Dr. David Hyman, MD
Larotrectinib (LOXO-101) has demonstrated consistent and durable antitumor activity in tropomyosin receptor kinase (TRK) fusion cancers across a wide range of patient ages and tumor types and was well tolerated by patients, according to results from three clinical trials presented today at the annual meeting of the American Society of Clinical Oncology in Chicago. David Hyman, MD, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK) and global principal investigator of the NAVIGATE trial testing larotrectinib, shared the landmark data from three multisite clinical trials in a press conference at the meeting.
“These data represent the promise of precision medicine fulfilled. TRK fusion-positive cancer may be among the first cancer types that is more appropriate to define on the basis of a shared genetic mutation than by the organ in which it arises,” explained Dr. Hyman. “No other novel targeted therapy has demonstrated consistent benefit across all tumor types that test positive for a specific mutation. In addition, this could be the first treatment developed and approved simultaneously for adult and pediatric patients.”
Dr. Hyman presented interim analyses from three ongoing clinical trials intended to support regulatory approval for larotrectinib. There were 55 patients with TRK fusion cancers enrolled in the trials, ranging in age from 4 months to 76 years (43 adult and 12 pediatric patients). In total, 17 discrete tumor types were treated. The overall response rate of the 50 patients evaluated thus far was 76 percent, and the longest responder still remains on the treatment after 25 months. At the time the data were analyzed, 93 percent of the responding patients remain on treatment or underwent surgery with curative intent, and because of this, the median duration of response could not yet be determined. The researchers will continue to follow the trial participants until a median duration is established. The most common treatment-related adverse side effects included fatigue, mild dizziness, and nausea. For 13 percent of patients, a dose reduction was required due to an adverse event, though all of these patients experienced continued tumor regression on the reduced dose. No patients discontinued use of larotrectinib due to an adverse event.
Larotrectinib is the only highly selective pan-TRK inhibitor in clinical development. It was granted a Breakthrough Therapy Designation by the FDA in July 2016 “for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments.”
TRK fusions are chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, or NTRK3) becomes abnormally connected to an unrelated gene. This abnormality results in uncontrolled TRK signaling, driving cancer growth. TRK fusions are “consistently uncommon,” meaning that while they are rare, they are widely distributed across both common and rare cancers, and they affect people of all ages. It is estimated that between 0.5 and 1 percent of cancer patients have TRK fusions, translating to thousands of patients potentially diagnosed each year.
Precision Medicine: A Promise Fulfilled
In the rapidly advancing field of precision medicine, clinical trial designs have evolved from looking at a single tumor type to testing drugs based on genetic mutations in tumors. Dr. Hyman and colleagues at MSK pioneered the concept of a basket trial, a type of research study that concentrates on a specific mutation found in a tumor. The team published the findings from the in the New England Journal of Medicine in 2015.
While this work builds upon earlier basket trial designs, until now, no novel targeted therapy has developed tumor type agnostic activity. As a result, although prior basket studies enrolled participants with multiple cancer types with the same mutation, treatment effectiveness has historically been evaluated within each tumor type. What differentiates this trial is that efficacy proved consistent across at least a dozen tumor types.
“The concept of precision medicine seemed wildly futuristic as recently as two decades ago,” said Dr. Hyman. “Through a combination of basic science, clinical practice, advances in genetic sequencing, and the evolving design of clinical trials, we are finally seeing the potential of targeted therapies come to life. Larotrectinib gives us the opportunity to treat a select patient population based solely on their mutation, regardless of cancer type. Our work builds on the recent approval of pembrolizumab (Keytruda®), an immunotherapy for any tumor that harbors a specific pattern of DNA damage known as microsatellite instability. It is our hope that we will continue to push the boundaries of precision medicine and that these two examples, which show the unequivocal benefits of comprehensive genomic profiling for all cancers, will be the first of many successes of this type.”
Sequencing
Although TRK fusions are rare in most individual cancers, in aggregate they represent thousands of patients diagnosed each year, many of whom have limited treatment options. TRK fusions are present from the onset of these cancers, meaning that physicians can test patients early in order to identify this actionable mutation.
In 2014, MSK researchers launched the genetic-sequencing test MSK-IMPACTTM, which looks for mutations in more than 400 genes that are known to play a role in cancer, including TRK fusions. MSK-IMPACT is one of many genetic-sequencing options available to patients. Unfortunately, there are still a number of challenges. Even today, not all next-generation sequencing tests detect TRK fusions, and those that do can sometimes miss them. In addition, many patients lack access to large cancer centers, like MSK, that offer the type of comprehensive tumor sequencing capable of detecting such genetic alterations as TRK fusions.
“In order to extend the benefit to more patients, there must be greater access to next-generation sequencing for all patients,” said Dr. Hyman. “These data provide us with a tumor type agnostic, highly actionable genomic biomarker and serve as further evidence that in the very near future, delivering the standard of care will require comprehensive genomic profiling for every cancer patient.”
Addressing Resistance in a First-of-its-Kind Trial
While responses to TRK inhibition can be dramatic, acquired resistance may eventually limit the duration of the response. Researchers are already exploring how to address this challenge. Dr. Hyman and colleagues published data today in Cancer Discovery from the first two patients with TRK fusion–positive cancers who developed acquired resistance mutations to larotrectinib and were treated with a next-generation TRK inhibitor, LOXO-195.
By accelerating preclinical development time lines and by utilizing a novel first-in-human study design in order to rapidly reach therapeutic doses, researchers were able to achieve rapid responses in both patients and, in doing so, extend the benefits of targeting TRK fusions in these patients, further confirming the role for sequential treatment. The unprecedented speed of entry of a next-generation TRK inhibitor in the clinic should also allow LOXO-195 to be tested and developed in predominantly the same patient population as larotrectinib, as a sequential therapy.
“Historically, it has taken years to bring next-generation inhibitors into the clinic,” explained Alexander Drilon, MD, a medical oncologist at MSK and the study’s first author. “Rarely, if ever, have some of the first patients participating in the initial studies of a targeted inhibitor had immediate access to a next-generation drug. This work validates a novel paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets.”
A phase I/II trial for patients with advanced TRK fusion–positive cancers whose tumors have progressed on a prior TRK inhibitor is about to open.
Clinical Trials and Early Drug Development at MSK
Precision medicine allows for specific and unique trial designs — in this case, one that treats a rare mutation seen consistently across a number of tumor types thus broadening eligibility and translating potential benefits to as large a patient population as possible. Clinical trials, and the patients who enroll in them, play a vital role in developing and improving treatments. After launching a comprehensive survey and determining that only 4 percent of all patients nationwide enroll in clinical trials for cancer each year, the MSK community is actively working to expand participation.
With more than 800 clinical trials currently open, MSK runs one of the world’s largest clinical cancer research programs. To address the critical and ongoing need to provide new and better treatment options to all patients, MSK leadership recently created the Early Drug Development Service, led by Dr. Hyman. The goal of this service is to create a multidisciplinary team structure composed of scientific, clinical, administrative, and operational expertise to identify, recruit, and execute early-phase studies at the highest level. MSK has a long history as a leader in clinical and translational research and is committed to investing in early-phase drug development that supports the institute’s scientific and clinical missions.
