City of Hope Physicians Present Innovative Cancer Research at ASCO20 Virtual Session

On May 30, 2020 City of Hope reported a targeted therapy for colorectal cancer and an immunotherapy drug for head and neck cancer are just some of the innovative treatments doctors are presenting at this year’s ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program, which starts today and ends May 31 (Press release, City of Hope, MAY 30, 2020, View Source [SID1234558749]).

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The American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s annual conference discusses the latest research on cancer treatment, detection and prevention.

"City of Hope physicians are leading a wide array of novel research initiatives that will ultimately result in more effective cancer treatments, prevention and detection," said Steven T. Rosen, M.D., provost and chief scientific officer; Irell & Manella Cancer Center Director’s Distinguished Chair. "The ASCO (Free ASCO Whitepaper) annual meeting brings together City of Hope and other leading cancer clinicians who are dedicated to sharing knowledge that will ultimately benefit patients."

City of Hope doctors and scientists will present oral and poster presentations on a wide array of topics.

Targeted therapy against KRAS G12C mutation in colorectal cancer shows promising results

Advanced colorectal cancer that progressed on standard chemotherapy has limited treatment options. This is particularly true for KRAS mutated cancers, which do not respond to epidermal growth factor receptor targeting. A novel drug that targets the KRAS G12C mutation may offer hope for metastatic colorectal patients with this mutation, which occurs in about 3-5% of these patients.

AMG 510 is a targeted therapy that is taken orally on a daily basis and can inhibit the growth of KRAS G12C tumors. During this year’s ASCO (Free ASCO Whitepaper) virtual session, City of Hope’s Marwan Fakih, M.D., professor in the Department of Medical Oncology & Therapeutics Research and medical director of the Judy & Bernard Briskin Center for Clinical Research, for the first time discusses progression free survival data results for colorectal cancer patients who took AMG 510 in a first in-human, multicenter phase 1 clinical trial.

The trial enrolled 42 patients with advanced colorectal cancer and included four cohorts of patients who were assigned different doses of AMG 510.

At all dose levels, patients had median progression free survival (PFS) of four months, with the majority reporting few serious side effects; side effects that occurred included diarrhea, nausea and anemia. In addition, patients had a median overall survival rate of 10 months.

At all dose levels, 7% of patient had significant tumor shrinkage (partial response) and 69% had stable disease, resulting in a 76% disease control rate in the overall population. At the highest dose level of 960mg/day, which is the recommended phase 2 dose level, 12% of patients had an objective response and 80% experienced disease control. The median PFS at the 960 mg/day dose level was 4.2 months.

"The bottom line is that these data are meaningful for colorectal cancer patients with KRAS G12C mutation," Fakih said. "AMG 510 appears to be more favorable in controlling metastatic colorectal cancer — and with few serious side effects — than current Food and Drug Administration-approved therapeutic agents that are used in third and fourth line treatment of this cancer."

Next steps include a phase 1b study evaluating AMG 510 in combination with other targeted therapies or immunotherapy to capitalize on a synergistic activity demonstrated in preclinical studies, he added.

City of Hope leads pioneering evidence-based geriatric oncology study

Geriatric oncology is a burgeoning field in cancer that focuses on treating older adults — who account for 60% of new cancer diagnoses — with innovative interventions geared toward them. One of those interventions is a geriatric assessment tool for older adults with cancer.

Developed by the late Arti Hurria, M.D., founding director of City of Hope’s Center for Cancer and Aging, the assessment tool captures multiple domains, including but not limited to functional status, comorbidity and cognition to determine the functional age of older adults, therefore enabling a more tailored approach to cancer care.

A City of Hope-led randomized clinical trial is one of the first to now demonstrate that geriatric assessment driven interventions can reduce chemotherapy side effects. The results were presented as part of ASCO (Free ASCO Whitepaper)20’s virtual program.

Six hundred City of Hope older patients with solid tumors were enrolled in the trial. Two-thirds of the patients were enrolled in geriatric assessment-driven intervention (GAIN) and a third were enrolled in a standard of care approach in which only an oncologist guides the patient’s treatment.

"Geriatric assessment focuses on capturing the whole person, such as how much physical activity the patient can perform, what serious medical conditions he or she might have, a patient’s psychological status and other factors," said Daneng Li, M.D., the trial’s principal investigator and an assistant clinical professor in City of Hope’s Department of Medical Oncology & Therapeutics Research. "What the assessment does is it really helps a patient’s medical team understand the true nature of the patient that you’re treating, rather than just one area of the patient. You’re getting a much richer picture of who this person is, how treatment can potentially impact them and approaches the medical team can take to reduce any negative impact."

The patients were followed until their chemotherapy ended, or for six months of chemo treatment, whichever came first. Researchers then measured how many serious chemotherapy-related toxicities such as nausea and fatigue each group developed.

"The patients that were treated in the ‘GAIN’ arm had a reduction of 10% in significant chemotherapy-related toxicity, compared to the standard of care arm," Li said. "The reason why this likely occurred is because the GAIN arm was composed of a multidisciplinary team of an oncologist, nurse practitioner, social worker, physical/occupational therapist, nutritionist and pharmacist, who worked together to offer interventions such as physical therapy, social support, nutrition recommendations, and review medication interactions to address potential areas of vulnerability detected on the geriatric assessment in older adults with cancer."

"This is one of the first studies to show that if you intervene based on a patient’s geriatric assessment and provide them with the appropriate interventions, you can actually decrease someone’s toxicity from chemotherapy in an older adult population," he added.

At the end of the study, advance directive completion also increased by 24% in patients in the GAIN group, compared to only a 10% increase in the standard of care group.

Li and his team now want to expand geriatric assessment and interventions to other cancer centers. Their plan is to develop implementation of geriatric assessment and interventions that can be delivered via telemedicine.

"One of Dr. Hurria’s dreams was that one day all older adults with cancer can receive personalized, tailored care," Li said. "We want to make sure that her dream is realized, and that patients continue to benefit from her vision."

City of Hope develops improved testing strategy to identify TP53 mutation

The inherited TP53 mutation significantly increases a person’s risk of developing cancer. Women with the rare mutation have a 50% chance of developing cancer by the age of 30 and a 90% chance over their lifetime; males with the syndrome have a 70% chance of developing cancer over their lifetime. The mutation can cause Li-Fraumeni syndrome, which can lead to the development of sarcomas, brain and breast tumors, and adrenocortical cancers.

But there is also another group of patients who have a TP53 mutation, and it is not inherited. These are patients who develop TP53 gene mutations in rapidly growing blood cells as they age, or is associated with exposure to chemotherapy. Knowing the difference is important, as care for each group is very different since those with the inherited mutation require more extensive cancer screenings and checkups.

Nevertheless, identifying which type of mutation a person has is a difficult task. Led by City of Hope’s Jeffrey Weitzel, M.D., City of Hope is presenting new research for ASCO (Free ASCO Whitepaper)’s virtual session on how the medical community can better discern whether a TP53 mutation a person has is inherited or acquired. (City of Hope is a leader in the research and treatment of patients with the TP53 mutation; it and other institutions recently received a $8.5 million grant from the National Institutes of Health to advance research and treatment for this serious syndrome.)

Approximately 20% of patients who are discovered to have a TP53 mutation with a commercial laboratory multigene panel test don’t have the inherited mutation, according to previous City of Hope studies. But researchers wanted to confirm which type of TP53 mutation these patients had.

"It’s a clinical conundrum because we have this challenge — you have a result that a clinician might normally interrupt as a mutation that the patient inherited and a clinician might think, ‘It’s Li-Fraumeni Syndrome,’" said Weitzel, director of City of Hope’s Division of Clinical Cancer Genomics and the Dr. Norman & Melinda Payson Professor in Medical Oncology. "But we know that a good portion of these are not the real McCoy."

Among 113 cases with commercially detected TP53 who are enrolled in the Clinical Cancer Genomics Community Research Network registry led by City of Hope and other institutions, Weitzel and his team identified 42 cases where there was adequate clinical history, tissue and biospecimens.

Using their multi-tissue strategy, they were able to discern that six cases were inherited and present in all of the tissues identified, five cases were determined to be post-zygotic mosaicism (the mutation was acquired early in embryo genesis so present in a reduced frequency of tissues but in many tissues) and two were indeterminate. Twelve of the patients had developed TP53 in aging blood cells, and thus were presumably not at risk for TP53-related tumors.

The studies are ongoing as part of the National Institutes of Health-funded LiFTUP (Li Fraumeni and TP53 Understanding and Progress).

"With the use of our strategy, we were able to discern what type of TP53 mutation these patients had," Weitzel said. "Our testing strategy helps us identify who has the inherited TP53 mutation and who doesn’t, which is critical in helping clinicians determine the best treatment plan for each type of patient."

City of Hope’s integrated supportive care model reduces hospital length of stay

Living with cancer can be a difficult journey, but City of Hope’s Department of Supportive Care Medicine is a unique care model that provides its patients with invaluable resources and support to ease the challenges. Its integrated supportive care model puts patients in touch with experts in the field of palliative care, psychiatry, psychology, interventional pain, social work, child-life, distress screening, and couples counseling to help patients and their families cope with a cancer diagnosis. This helps patients spend as much quality time away from the hospital as possible.

"City of Hope has a special program here, one that brings together under one umbrella, a wide range of service working closely together as a unit, rather than as isolated parts," said William Dale, M.D., Ph.D., the Arthur M. Coppola Family Chair of Supportive Care Medicine at City of Hope, and a health policy expert. "In this way, we wrap our patients with a comprehensive care plan. But more data is needed about this way of caring for patients, which is why our team collected this."

"While we know that individual supportive care services can improve patient-reported outcomes and quality of life, few studies exist that evaluate the full impact of an integrated supportive care model like we have here at City of Hope," said Jessica Kaltman, M.D., M.S.H.P.M, assistant clinical professor in the Division of Supportive Medicine within the Department of Supportive Care Medicine.

Kaltman, Dale, and other members of the research team, using data collected from City of Hope, set out to change that. Their research was featured during ASCO (Free ASCO Whitepaper)20’s virtual program. They collected data on 1,627 patients (809 with hematologic malignancies, 818 with solid tumors) who were hospitalized at City of Hope and then tracked if they were part of the integrated supportive care model either prior to hospitalization or after admission. Then, they compared the two groups to see if earlier supportive care, before a hospitalization occurred, influenced lengths of stay, ICU stays, or hospital costs.

For both hematology and medical oncology patients, they found that participation in this care model earlier, prior to hospitalization, resulted in decreased length of stay and decreased chance of ICU admission when compared to patients whose first contact with supportive care was only after the initial admission. Additionally, earlier contact with the integrated supportive care model led to decreased inpatient costs compared with those seen only after the first admission.

"Health systems constantly seek ways to increase inpatient and ICU bed capacity as demand for inpatient beds often outnumbers those available," Kaltman said. "Our study suggests that involvement of an integrated supportive care model prior to a patient’s first hospitalization aids in increasing hospital bed capacity. This allows patients who require a higher level of care to receive timely treatment rather than being diverted to another hospital or spending a prolonged time in the emergency room."

"In the past, when there wasn’t such concerns about long hospital stays or bed capacity, it was alright for patients to stay longer," Dale added. "It is now recognized that longer hospital stays are bad for patients, leads to more complications, and is more expensive for the system. In a value-based care environment, shortening hospital stays, avoiding ICU days, and lowering costs is crucial. We found that an integrated and coordinated approach to supportive care, when enacted earlier, during out-patient care, can achieve all of these outcomes for cancer patients."

The next steps are to study how early interaction with City of Hope’s integrated supportive care model impacts health care utilization and costs in the outpatient setting, and to see if it also leads to benefits. In the end, this data is leading the way toward showing that, by treating patients and families early, in a coordinated way, can both improve outcomes and lower costs, and those investments in supportive care can pay for themselves down the road.

Potential new treatment for head and neck cancer

Current standard of care for advanced head and neck squamous cell carcinoma is to use the anti-PD1 checkpoint inhibitor, pembrolizumab, with chemotherapy (platinum/5-fluorouracil) or without it. A clinical trial led by Erminia Massarelli, M.D., Ph.D., M.S., associate clinical professor in City of Hope’s Department of Medical Oncology & Therapeutics Research, has added an immunotherapy drug to that standard of care. Massarelli is presenting the trial’s safety results during ASCO (Free ASCO Whitepaper)20’s virtual program.

The immunotherapy is GSK3359609 (GSK609), which binds the inducible T cell co-stimulatory receptor (ICOS) molecule that is expressed on activated T cells.

"It’s a different mechanism than checkpoint inhibitors," Massarelli explained. "The ICOS molecule is a receptor on the activated T cell. The binding of this receptor increases the activation on the T cell and therefore the immune response against cancer."

By using GSK609 with an anti-PD1 checkpoint inhibitor such as pembrolizumab, a T cell is activated with two different mechanisms of action — ICOS, a direct activation, and pembrolizumab — an indirect activation of the T cell.

INDUCE-1 is a multi-cohort phase 1 clinical trial with two cohorts and 29 patients enrolled. The first group (10 patients) received GSK609 and chemotherapy (platinum and 5-fluorouracil), and another group (19 patients) received the immunotherapy, chemo (also platinum and 5-fluorouracil) and pembrolizumab.

"We found that these three and four drug regimens together are safe, and the addition of GSK609 doesn’t increase side effects, or cause any serious ones," Massarelli said.

Most side effects were mild and consistent with pembrolizumab and chemotherapy toxicities.

Massarelli and her team now plan to open a phase 2/3 trial that will compare the use of the four drug regimen as a first-line therapy for patients with low PDL1 to standard of care treatment.

bridgebio pharma’s qed therapeutics presents data on infigratinib in cholangiocarcinoma and urothelial carcinoma at the american society of clinical oncology 2020 virtual scientific program

On May 29, 2020 BridgeBio Pharma, Inc. (Nasdaq: BBIO) affiliate QED Therapeutics reported that it will present data at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program showing clinical advancement for infigratinib, QED’s oral FGFR1-3 inhibitor, in both urothelial carcinoma and cholangiocarcinoma (CCA) (Press release, BridgeBio, MAY 29, 2020, View Source [SID1234576229]).

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Title: Infigratinib (BGJ398) in advanced/unresectable or metastatic urothelial carcinoma demonstrates consistent treatment response in both first-line and later-line treatment settings

Abstract: 5038

Presenter: Yung Lyou, City of Hope Comprehensive Cancer Center

An analysis of response rates in patients with advanced/unresectable or metastatic urothelial carcinoma based on the amount of prior lines of treatment showed consistent response to infigratinib. The objective response rate (ORR) for all patients (n=67) was 25% (95% CI 15.5-37.5), while the ORR for patients receiving infigratinib as first-line treatment (n=13) saw a response rate of 31% (95% CI 9.1-61.4) compared to 24% (95% CI 13.5-37.6) for patients receiving infigratinib as a second-line or later treatment (n=54). All eight patients in the study with upper tract urothelial carcinoma (UTUC) received infigratinib as second-line or later therapy. The response rates were higher for patients with UTUC, with an ORR of 50% (95% CI 15.7–84.3) and a disease control rate of 100%. In the study, treatment emergent adverse events occurring in >30% of patients were: hyperphosphatemia (46%), elevated creatinine (42%), fatigue (37%), constipation (37%), anemia (36%), decreased appetite (33%), dry mouth (31%), and alopecia (31%).

"These findings support the design of the ongoing, placebo-controlled PROOF 302 study to evaluate the efficacy of infigratinib in adjuvant urothelial carcinoma," said author and PROOF 302 trial lead Sumanta Pal, MD, professor of medical oncology and therapeutics research at City of Hope Comprehensive Cancer Center. "The results in upper tract urothelial cancer (UTUC) build upon earlier research that the disease has a different genetic profile than urothelial carcinoma of the bladder, particularly with respect to FGFR3 alterations, and warrants further investigation in an even earlier setting."

Title: A retrospective analysis of post second-line chemotherapy treatment outcomes for patients with advanced or metastatic cholangiocarcinoma and FGFR2 fusions

Abstract: 4591

Presenter: Milind M. Javle, MD Anderson Cancer Center

In a retrospective analysis of a subset of a single-arm Phase 2 study of infigratinib (n=37), outcomes from patients with FGFR-fusion-positive bile duct cancer receiving infigratinib as third- and later-line therapy were compared with the tumor response when those same patients received second-line therapy with chemotherapy. Treatment with infigratinib resulted in progression free survival (PFS) improvements. The median PFS was 6.8 months (95% CI 3.9-7.8 months) for third- and later-line infigratinib treatment compared to 4.6 months (95% CI 2.7-7.2 months) for second-line chemotherapy.

"Through this retrospective analysis, we can see that infigratinib may have potential for patients whose tumors progress after second-line chemotherapy," said Susan Moran, MD, MSCE, chief medical officer for QED. "These data support continued investigation of infigratinib in patients with FGFR-driven cholangiocarcinoma."

Athenex Presents Interim Data from Oral Paclitaxel Phase II Study in Cutaneous Angiosarcoma at ASCO20 Virtual Scientific Program

On May 29, 2020 Athenex, Inc. (Nasdaq: ATNX), a global biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies for the treatment of cancer, reportted interim data from an ongoing Phase II clinical trial in which oral paclitaxel and encequidar ("Oral Paclitaxel", formerly known as Oraxol) monotherapy showed encouraging efficacy and tolerability in elderly patients with unresectable cutaneous angiosarcoma, an aggressive malignancy with poor prognosis (Press release, Athenex, MAY 29, 2020, View Source [SID1234573876]). The interim results are being presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 (ASCO20) Virtual Scientific Program, being held from May 29 to 31, 2020, and reflect data from 22 evaluable patients out of 26 enrolled patients (16 males and 10 females, median age 75 years (range: 49-93 years)).

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The interim data showed a clinical benefit rate (CR+PR+SD) of 100% in 22 evaluable patients receiving Oral Paclitaxel treatment, who reached their first post treatment efficacy evaluation. All 22 patients experienced reduction in tumor size. Complete responses (CR) were observed in 27.3% of patients (6/22), partial responses (PR) were observed in 22.7% of patients (5/22), and stable disease was observed in 50% of patients (11/22). Oral Paclitaxel has been generally well tolerated in this predominantly elderly population.

"The responses to Oral Paclitaxel observed thus far are very encouraging, especially given the highly aggressive nature of cutaneous angiosarcoma and the lack of approved treatment options for this disease," said lead investigator Vinod Ravi, MD, MBA, associate professor in the Department of Sarcoma Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas. "Oral Paclitaxel appears to be well tolerated, even in older patients. We look forward to continue advancing the study, which will allow us to further characterize this potentially valuable treatment option for angiosarcoma."

Dr. Rudolf Kwan, Chief Medical Officer of Athenex, commented, "The interim data in this Phase II trial add to the growing body of evidence supporting the potential broad clinical utility of Oral Paclitaxel, which has already shown strong clinical data in a Phase III pivotal trial in patients with metastatic breast cancer."

The interim Phase II data, presented as Poster #11517 A Phase II Study of Oral Paclitaxel with Encequidar in the Treatment of Unresectable Cutaneous Angiosarcoma will be part of the Sarcoma Highlights Session on Sunday, May 31 at 3:30pm ET, at the ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program. A copy of the poster presentation is available on Athenex’s website here.

About the Phase II Study of Oral Paclitaxel in Angiosarcoma

This single-arm Phase II study evaluates the activity, safety and tolerability of Oral Paclitaxel administered once daily for three consecutive days per week in patients with unresectable cutaneous angiosarcoma. Enrollment is ongoing at sites in the U.S., United Kingdom, Hong Kong and Taiwan, with a planned total enrollment of 43 subjects. For more information, refer to Identifier: NCT03544567.

In April 2018, the U.S. Food and Drug Administration granted an Orphan Drug Designation for Oral Paclitaxel for the treatment of angiosarcoma. In addition, in October 2019, the Company received Orphan Designations from the European Commission for oral paclitaxel and encequidar for the treatment of soft tissue sarcoma.

The Orascovery platform, based on P-gp pump inhibition technology, was initially developed by Hanmi Pharmaceuticals and licensed exclusively to Athenex for all major worldwide territories except Korea, which is retained by Hanmi.

Sihuan Pharm Obtained Phase I to III Clinical Trial Approval for the Third Generation of EGFR Inhibitor XZP-5809

On May 29, 2019 Sihuan Pharmaceutical Holdings Group Ltd. (HKEx: 0460), the largest cardio-cerebral vascular ("CCV") drug manufacturer in China’s prescription drug market, reported the third generation of EGFR inhibitor XZP-5809, a Category 1 innovative drug developed by the Group, has been granted drug clinical trial approval by the National Medical Products Administration of the PRC (Press release, Sihuan Pharmaceutical, MAY 29, 2019, View Source [SID1234570979]).. The New Drug is a Category 1 innovative drug of the PRC developed by the Group .

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The New Drug is a novel third-generation epithelial growth factor receptor-tyrosine kinase inhibitor (”EGFR-TKI”) that has strong targeting capability, and can be taken orally. It features innovative structure, established mechanism and irreversible binding to EGFR. The New Drug has better selection with higher activity against gene-mutation EGFR and lower activity against wild-type EGFR.

Compared with products of the same type, the New Drug has distinct advantages in its activity and safety, based on the data collected from the completed preclinical trial. The New Drug and its metabolite have demonstrated lower activity against wild-type EGFR. With its better safety profile and global competitive advantage, the New Drug will be considered as a new treatment option for cancer patients.

Dr. Che Fengsheng, Chairman and CEO of Sihuan Pharmaceutical, said, "Significant progress has been made in the field of lung cancer treatment, including anti-cancer immunotherapy, but targeted therapy is still considered the best choice for non-small cell lung cancer (‘NSCLC’) with EGFR mutation."

The preclinical pharmacodynamic data and toxicological data indicate that the New Drug has the following characteristics: good efficacy against EGFR sensitive mutations (exon 19 deletion and L858R mutation) and against acquired resistance mutations (T790M mutation); potential clinical efficacy for patients with lung cancer brain metastasis; better safety profile and less impact on cardiac function when compared with drugs of the same type on the market. The clinical indication for the New Drug candidate is potential to be solid tumors such as locally advanced or metastatic lung cancer with EGFR-sensitive mutations (exon 19 deletion and L858R mutation) and acquired resistance mutations (T790M mutation).

Dr. Che stated, "The Group is committed to the fundamental research of innovative drugs, and finally obtains the clinical trial approval of the New Drug by overcoming the technical difficulties encountered. The obtained clinical trial approval for the New Drug will further enrich the Group’s product line layout in innovative drugs. In addition to the New Drug, the Group currently has Janagliflozin, an innovative drug in the field of anti-diabetes and a number of small molecule targeted innovative drugs such as Birociclib in the field of anti-tumor are in clinical trials and are making progress well. The layout of innovative drugs in various therapeutic fields has established a solid foundation for the Group’s research and development platform of innovative drugs."

Lung cancer is one of the malignant tumors with the highest morbidity and mortality in the world. In 2018, the number of cases of lung cancer around the world was 2.093 million. According to the cancer report statistics of the PRC, in terms of the number of cases, lung cancer ranks the first in the incidence of malignant tumors with approximately 781 thousand as the annual incidence cases number. According to the World Health Organization’s forecast, the number of lung cancer deaths in the PRC will exceed 1 million each year by 2025.

Turning Point Therapeutics Presents Preclinical Data For Novel RET Inhibitor Candidate, TPX-0046

On May 29, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported at the ASCO (Free ASCO Whitepaper) Annual Meeting presented a preclinical update for its novel, clinical-stage, selective RET-inhibitor drug candidate, TPX-0046 (Press release, Turning Point Therapeutics, MAY 29, 2020, View Source [SID1234564371]).

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In the updated preclinical studies comparing proxy molecules for approved and investigational RET inhibitors, TPX-0046 demonstrated potent in vitro and in vivo activity against a range of RET alterations, including greater potency against solvent-front mutations, G810S, G810R, G810C and G810N.

A phase 1/2 trial of TPX-0046 in RET TKI-naïve and -pretreated patients is ongoing.

"TPX-0046 was designed as a potent RET inhibitor with the potential to address TKI-naïve and RET inhibitor-resistant RET-dependent cancers," said Alexander Drilon, M.D., medical oncologist and acting chief of the Early Drug Development Service, Memorial Sloan Kettering Cancer Center, and a principal investigator for the TPX-0046 clinical study. "Specifically, in preclinical studies, TPX-0046 inhibited RET solvent front mutations that have been observed in biopsies from patients with progression on a prior RET inhibitor. Developing a next-generation RET inhibitor is an unmet need."

In enzymatic and cellular assays presented at ASCO (Free ASCO Whitepaper), TPX-0046 was potent against wildtype RET and multiple RET mutations and fusions.TPX-0046 also demonstrated antitumor activity in RET-driven cell-derived and patient-derived xenograft tumor models, including those that harbor a RET G810R solvent-front mutation.

The ongoing Phase 1/2 open-label, single-arm, multi-center clinical study of TPX-0046 is enrolling TKI-naïve and -pretreated patients with RET-altered non-small-cell lung, thyroid, and other advanced cancers in a Phase 1 dose escalation study of approximately 50 patients, and Phase 2 expansion study of approximately 300 patients with multiple cohorts, to assess safety, tolerability, pharmacokinetics (PK) and clinical activity. The study design allows intra-patient dose escalation based on tolerability. For more information, visit and search NCT04161391.

"The preclinical studies we are presenting today support a potential role for TPX-0046 in both TKI-naïve and TKI-pretreated patients," said Athena Countouriotis, M.D., president and chief executive officer of Turning Point Therapeutics. "With a compact design, and lower molecular weight than other investigational or approved RET inhibitors, TPX-0046 has shown encouraging preclinical activity against multiple RET G810 mutations, where there are currently no approved therapeutic options for patients."

TPX-0046 is a multi-targeted RET and SRC kinase inhibitor with a novel three-dimensional macrocyclic structure that is smaller and structurally distinguished from other approved or investigational RET inhibitors. Activation of RET– a receptor tyrosine kinase –through gain-of-function mutations or fusions has been found in multiple tumor types, including non-small-cell lung and thyroid cancers. In preclinical studies TPX-0046 spared vascular endothelial growth factor (VEGF) receptors 1, 2 and 3. According to research published in the European Journal of Cancer1, hypertension was the most common adverse effect (up to 46 percent) among multiple anti-cancer therapeutics that inhibit VEGF. Dual inhibition of RET and SRC represents a novel therapeutic strategy to target abnormal RET signaling in cancers. Inhibition of SRC family kinases has the potential to reduce bypass resistance from signaling through multiple receptor tyrosine kinases and therefore has the potential to increase the therapeutic effect of TPX-0046.