Mesoblastic Nephroma

Kena Betancur/VIEWpress/Corbis via Getty Images It’s been a month since cancer drug developers presented their latest research at the American Society of Clinical Oncology (ASCO) annual meeting, and the highlights are still reverberating across the industry. Updates on Bayer’s Vitrakvi (larotrectinib) were presented across several sessions, including one regarding the efficacy and safety of the oral medicine in pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive cancer. BioSpace connected with Theodore Laetsch, M.D., lead investigator of the pediatric SCOUT trial, to gain more insight into the drug, the study and how patients' lives are being affected. Laetsch is a pediatric oncologist who serves as director of both the developmental therapeutics program (DVL) and the very rare malignant tumors program (VRMTP) at the Children’s Hospital of Philadelphia. He is also an associate professor of pediatrics at the University of Pennsylvania. He shared with BioSpace that he originally began working in medicine because his mom was a pediatrician. When Laetsch was in high school, she helped to connect him with a pediatric oncologist from Arizona who simultaneously did laboratory research and cared for patients. “I really loved that mix of being able to help individual patients, but also being able to try to enhance the field. I never changed my mindset.” Mechanism of Action Against NTRK Fusions Bayer’s larotrectinib works by blocking neurotrophic tyrosine receptor kinase (NTRK) gene fusions, which are genetic changes that occur in certain cancers. Laetsch said they believe these fusions are one of the events that can prompt the formation of cancer. “This medicine blocks that genetic change, which turns off the signaling that drives cancers,” he said. “We've seen that it causes many cancers to shrink quickly in the setting of having one of those genetic changes, but it doesn't work in any tumors that don't have that genetic change.” NTRK fusions happen across a range of cancer types. Laetsch explained that in some rare pediatric cancers, such as infantile fibrosarcoma and congenital mesoblastic nephroma, there can be NTRK fusion-positive tumors. “There are common pediatric cancers, like brain tumors, where NTRK fusions do occur, but rarely. Most children don’t have an NTRK fusion, but a few do. The medicine works in both of those types of tumors,” he said. Larotrectinib is effective in both pediatric and adult patients. “In adults, the same kind of genetic changes happen in lung cancer and colon cancer. The medicine works regardless of the tumor type if there's an NTRK gene fusion present.” Larotrectinib is Showing Curative Potential Updates on the ongoing trial announced at ASCO include that “we’ve continued to accrue patients and also follow patients for longer, which means that we have longer follow-up data. We have more patients with a few additional diagnoses that weren't seen in the original data set that we published and presented before,” Laetsch said. He shared the story of one of the very first patients in the trial, a girl with a large sarcoma in the back of her abdomen that was wrapped around her aorta and spread to her lungs. “She had a lot of fluid from the tumor in her abdomen,” he said. They started the medicine, and within a couple of weeks, the fluid had resolved. Laetsch said that “the first scan showed that the tumor had shrunk dramatically. She went on to have a complete response, which meant that there was no more tumor that we could find in her body. She has now been on therapy and doing quite well for more than five years.” He also highlighted patients with localized tumors, most of whom were suffering from infantile fibrosarcoma. Larotrectinib caused their tumors to shrink to the point that surgical removal was possible, and then they were able to stop taking the medicine altogether. “We have examples of patients that have been able to stop the medicine for several years and not have tumors reoccur. We're hopeful that for those patients this combination of medicine and surgery may be curative, and that they may not need any further therapy.” Larotrectinib was approved by the U.S. Food and Drug Administration (FDA) in 2018 for children and adults with NTRK gene fusions in metastatic or locally advanced tumors, or in patients without other treatment options. “We’re continuing to study and gain additional information about how best to use this drug in children, and what the long-term effects of the medicine are,” Laetsch said. For some patients, this medication could take the place of chemotherapy. “We're now conducting a study through the Children's Health Group to evaluate the use of larotrectinib as the first therapy that patients with NTRK fusion-positive cancer receive to try to see if we can spare the need for traditional chemotherapy and its associated side effects.” The doctor shared that for some patients, such as the girl with a sarcoma in her abdomen, the treatment can have a life-changing impact. “She had a tumor that had progressed through standard chemotherapy. There really were no other treatment options for her. This therapy was clearly life-saving,” he said. “I think there are different impacts in different patients, but certainly we've seen profound impacts on patients for whom these genetic alterations have been identified.” The SCOUT trial will continue to follow patients, monitoring long-term side effects. An important aspect of larotrectinib is that it only works for patients who have NTRK fusions. Laetsch emphasized the importance of testing tumors for these genetic mutations as well as others. “If you don’t test, you'll never know whether the patient may benefit. There are other medications targeting other genetic changes in tumors that are showing really promising results recently. I focus a lot of my time on suggesting that patients get genetic testing to try and understand the driver of their tumor.”

Early Clinical Activity and Safety Pro Continued Investigation of Repotrectinib in Pediatric Tumors Harboring ALK, ROS1 or NTRK Alterations Repotrectinib Demonstrated Confirmed Responses in 3 of 4 TKI-Naïve Patients SAN DIEGO, Oct. 23, 2021 (GLOBE NEWSWIRE) -- Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, today announced the presentation of early clinical data from the ongoing Phase 1/2 CARE study in pediatric and young adult patients with advanced solid tumors harboring ALK, ROS1 or NTRK alterations. These data are being presented today at the virtual 53rd Congress of the International Society of Paediatric Oncology (SIOP) being held October 21-24. “These early data for repotrectinib demonstrate encouraging clinical activity in this pediatric patient population,” said Mohammad Hirmand, M.D., chief medical officer. “Patient enrollment is continuing in the Phase 1/2 CARE study, and we look forward to further advancing the development of repotrectinib in this patient population.” Early Data from Phase 1/2 CARE Study The primary objective of the Phase 1 dose escalation portion of the study is to evaluate the safety and tolerability and determine the recommended Phase 2 dose (RP2D) of repotrectinib in pediatric patients less than 12 years old. The primary objective of the Phase 2 portion of the study is to determine the anti-tumor activity of repotrectinib in pediatric and young adult patients less than 25 years old. Repotrectinib is administrated in capsule or suspension formulation using weight-based dosing for patients less than 12 years old. Patients 12 to 25 years old can enroll directly into the Phase 2 portion of the study with a repotrectinib dose of 160 mg QD for the first 14 days and may increase to 160 mg BID thereafter. The early Phase 1/2 CARE dataset utilizes an August 2, 2021 data cutoff date. Ten patients were treated across two dose levels. The safety analysis includes the ten treated patients, and the preliminary efficacy analysis includes eight evaluable patients. Patients included in the efficacy analysis had baseline measurable disease and at least one post-baseline evaluable scan. Response evaluation was by physician assessment and per RECIST v1.1 or RANO for CNS tumors. Responses were confirmed with a subsequent scan at least 28 days later. The findings were reported in a pre-recorded presentation by Steven G. Dubois, M.D., associate professor of Pediatrics, Harvard Medical School available on October 23 at 9:12 a.m. ET on the meeting website. Preliminary Safety Analysis (n=10) and Pharmacokinetic Analysis Repotrectinib was generally well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia (n=5) and fatigue (n=5). Among patients with anemia, three had baseline history of anemia. Dizziness events (n=4) were grade 1 or 2 and none led to treatment discontinuation. No patients discontinued treatment due to reasons other than disease progression and no patients had TEAEs that led to dose reduction. No dose-limiting toxicities were reported. Preliminary pharmacokinetics data indicated that the exposure of repotrectinib in different age groups was comparable to the adult exposure at steady-state. Preliminary Efficacy Analysis (n=8) Eight patients were evaluable for efficacy, including four TKI-naïve and four TKI-pretreated patients. TKI-naive patients included those with NTRK amplified anaplastic ependymoma (n=1), NTRK fusion glioblastoma multiforme (GBM)/high grade glioma (n=1), NTRK fusion sarcoma (n=1), and ROS1 fusion inflammatory myofibroblastic tumor (IMT) (n=1). TKI-pretreated patients included those with NTRK fusion GBM/high grade glioma (n=2), NTRK fusion mesoblastic nephroma (n=1), and NTRK fusion sarcoma (n=1). Three TKI-naïve patients (2 NTRK fusion solid tumors; 1 ROS1 fusion IMT) achieved confirmed responses. One of the three responding patients had a NTRK fusion GBM/high grade glioma, was previously treated with tumor resection, whole brain radiotherapy, and multi-agent chemotherapy, and achieved a complete response (CR) and remained in a response for 3.8+ months as of the data cutoff date. The other two confirmed responders remained in response with duration of response of 7.3+ and 12.1+ months, respectively. Of the four TKI-pretreated patients, one patient with NTRK fusion sarcoma had a best response of stable disease. The Phase 1 dose finding portion of the study is ongoing in pediatric patients less than 12 years old to confirm the pediatric RP2D. The Phase 2 portion of the study is ongoing for patients 12 to 25 years old. Turning Point also announced the publication of preclinical data of repotrectinib in neuroblastoma, the most common pediatric extracranial solid tumor, in the American Association of Cancer Research’s peer reviewed journal, Molecular Cancer Therapeutics. Preclinical studies described in the publication titled “Translational Strategies for Repotrectinib in Neuroblastoma” show that repotrectinib inhibits tumor growth and prolongs survival in patient-derived neuroblastoma xenograft models. In addition, the studies indicated that combining repotrectinib with chemotherapy may be a promising treatment paradigm for neuroblastoma patients. About Turning Point Therapeutics Inc. Turning Point Therapeutics is a clinical-stage precision oncology company with a pipeline of internally discovered investigational drugs designed to address key limitations of existing cancer therapies. The company’s lead drug candidate, repotrectinib, is a next-generation kinase inhibitor targeting the ROS1 and TRK oncogenic drivers of non-small cell lung cancer and advanced solid tumors. Repotrectinib, which is being studied in a registrational Phase 2 study in adults and a Phase 1/2 study in pediatric patients, has shown antitumor activity and durable responses among kinase inhibitor treatment-naïve and pre-treated patients. The company’s pipeline of drug candidates also includes elzovantinib, targeting MET, CSF1R and SRC, which is being studied in a Phase 1 trial of patients with advanced or metastatic solid tumors harboring genetic alterations in MET; TPX-0046, targeting RET, which is being studied in a Phase 1/2 trial of patients with advanced or metastatic solid tumors harboring genetic alterations in RET; and TPX-0131, a next-generation ALK inhibitor, which is being studied in a Phase 1/2 trial of previously treated patients with ALK-positive advanced or metastatic non-small cell lung cancer. The company is driven to develop therapies that mark a turning point for patients in their cancer treatment. For more information, visit . Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “plans”, “will”, “believes,” “anticipates,” “expects,” “intends,” “goal,” “potential” and similar expressions are intended to identify forward-looking statements. Such forward-looking statements in this press release include statements regarding, among other things, the efficacy, safety and therapeutic potential of repotrectinib, and the results, conduct, progress and timing of Turning Point Therapeutics’ Phase 1/2 CARE clinical study. These forward-looking statements are based upon Turning Point Therapeutics’ current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Turning Point Therapeutics’ business in general, risks and uncertainties related to the impact of the COVID-19 pandemic to Turning Point Therapeutics’ business and the other risks described in Turning Point Therapeutics’ filings with the Securities and Exchange Commission (SEC), including its quarterly report on Form 10-Q filed with the SEC on August 9, 2021. All forward-looking statements contained in this press release speak only as of the date on which they were made. Turning Point Therapeutics undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. FOR IMMEDIATE RELEASE Contact: Scott Lipman ir@tptherapeutics.com 858-876-3985