is truly a magic bullet for our patients with TRK-positive cancer," said coauthor Leo Mascarenhas, MD, deputy director of the Children's Center for Cancer and Blood Diseases in Los Angeles, California, in a statement. Currently, surgical management of advanced infantile fibrosarcoma can be highly disfiguring or require amputation, he pointed out.

"After treating our patient with infantile fibrosarcoma with larotrectinib, the cancer shrunk sufficiently, and we were able to surgically remove the tumor while preserving the patient's leg," said Mascarenhas, who helped design the trial's pediatric protocol.

Problem With Acquired Resistance

However, as with all targeted therapies, eventually the problem of acquired resistance arises.

With larotrectib, disease progression during treatment was seen in 10 patients after they had experienced a documented objective response or the disease had been stable for at least 6 months. Most such occurrences were the result of acquired mutations that altered the kinase domain of TRK, the investigators point out.

By sequencing tumor and plasma samples from nine patients, they were able to identify "a convergent, on-target mechanism of acquired drug resistance."

They add that this finding "has immediate therapeutic relevance."

The researchers hope that patients who acquire resistance to larotrectinib can be treated with a next-generation TRK inhibitor, such as LOXO-195, which is currently being evaluated in a phase 1/2 study.

Early evidence of clinical activity with this new drug indicates it could prove useful in addressing acquired kinase domain mutations such as solvent front substitutions, Hyman and colleagues predict.

Could Be Practice Changing

In an accompanying editorial, Fabrice André, MD, PhD, from the Institut Gustave Roussy, at Université Paris Sud, in Villejuif, France, suggests this "non-comparative, genomic-driven, single-group trial across tumor types" could be practice changing.

"This study is an illustration of what is likely to be the future of drug development in rare genomic entities," he writes.

However, he emphasizes the rarity of such events.

Although orphan molecular segments such as NTRK fusions can be found in more than 20 cancer types, they are present in fewer than 1% of cancers.

"The major unknown factor in this field is how many other orphan molecular entities will meet the same therapeutic success as the one observed with larotrectinib," he adds.

When data on loratrectinib were first presented last year, cancer experts reacted enthusiastically, as reported by Medscape Medical News. This new drug "brings us into a new era, where treatment is truly based on mutation, not location," commented American Society of Clinical Oncology expert Sumanta Kumar Pal, MD, from City of Hope's comprehensive cancer center near Los Angeles, California. With these new data, "we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and is instead based on molecular criteria."

This has been the dream of precision medicine, but so far it has not been realized, as some mutations show activity in certain cancer types but not others. An example is BRAF inhibitors, which work in BRAF-mutated melanoma and thyroid cancer but not BRAF-mutated colorectal cancer.

"These data suggest larotrectinib is likely to be the most effective treatment option for any patient with an advanced solid tumor harboring a TRK fusion," Hyman told Medscape Medical News. "Further follow-up will determine the exact duration of this benefit, although it is already in a very clinically meaningful range."

Targeted Oral Drug

Larotrectinib is a highly selective inhibitor for all three TRK genes — NTRK1, NTRK2, and NTRK3. In the pooled analysis of 55 patients, NTRK1 was identified in 45% of patients, NTRK2 in 2%, and NTRK3 in 53% of patients.

"Our data not only validate TRK fusions as therapeutic targets but also show that they lead to tumor-agnostic sensitivity to larotrectinib," the study authors write.

Larotrectinib is not the only tumor-agnostic therapy that targets specific genetic defects rather than a specific tumor type. As reported by Medscape Medical News, the immunotherapy pembrolizumab (Keytruda, Merck & Co) was approved in 2017 for the treatment of patients with tumors that are mismatch repair deficient and/or have high microsatellite instability.

The immunotherapy pembrolizumab is administered intravenously, whereas the highly targeted drug larotrectinib is is taken orally.

Support for Broad Tumor Profiling

Data from the current trial provide support for the use of broad molecular tumor profiling in any patient with advanced cancer, said Hyman.

Unlike single-gene analysis, broad profiling panels make it possible to detect tumor-agnostic and tumor-specific biomarkers at the same time, he explained. This offers "the greatest overall chance of identifying a true actionable alteration.

"I believe this testing efficiency will likely drive adoption of these technologies over single analysis testing that has previously been the focus of regulatory review and approval. This broad testing paradigm will likely be facilitated by changes in the regulatory and reimbursement areas, including a pending National Coverage Determination from CMS [Centers for Medicare & Medicaid Services] for broad NGS [next-generation sequencing] tests," Hyman told Medscape Medical News.

In his editorial, André agrees. If advances in the treatment of orphan molecular entities are to be effectively implemented, broad access to genomic tests (next-generation sequencing, not single-test companion diagnostic testing) must be provided, he says.

In addition, efficacy data will need to be consolidated in post-approval studies, and molecular assays will have to be developed so that patients whose disease is refractory to conventional treatment can be identified early in the course of disease, André writes. Second- and third-generation inhibitors will also need to be developed to overcome drug resistance.

"These four considerations could lead to a model of care in which molecular testing is done in a large number of centers and in which patients with orphan molecular entities are referred to a few expert centers that could run the relevant research protocols," André says.

Study Details

In the study, 55 consecutive patients who had TRK fusion–positive cancers were enrolled into one of three protocols from March 2015 through February 2017. These protocols included a phase 1 study in adults, a phase 1/2 study in children, and a phase 2 "basket" study in adolescents and adults.

For all participants, either disease progression had occurred following prior treatment, or no further treatment options were available.

There was a wide diversity of cancer types in the study population. Twelve participants had mammary analogue secretory carcinoma of the salivary gland; seven had infantile fibrosarcoma; five had a thyroid tumor; four patients had a colon tumor; four had a tumor of the lung; four had melanoma; three had a gastrointestinal stromal tumor; and 16 had other cancers.

In the phase 1 studies involving adults and children, all were treated during dose escalation. In the phase 2 study involving adolescents and adults, the recommended dosage was 100 mg of larotrectinib twice daily administered orally on a continuous basis.

Although the median duration of response and progression-free survival had not been reached in the study, 38 of 44 patients (86%) were continuing treatment or had undergone surgery with the intention of cure after a median follow-up of 9.4 months. The patient with the longest response was still receiving therapy at 27 months.

The median time to response was 1.8 months. This finding, which was seen independently of TRK fusion characteristics, was consistent with the trial's earlier assessment of response at 8 weeks.

With regard to safety, 93% of the treatment-related adverse events were of grade 1 or 2. The most common were anemia, weight gain, and a decrease in neutrophil count. There were few grade 3 or 4 drug-related adverse events, and no patients had to discontinue therapy because of treatment.

This study was funded by Loxo Oncology, the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, the National Center for Advancing Translational Sciences, and the Alex's Lemonade Stand Foundation. A listing of the authors' relevant financial relationships is available on the journal's website.

N Engl J Med. Published online February 21, 2018. Abstract, Editorial

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