On March 10, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast and gynecological cancers harboring ESR1 mutations, and Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported the initiation of a registrational Phase 3 clinical study comparing targeted lasofoxifene in combination with the CDK 4/6 inhibitor abemaciclib versus fulvestrant plus abemaciclib in pre- and post-menopausal subjects with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation (Press release, Guardant Health, MAR 10, 2023, View Source;and-Post-Menopausal-Patients-with-Locally-Advanced-or-Metastatic-ERHER2–Breast-Cancer-with-an-ESR1-Mutation-as-Detected-by-Guardant-Heal/default.aspx [SID1234628418]).

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This global randomized study will enroll 400 subjects (pre- and post-menopausal women or men) with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation, who have progressed on palbociclib or ribociclib plus an aromatase inhibitor (AI) and up to one line of chemotherapy. Subjects will be randomized 1:1 to receive either lasofoxifene or fulvestrant, and both groups will also receive 150 mg of abemaciclib twice daily. Study subjects will be prospectively screened for an ESR1 mutation using the Guardant360 CDx liquid biopsy, a next generation sequencing (NGS)-based test that detects genomic alterations using circulating tumor DNA from blood. Eli Lilly and Company – which provided abemaciclib (Verzenio) for the ELAINE-2 study – has entered into a new clinical trial collaboration and drug supply agreement with Sermonix and will provide abemaciclib for the ELAINE-3 study.

"The totality of data we have compiled on lasofoxifene to date, including from our completed ELAINE-1 and ELAINE-2 Phase 2 studies, show compelling anti-tumor activity against tumors with increasingly prevalent ESR1 mutations," said Dr. Paul Plourde, vice president for clinical oncology development at Sermonix. "We look forward to further studying lasofoxifene in a large, rigorously designed Phase 3 study, which will include the use of the Guardant360 CDx test to identify patients who have an ESR1 mutation upon progression after first line therapy."

The primary efficacy endpoint is progression-free survival (PFS). Key secondary endpoints include overall response rate (ORR) and overall survival (OS). Additional secondary endpoints to be assessed include clinical benefit rate (CBR), duration of response (DoR), time to disease recurrence (TTR), time to chemotherapy, quality of life, patient reported outcomes on vaginal and sexual health, and safety. Sermonix anticipates dosing the first subject in the first half of 2023.

"The initiation of this Phase 3 combination study is a significant step forward for Sermonix, as we work to develop a novel targeted endocrine treatment option for metastatic breast cancer patients who are post-CDK4/6i with an ESR1 mutation and have limited treatment options that can provide meaningful clinical response," said Dr. David Portman, Sermonix founder and chief executive officer. "We believe the inclusion of the Guardant360 CDx liquid biopsy to accurately identify eligible trial participants will enable us to execute this important study as efficiently as possible. We look forward to dosing the first patients very soon in this area of great unmet medical need."

The Guardant360 CDx test is the first U.S. Food & Drug Administration-approved blood test for comprehensive genomic profiling for all solid tumors. It provides doctors with guideline-complete genomic results in seven days from a simple blood draw to inform treatment decisions.

"We are very pleased to partner with Sermonix on the continued development of lasofoxifene, a promising investigational treatment for select metastatic breast cancer patients who are increasingly resistant to existing endocrine therapies," said Helmy Eltoukhy, co-CEO of Guardant Health. "The Guardant360 CDx test has played a key role in the pivotal trials of several recent precision cancer therapies, and we are excited to partner with Sermonix and support its efforts to address this important and underserved patient population."

About Lasofoxifene
Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with abemaciclib in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue-selective oral endocrine therapy with additional potential benefits on bone, lipid and vaginal health, could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

About Sermonix
Sermonix Pharmaceuticals Inc. is a privately held biopharmaceutical company focused on the development of female-specific and patient-centric oncology products and has currently completed two Phase 2 clinical studies of lasofoxifene, its lead investigational drug. The Sermonix management team, led by founder Dr. David Portman, has significant experience in all stages of the drug development, regulatory and commercialization processes. Paul Plourde, M.D., vice president of oncology clinical development, has many decades of experience at AstraZeneca in the breast cancer drug development arena. Barry Komm, Ph.D., chief scientific officer, is recognized for his expertise in nuclear receptor biology. Miriam Portman, M.D., is co-founder and chief operating officer, with expertise in clinical trial conduct and patient recruitment. Elizabeth Attias, M.M.Sc., Sc.D., chief strategy and development officer, has extensive experience in pharmaceutical drug commercialization. Simon Jenkins, Ph.D., vice president of operations, has over 30 years of experience in global drug development leadership. Sermonix non-executive chairman of the board is Anthony Wild, Ph.D., former president of both Parke-Davis Pharmaceuticals and Warner-Lambert’s Pharmaceutical Division. Learn more at SermonixPharma.com.

On March 9, 2023 Utah company, Kuda Therapeutics reported the company received a Phase II grant from the National Cancer Institute for $2,050,000 to continue research on novel therapies targeting kidney cancer through the competitive Small Business Innovation Research (SBIR) program (Press release, Kuda Therapeutics, MAR 9, 2023, View Source [SID1234643989]).

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The clear cell subtype of kidney cancer, the most common and aggressive form of this disease, is among the most drug resistant of solid tumors and is uniquely dependent upon the hypoxia-inducible factors (HIF) for its continued growth and progression. Clear cell kidney cancer cells are also exquisitely sensitive to ferroptosis, a newly discovered form of cell death driven by iron accumulation.

Kuda Therapeutics, led by co-founder and CEO, Dr. Mei Yee Koh, and co-founder and CFO, Mr. Travis Ehlinger, identified a molecule that specifically blocks HIF production and induces tumor cell death through ferroptosis. The company’s SBIR Phase II-funded studies will advance the commercial development of this molecule as a new medicine for the treatment of kidney cancer.

"KD061 is a novel first-in-class molecule that inhibits HIF-1/2α and triggers cell death via ferroptosis, thus exploiting two specific vulnerabilities of kidney cancer," said Koh. "This SBIR Phase II grant enables Kuda to advance KD061 towards an Investigational New Drug (IND) filing and first-in-human studies where we can begin to make a difference in the lives of patients."

The company previously received a $560,000 Department of Defense Kidney Cancer Research Program Idea Award (2020-2023) and a $300,000 Phase I SBIR award from the National Cancer Institute (2018-2020). The company worked with the Utah Innovation Center for all three winning proposals.

"The Utah Innovation Center, with their expertise in these grant funding mechanisms’ has provided invaluable assistance to our team in preparing and proofreading these winning proposals. I would encourage other young companies seeking federal funding to utilize this free resource provided by the State of Utah," Koh added.

The Utah Innovation Center is available to assist other Utah companies looking for non-dilutive funding through the federal SBIR/STTR programs. The Innovation Center can be contacted at [email protected].

On March 9, 2023 Amgen Inc. (the "Company") reported that it has entered into a third amended and restated revolving credit agreement with Citibank, N.A., as administrative agent ("Citibank"), JPMorgan Chase Bank, N.A., as syndication agent, and the other banks party thereto (the "Revolving Credit Agreement"), for a total commitment of $4.0 billion (Filing, Amgen, MAR 9, 2023, View Source [SID1234628510]). Financing under the Revolving Credit Agreement is available for general corporate purposes, including as a liquidity backstop to our commercial paper program. The commitments under the Revolving Credit Agreement may be increased by up to $1.25 billion in the aggregate upon our request at the discretion of the banks and subject to certain customary requirements. The commitments of each bank under the Revolving Credit Agreement have an initial term of five years and may be extended for up to two additional one year periods upon our request at the discretion of the respective banks, subject to certain customary requirements. The Revolving Credit Agreement amends and restates our existing revolving credit agreement dated as of December 12, 2019.

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Advances under the Revolving Credit Agreement will bear interest at an annual rate of, at our option, either (i) Adjusted Term SOFR Rate as defined in the Revolving Credit Agreement (or EURIBOR Rate as defined in the Revolving Credit Agreement for certain advances denominated in Euros) plus between 0.68% and 1.10%, depending on the rating of our senior long-term unsecured debt or (ii) the highest of (A) Citibank’s base commercial lending rate, (B) the overnight federal funds rate plus 0.50%, and (C) one-month Adjusted Term SOFR Rate plus 1.00%, plus between 0.00% and 0.10%, depending on the rating of our senior long-term unsecured debt. We have also agreed to pay a fee for committed funds under the Revolving Credit Agreement, whether used or unused, of between 0.07% and 0.15% per annum depending on the rating of our senior long-term unsecured debt. The Revolving Credit Agreement includes a $300 million sub-limit for issuances of letters of credit.

The Revolving Credit Agreement contains customary affirmative and negative covenants, including limitations on mergers, consolidations and sales of assets, limitations on liens and sales and leasebacks, limitations on transactions with affiliates, and limitations on subsidiary indebtedness. In addition, the Revolving Credit Agreement requires maintenance of a minimum consolidated interest coverage ratio of EBITDA to total interest expense, each on a consolidated basis.

The description of the Revolving Credit Agreement above does not purport to be complete and is qualified in its entirety by reference to the Revolving Credit Agreement, which is filed as Exhibit 10.1 to this report.

Termination of a Material Definitive Agreement.

On December 12, 2022, the Company, Citibank, as administrative agent, Bank of America, N.A. ("Bank of America"), as syndication agent, and Citibank and Bank of America, as lead arrangers and book runners, entered into a bridge credit facility (the "Bridge Credit Facility") (as filed in our Current Report on Form 8-K on December 12, 2022) providing for borrowings of up to $28.5 billion to finance the Company’s acquisition of Horizon Therapeutics plc (the "Acquisition").

The commitments under the Bridge Credit Facility were automatically reduced on December 22, 2022 by the amount of our term loan credit facility (the "Term Loan Credit Facility") (as filed in our Current Report on Form 8-K on December 22, 2022) entered into by the Company, Citibank, as administrative agent, Bank of America, as syndication agent, Citibank, Bank of America, Goldman Sachs Bank USA and Mizuho Bank, Ltd., as lead arrangers and bookrunners, and Goldman Sachs Bank USA and Mizuho Bank, Ltd., as documentation agents, providing for (1) a $2,000,000,000 18-month term loan tranche and (2) a $2,000,000,000 3-year term loan tranche. The commitments under the Bridge Credit Facility were further reduced on March 2, 2023 by the net cash proceeds to the Company from the issuance and sale of senior notes of approximately $23,766,627,500 (the "Senior Note Proceeds"), after deducting underwriters’ discounts and estimated offering expenses payable by the Company (as described in our Current Report on Form 8-K filed on March 2, 2023).

On March 9, 2023, we elected to terminate all remaining outstanding commitments under our Bridge Credit Facility and terminate the Bridge Credit Facility in its entirety in accordance with its terms. In connection with the termination of the Bridge Credit Facility, all accrued and unpaid fees thereunder were paid in full. We elected to terminate the remaining outstanding commitments under our Bridge Credit Facility, as, together with cash on hand, the Senior Note Proceeds, and the commitments under our Term Loan Credit Facility, we have sufficient liquidity to finance the completion of the Acquisition, and the remaining commitments under the Bridge Credit Facility are not needed.

On March 9, 2023 ALX Oncology Holdings Inc., ("ALX Oncology") (Nasdaq: ALXO), a clinical-stage immuno-oncology company developing therapies that block the CD47 checkpoint pathway, reported financial results for the fourth quarter and year ended December 31, 2022 and provided clinical development and operational highlights (Press release, ALX Oncology, MAR 9, 2023, View Source [SID1234628509]).

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"2022 was a productive year for us, with numerous clinical and corporate development accomplishments highlighted by the advancement of our lead program, evorpacept, for the treatment of multiple solid tumor indications and hematological malignancies. We also expanded evorpacept into new indications and combinations," said Dr Jaume Pons, Ph.D., Founder, President and Chief Executive Officer of ALX Oncology. "These included a Phase 1 trial in urothelial cancer ("UC") in combination with PADCEV, and a new investigational treatment arm in the I-SPY-P1 trial for the treatment of patients with unresectable or metastatic HER2-positive and HER2-low breast cancer in combination with ENHERTU in partnership with Quantum Leap Healthcare Collaborative."

Dr. Pons added, "2023 is expected to be an eventful year for ALX Oncology with the presentation of data from ASPEN-06, a randomized Phase 2 trial of evorpacept in combination with trastuzumab, ramucirumab and paclitaxel for the treatment of patients with HER2-positive gastric/gastroesophageal junction ("GEJ") cancer in the second half of 2023, and the presentation of dose optimization results from ASPEN-02, a Phase 1b clinical trial of evorpacept in combination with azacitidine in patients with myelodysplastic syndromes ("MDS") in the second half of 2023. Additionally, we are on track to file an Investigational New Drug ("IND") application in the first half of 2023, in collaboration with Tallac Therapeutics, for ALTA-002 that will further expand our clinical pipeline beyond evorpacept."

Anticipated Key Milestones in 2023

Presentation of data from a randomized Phase 2 trial of evorpacept in combination with trastuzumab, ramucirumab and paclitaxel for the treatment of patients with HER2-positive gastric/GEJ cancer (ASPEN-06) in the second half of 2023.
Presentation of dose optimization results of a Phase 1b clinical trial of evorpacept in combination with azacitidine in patients with MDS (ASPEN-02) in the second half of 2023.
Initiation of a Phase 1b dose optimization clinical trial of evorpacept in combination with azacitidine and venetoclax for the treatment of patients with relapsed or refractory ("r/r") or newly diagnosed ("ND") acute myeloid leukemia ("AML") (ASPEN-05) in the second half of 2023.
Filing an IND for ALTA-002, a SIRPα Toll-like receptor agonist antibody conjugate in collaboration with Tallac Therapeutics in the first half of 2023.
Expansion of the antibody-drug conjugate ("ADC") platform acquired from ScalmiBio to identify clinical development candidates by the second half of 2023.
Recent Clinical Developments for Evorpacept

First patient dosed in ASPEN-07 study evaluating evorpacept in combination with PADCEV (enfortumab vedotin-ejfv), an ADC, in patients with UC.
In February 2023, ALX Oncology announced the first patient was dosed in the Phase 1 ASPEN-07 study evaluating evorpacept in combination with enfortumab vedotin-ejfv, an ADC, in patients with UC. ASPEN-07 is a phase 1, open-label, multi-center study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of evorpacept in combination with enfortumab vedotin-ejfv in subjects with unresectable locally advanced or metastatic UC.
Presented initial clinical data from the Phase 1a dose escalation portion of the ASPEN-05 trial evaluating evorpacept in combination with azacitidine and venetoclax for the treatment of patients with r/r or ND AML at American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH").
In December 2022, ALX Oncology presented a poster presentation at ASH (Free ASH Whitepaper) showing that the combination of evorpacept with azacitidine and venetoclax is active and generally well tolerated. As of October 3, 2022, 14 patients with either r/r or ND AML have been treated with evorpacept in the Phase 1 dose escalation part of the study, administered at 20 mg/kg or 30 mg/kg once every 2 weeks or 60 mg/kg once every 4 weeks ("Q4W") together with standard dosing of azacitidine and venetoclax.
Evorpacept in combination with azacitidine and venetoclax was generally well tolerated (N=14) with no maximum tolerated dose identified and a maximum administered dose of 60 mg/kg Q4W. In 10 relapsed or refractory AML response-evaluable patients, including 8 that had progressed after prior venetoclax treatment, all experienced a reduction in bone marrow blasts, and 4 achieved a response. In 3 newly diagnosed AML response-evaluable patients, all 3 achieved a response, including 1 complete response ("CR"), 1 CR with incomplete hematologic recovery, and 1 morphologic leukemia free state.
Presented data from ASPEN-03 and ASPEN-04, the Company’s Phase 2 head and neck squamous cell carcinoma ("HNSCC") studies at Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) ("SITC").
In November 2022, ALX Oncology presented two Trials in Progress abstracts at SITC (Free SITC Whitepaper) related to ASPEN-03 and ASPEN-04. ALX Oncology continues to advance ASPEN-03 and ASPEN-04, which are two distinct randomized Phase 2 studies for the treatment of patients with advanced HNSCC in combination with pembrolizumab with or without chemotherapy. Patient enrollment for ASPEN-03 and ASPEN-04 continues as planned.
Recent Corporate Updates

In October 2022, ALX Oncology entered into a loan facility with Oxford Finance LLC and Silicon Valley Bank for up to $100 million of non-dilutive financing. Under the terms of the loan agreement, ALX Oncology drew $10 million of an initial $50 million tranche at closing, with the remaining $40 million available at its discretion through the end of 2023. ALX Oncology also has access up to an additional $50 million with $12.5 million available in each of two tranches based upon the achievement of milestones related to the development of evorpacept and one pre-clinical product candidate, and $25 million available at the Lenders’ discretion.
In November 2022, strengthened board of directors by adding an additional independent board member with significant operational and commercial leadership experience in the biopharmaceutical industry:
Scott Garland, currently strategic advisor and member of the board of directors at Pact Pharma and previously Chief Executive Officer of Portola Pharmaceuticals, has more than 30 years of biopharmaceutical industry knowledge and brings deep commercial and executive leadership experience.
Full Year and Fourth Quarter 2022 Financial Results:

Cash, Cash Equivalents and Investments: Cash, cash equivalents and investments as of December 31, 2022 were $282.9 million. ALX Oncology believes its cash, cash equivalents, investments and the ability to draw down up to an additional $40 million of its term loan are sufficient to fund planned operations through mid-2025.
Research and Development ("R&D") Expenses: R&D expenses consist primarily of pre-clinical, clinical and manufacturing expenses related to the development of the Company’s current lead product candidate, evorpacept, and R&D employee-related expenses. These expenses for the three months ended December 31, 2022 were $25.2 million, compared to $20.9 million for the prior-year period. R&D expenses for the year ended December 31, 2022 were $98.4 million, compared to $60.2 million for the prior-year period.
General and Administrative ("G&A") Expenses: G&A expenses consist primarily of administrative employee-related expenses, legal and other professional fees, patent filing and maintenance fees, and insurance. These expenses for the three months ended December 31, 2022 were $7.0 million, compared to $7.6 million for the prior-year period. G&A expenses for the year ended December 31, 2022 were $29.0 million, compared to $23.4 million for the prior-year period.
Net loss: GAAP net loss was $30.7 million for the fourth quarter ended December 31, 2022, or $0.75 per basic and diluted share, as compared to a net loss of $28.4 million for the fourth quarter ended December 31, 2021, or $0.70 per basic and diluted share. GAAP net loss for the year ended December 31, 2022 was $123.5 million, or $3.03 per basic and diluted share, as compared to $83.5 million, or $2.07 per basic and diluted share, for the year ended December 31, 2021. Non-GAAP net loss was $24.4 million for the fourth quarter ended December 31, 2022, as compared to a net loss of $22.8 million for the fourth quarter ended December 31, 2021. Non-GAAP net loss for the year ended December 31, 2022 was $99.6 million, as compared to $69.5 million for the year ended December 31, 2021. A reconciliation of GAAP to non-GAAP financial results can be found at the end of this news release.

On March 9, 2023 AnHeart Therapeutics, a clinical-stage global biopharmaceutical company committed to developing novel precision oncology therapeutics, reported the publication of clinical trial design of TRUST-II, a global Phase 2 clinical study of taletrectinib in ROS1-positive non-small cell lung cancer and other solid tumors, in the peer-reviewed medical journal, Future Oncology (Press release, AnHeart Therapeutics, MAR 9, 2023, View Source [SID1234628491]).

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The paper, "TRUST-II: A global phase II study of taletrectinib in ROS1-positive non-small cell lung cancer and other solid tumors," describes the rationale and design of TRUST-II, a global Phase 2 study of taletrectinib in patients with locally advanced/metastatic ROS1+ NSCLC and other ROS1+ solid tumors. The primary endpoint is objective response rate by IRC. Key secondary endpoints include duration of response, progression-free survival, overall survival, and safety. This trial is currently enrolling patients globally. The paper is published online and can be accessed at: www.futuremedicine.com/doi/10.2217/fon-2022-1059.

"Many patients develop resistance to first-generation inhibitors such as crizotinib within two years of treatment due to progression in the brain or emergence of secondary mutations such as G2032R," said Dr. Misako Nagasaka, lead author, a medical oncologist at the University of California Irvine. "There is a significant unmet medical need for a next-generation ROS1 inhibitor, such as taletrectinib, which is potent against secondary mutations and effectively treats brain metastases while maintaining a favorable safety profile."

"Taletrectinib, a novel next-generation ROS1 inhibitor, was designed specifically to improve efficacy and overcome resistance to first-generation ROS1 inhibitors, and address brain metastasis while conferring fewer neurological adverse events," said Lian Li, M.D., Ph.D., US Chief Medical Officer of AnHeart Therapeutics. "We look forward to advancing the TRUST-II study and bringing the potential effective therapy to patients across the globe who are in desperate need for novel therapies that have improved safety and efficacy. The publication in Future Oncology is critical for the medical community to learn about the rationale and details of the study design."

In another ongoing taletrectinib regional Phase 2 trial (TRUST-I, NCT04395677), the interim data showed an ORR of 92.5% (95% CI: 83.4-97.5) and 50.0% (95% CI: 33.4-66.6) in 67 ROS1 TKI-naïve patients and 38 ROS1 TKI-pretreated patients, respectively. Among the 5 patients with the ROS1 G2032R resistance mutation, 4 of them achieved partial response (PR) and 1 achieved stable disease (SD). In 12 patients with measurable baseline CNS metastases, the IC-ORR was 91.7% (95% CI: 61.5-99.8). Taletrectinib was well-tolerated and most adverse events observed were mild and reversible.

Based on the clinical data accumulated to date, taletrectinib has received Breakthrough Therapy Designation (BTD) from both the US FDA and China NMPA for the treatment of patients with advanced or metastatic ROS1+ NSCLC, who are either ROS1 TKI treatment naïve or previously treated with crizotinib.