On April 11, 2021 Eli Lilly and Company (NYSE: LLY) reported for the first time data from the Phase 1/2 LIBRETTO-001 trial showing treatment with Retevmo (selpercatinib) demonstrated encouraging antitumor activity and safety across RET fusion-positive advanced solid tumors beyond lung and thyroid cancers, including multiple treatment-refractory gastrointestinal (GI) malignancies (Press release, Eli Lilly, APR 11, 2021, View Source [SID1234577842]). The data were presented at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, held virtually April 10-15, 2021.

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"We are excited to broaden the body of evidence for Retevmo in RET fusion-positive cancers beyond lung and thyroid tumors," said David Hyman, M.D., chief medical officer, oncology at Lilly. "These encouraging outcomes, including in difficult-to-treat GI malignancies, support a growing body of evidence that RET fusions are potentially actionable in a wide range of tumor types. These findings further demonstrate the importance of broad tumor profiling in advanced cancers. We look forward to discussing these new data with regulatory authorities this year."

In the Phase 1/2 LIBRETTO-001 trial, 32 adult patients with 12 unique RET fusion-positive advanced cancer types were enrolled by the efficacy cutoff date of September 19, 2020 (with follow-up through March 19, 2021). Cancer types treated included pancreatic, colon, breast, salivary, sarcoma, carcinoid, rectal neuroendocrine, small intestine, xanthogranuloma, ovarian, pulmonary carcinosarcoma, and unknown primary cancers. Among the 32 patients, 62.5 percent had gastrointestinal tumors (defined as pancreatic [n=9], colon [n=9], small intestine [n=1], and rectal neuroendocrine [n=1]). Across all 32 patients, the confirmed objective response rate (ORR) was 47 percent (95% CI: 26-65%). Confirmed responses were observed in nine unique RET fusion-positive advanced cancer types. The median duration of response (DoR) was not reached, with median follow-up of 13 months. Responses were ongoing in 73 percent (11/15) of responding patients.

Retevmo Efficacy

Objective Response Rate* % (95% CI)

47% (29-65), n=32

Median Duration of Response (range)

Not Reached (2 -33+ months)

Responses Ongoing

73% (11/15)

Median Duration of Follow up

13 months

* per investigator assessment, + indicates patient ongoing

Safety among patients in this cohort was consistent with the known safety profile of Retevmo. In this cohort, the most common treatment-emergent adverse events of any grade (≥20%) were increased aspartate aminotransferase (AST)/increased alanine aminotransferase (ALT), dry mouth, hypertension, diarrhea, fatigue, nausea, and abdominal pain. No patients in this cohort discontinued treatment due to treatment-related adverse events.

"While uncommon, RET fusions occur in a ‘long tail’ of solid tumors beyond lung and thyroid cancers, and these patients do not yet have an approved targeted therapy option to address the underlying genomic driver of their cancer," said Vivek Subbiah, MD, associate professor in the Investigational Cancer Therapeutics Department and center clinical medical director of the Clinical Center for Targeted Therapy, of the Cancer Medicine Division, at The University of Texas MD Anderson Cancer Center. "These results demonstrate selpercatinib’s potential for this patient population and reiterate the importance of broad-based genomic profiling to identify actionable oncogenic drivers, including RET fusions."

In May 2020, Lilly’s first-in-class selective RET inhibitor Retevmo received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), in adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, and in adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). Retevmo was approved based on the Phase 1/2 LIBRETTO-001 trial’s endpoints of ORR and DoR. Retevmo (marketed as Retsevmo outside the U.S.) was approved by the European Commission in February 2021.

About LIBRETTO-001

The Phase 1/2 LIBRETTO-001 trial is the largest clinical trial of patients with RET-driven cancers treated with a RET inhibitor. The trial, which spans 16 countries and 89 sites, included a dose escalation phase (Phase 1) and a dose expansion phase (Phase 2). The Phase 2 portion of the trial had major efficacy outcomes of ORR and DoR, and prespecified secondary endpoints of central nervous system (CNS) ORR and CNS DoR, as determined by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

LIBRETTO-001 continues to enroll patients with RET-altered tumors beyond lung cancer.

About Retevmo (selpercatinib)

Retevmo (selpercatinib, formerly known as LOXO-292) (pronounced reh-TEHV-moh) is a selective and potent RET kinase inhibitor. Retevmo may affect both tumor cells and healthy cells, which can result in side effects. RET-driver alterations are predominantly mutually exclusive from other oncogenic drivers. Retevmo is an U.S. FDA-approved oral prescription medicine, 120 mg or 160 mg dependent on weight (<50 kg or ≥50 kg, respectively), taken twice daily until disease progression or unacceptable toxicity.i Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION FOR RETEVMO (selpercatinib)

Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.6% of patients treated with Retevmo. Increased aspartate aminotransferase (AST) occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased alanine aminotransferase (ALT) occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years). Monitor ALT and AST prior to initiating Retevmo, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Retevmo based on the severity.

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Retevmo in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Retevmo based on the severity.

Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment. Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Retevmo based on the severity.

Serious, including fatal, hemorrhagic events can occur with Retevmo. Grade ≥3 hemorrhagic events occurred in 2.3% of patients treated with Retevmo including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage.

Hypersensitivity occurred in 4.3% of patients receiving Retevmo, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume Retevmo at a reduced dose and increase the dose of Retevmo by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Tumor lysis syndrome (TLS) occurred in 1% of patients with medullary thyroid carcinoma receiving Retevmo. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect wound healing. Withhold Retevmo for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Retevmo after resolution of wound healing complications has not been established.

Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose. There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.

Severe adverse reactions (Grade 3-4) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were hypertension (18%), prolonged QT interval (4%), diarrhea (3.4%), dyspnea (2.3%), fatigue (2%), abdominal pain (1.9%), hemorrhage (1.9%), headache (1.4%), rash (0.7%), constipation (0.6%), nausea (0.6%), vomiting (0.3%), and edema (0.3%).

Serious adverse reactions occurred in 33% of patients who received Retevmo. The most frequently reported serious adverse reaction (in ≥ 2% of patients) was pneumonia.

Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3).

Common adverse reactions (all grades) occurring in ≥15% of patients who received Retevmo in LIBRETTO-001, were dry mouth (39%), diarrhea (37%), hypertension (35%), fatigue (35%), edema (35%), rash (27%), constipation (25%), nausea (23%), abdominal pain (23%), headache (23%), cough (18%), prolonged QT interval (17%), dyspnea (16%), vomiting (15%), and hemorrhage (15%).

Laboratory abnormalities (all grades; Grade 3-4) ≥20% worsening from baseline in patients who received Retevmo in LIBRETTO-001, were AST increased (51%; 8%), ALT increased (45%; 9%), increased glucose (44%; 2.2%), decreased leukocytes (43%; 1.6%), decreased albumin (42%; 0.7%), decreased calcium (41%; 3.8%), increased creatinine (37%; 1.0%), increased alkaline phosphatase (36%; 2.3%), decreased platelets (33%; 2.7%), increased total cholesterol (31%; 0.1%), decreased sodium (27%; 7%), decreased magnesium (24%; 0.6%), increased potassium (24%; 1.2%), increased bilirubin (23%; 2.0%), and decreased glucose (22%; 0.7%).

Concomitant use of acid-reducing agents decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid concomitant use of proton-pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, and locally-acting antacids with Retevmo. If coadministration cannot be avoided, take Retevmo with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Concomitant use of strong and moderate CYP3A inhibitors increases selpercatinib plasma concentrations which may increase the risk of Retevmo adverse reactions including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently.

Concomitant use of strong and moderate CYP3A inducers decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid coadministration of Retevmo with strong and moderate CYP3A inducers.

Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases their plasma concentrations which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of Retevmo with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

The safety and effectiveness of Retevmo have not been established in pediatric patients less than 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing Retevmo if abnormalities occur.

No dosage modification is recommended for patients with mild to severe renal impairment (estimated Glomerular Filtration Rate [eGFR] ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease [MDRD] equation). A recommended dosage has not been established for patients with end-stage renal disease.

Reduce the dose when administering Retevmo to patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times upper limit of normal [ULN] and any AST). No dosage modification is recommended for patients with mild or moderate hepatic impairment. Monitor for Retevmo-related adverse reactions in patients with hepatic impairment.

Please see full Prescribing Information for Retevmo.

SE HCP ISI All_25MAR2021

About Loxo Oncology at Lilly

Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research Laboratories oncology organization and Loxo Oncology, which was acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus and spirit of a biotech with the scale and resources of large pharma, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new oncology medicines that unequivocally work early in clinical development and will matter to patients.

On April 10, 2021 Bolt Biotherapeutics, Inc. (Nasdaq: BOLT), a clinical-stage biotechnology company pioneering a new class of immuno-oncology agents that combine the targeting precision of antibodies with the power of both the innate and adaptive immune systems, reported that an online oral presentation with live Q&A and a Trial in Progress poster presentation for lead agent BDC-1001 are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held virtually from April 10-15th (Press release, Bolt Biotherapeutics, APR 10, 2021, View Source [SID1234618697]).

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The oral presentation explores immunosuppression mediated by various cells in the tumor microenvironment (TME), as well as the tumor-supportive nature of antigen presenting cells (APCs) in the TME in preclinical models. Reawakening these immunosuppressed APCs may result in a productive and durable anti-tumor immune response. Bolt is utilizing its Boltbody platform to create immune-stimulating antibody conjugates (ISACs), such as BDC-1001, that invoke this mechanism and provided complete tumor regression in preclinical tumor models.

"In murine models we have seen efficacy in a variety of tumors that are immunologically cold and well-established. Furthermore, consistent with our proposed mechanism of action for ISACs, we see evidence of increased myeloid and T cell infiltration in the tumor microenvironment mediated by BDC-1001 surrogate ISACs," said David Dornan, Ph.D., Chief Scientific Officer at Bolt Biotherapeutics. "We’re excited to share our rationale for selecting the linker-payload for BDC-1001 to optimize anti-tumor activity while minimizing the potential for the formation of anti-drug antibodies."

BDC-1001 is comprised of a tumor antigen-targeting monoclonal antibody (mAb), a trastuzumab biosimilar and an immune-stimulating agent (a TLR7/8 agonist) conjugated to each other with a non-cleavable linker. In a series of preclinical studies with BDC-1001, Bolt demonstrated the mechanism of action for their HER2-targeted ISAC. BDC-1001 surrogate was able to eliminate established, treatment-resistant tumors through the engagement of both innate and adaptive immunity. There were no adverse findings in toxicology studies of BDC-1001.

A Trial in Progress poster is also being presented by Manish R. Sharma, M.D. of START Midwest, a principal investigator in Bolt’s ongoing BDC-1001 Phase 1/2 trial. The poster details the design of the study: a four-part study with two dose-escalation parts and two dose-expansion parts. The study is evaluating BDC-1001 administered intravenously with or without an immune checkpoint inhibitor targeting PD-1 in up to 390 patients with HER2-expressing or HER2-amplified advanced or metastatic solid tumors. The dose escalation parts will evaluate sequential doses of BDC-1001 as a monotherapy or in combination with a PD-1 checkpoint inhibitor in a 3+3 design, with the ability to backfill up to an additional 12 patients in each dose cohort. The dose expansion parts will evaluate the recommended Phase 2 dose as monotherapy or in combination with a PD-1 checkpoint inhibitor in four cohorts of patients.

The primary objective of the dose escalation portion of the study is to assess safety as measured by the incidence of adverse events and serious adverse events; dose-limiting toxicities within the 3+3 design; and potential immune-related toxicities and determine the recommended phase 2 dose. Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. These exploratory studies will help reinforce the ISAC mechanism of action in humans and seek to identify biomarkers associated with BDC-1001 biological activity with or without an immune checkpoint inhibitor.

In January, Bolt presented a preliminary clinical update on the first 20 patients that showed early signs of clinical activity, including stable disease in several patients and a confirmed partial response by RECIST, and acceptable safety with all 20 patients completing their dose-limiting toxicity (DLT) evaluation period without DLTs or drug-related serious adverse events. Treatment-emergent adverse events deemed to be related to BDC-1001 have been mild or moderate in severity, including mild infusion-related reactions without interruption to dosing. Bolt expects to provide an update on the trial sometime in the second half of 2021.

About Bolt Biotherapeutics’ Immune Stimulating Antibody Conjugate (ISAC) Platform Technology
The Boltbody ISAC platform technology harnesses the ability of innate immune agonists to convert cold tumors into immunologically hot tumors, thereby illuminating tumors to the immune system and allowing them to be invaded by tumor killing cells. Boltbody ISACs have demonstrated the ability to eliminate tumors following systemic administration as monotherapy in preclinical models and have also led to the development of immunological memory, which is predicted to translate into more durable clinical responses for patients.

About the Ongoing BDC-1001 Phase 1/2 Study in Patients with HER2-Expressing Solid Tumors
The Phase 1/2, multi-center, open-label study is evaluating the safety, pharmacokinetics, pharmacodynamics and proof of mechanism of BDC-1001 in patients with HER2-expressing solid tumors. The first portion of the study includes a monotherapy dose-escalation phase in which cohorts of patients will receive ascending intravenous doses of BDC-1001 to determine the maximum tolerated dose and/or the recommended dose to advance into expansion cohorts and Phase 2 based on safety and tolerability. The second portion of the study is a dose expansion phase in which patients will receive BDC-1001 monotherapy to further evaluate the safety, tolerability and clinical antitumor activity of the recommended Phase 2 dose. Please refer to www.clinicaltrials.gov NCT04278144 for additional clinical trial information.

On April 10, 2021 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of small molecule, MasterKey therapies, reported the presentation of preclinical data on BDTX-189 and BDTX-1535 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR) (Free AACR Whitepaper), taking place April 9-14, 2021 (Press release, Black Diamond Therapeutics, APR 10, 2021, View Source [SID1234584639]).

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"These preclinical data demonstrate achievement of a key goal of our pharmacokinetic (PK)/pharmacodynamic (PD) strategy for BDTX-189 with a preclinical PK/PD profile designed for rapid and sustained target inhibition with rapid clearance," said Elizabeth Buck, Ph.D., Executive Vice President, Discovery and Translational Sciences at Black Diamond Therapeutics. "We look forward to presenting preliminary clinical data, including detailed PK data, from the Phase 1 dose-escalation portion of the MasterKey-01 study in the first half of this year."

Dr. Buck continued: "Additionally, these data illustrate the MasterKey profile of BDTX-1535 as a brain-penetrant, epidermal growth factor receptor (EGFR) mutant selective inhibitor. BDTX-1535 has been shown to potently and selectively inhibit the family of EGFR variants implicated in glioblastoma multiforme (GBM), as well as Exon 18 mutations and the C797S mutations evident in non-small cell lung cancer (NSCLC). This breadth of coverage, coupled with a brain-penetrant PK profile, supports the potential to develop a novel and differentiated candidate for GBM and solid tumors expressing un-drugged EGFR mutations, including NSCLC."

The presentations describe the following data:

Preclinical PK BDTX-189 Data:

Black Diamond employed a novel physiologically based pharmacokinetic (PBPK) modeling strategy, accounting for compound-specific determinants of BDTX-189 metabolism and disposition, to prospectively predict the clinical PK profile and active dose range of BDTX-189.
Preclinical PBPK modeling indicated that BDTX-189 would be readily orally absorbed with a short elimination half-life (approximately two hours) while maintaining suppression of ErbB pathway biomarkers over the dosing interval, consistent with the irreversible mechanism of action and the desired PK/PD profile.
Active dose levels in humans were projected to be in the 400–800 mg QD range based on the exposure-tumor growth inhibition relationship in multiple mouse patient-derived xenograft (PDX) models harboring ErbB allosteric mutations.
Enrollment and dosing of patients in the Phase 1/2 MasterKey-01 study of BDTX-189 is ongoing, and the Company is on track to complete the dose-escalation portion of the Phase 1 clinical trial in the first half of 2021.
Preclinical BDTX-1535 Data:

GBM tumors express a family of allosteric oncogenic EGFR variants that often appear together in GBM and, as shown by the Company’s preclinical work, must all be effectively inhibited to secure a meaningful anti-tumor response. In cell-based assays, BDTX-1535 achieved potent and selective inhibition of all members of the family of oncogenic EGFR variants expressed in GBM.
BDTX-1535 demonstrated a favorable brain-penetrant PK profile in mouse, rat, and dog models.
Tumor growth inhibition in mouse models bearing intracranial GBM6 patient-derived tumors expressing allosteric EGFR mutants was achieved.
BDTX-1535 demonstrated potent and selective inhibition of rare Exon 18 mutations and the C797S mutation, supporting the potential for utility beyond GBM, such as in NSCLC.
Black Diamond expects to file an Investigational New Drug (IND) application for BDTX-1535 in the first half of 2022.
"Collectively, these data support the differentiated profiles of both BDTX-189 and BDTX-1535, the foundation of our ErbB franchise, and our ability to develop novel therapies for patients with genetically defined cancers," said David M. Epstein, Ph.D., President and Chief Executive Officer of Black Diamond Therapeutics.

The presentations from the AACR (Free AACR Whitepaper) meeting are available on the "Scientific Presentations and Publications" section of the Black Diamond Therapeutics website.

About BDTX-189
BDTX-189 is an orally available, irreversible small molecule inhibitor that is designed to block the function of family of oncogenic proteins defined by driver mutations across a range of tumor types, and which affect both of the epidermal growth factor receptor (EGFR) and the tyrosine-protein kinase, ErbB-2, or human epidermal growth factor receptor 2 (HER2). BDTX-189 is designed as a MasterKey inhibitor targeting a family of previously undrugged and functionally similar mutations in a tumor-agnostic manner. These mutations include extracellular domain allosteric mutations of HER2, as well as EGFR and HER2 kinase domain Exon 20 insertions, and additional activating oncogenic drivers of ErbB. The ErbB receptors are a group of receptor tyrosine kinases involved in key cellular functions, including cell growth and survival. BDTX-189 is also designed to spare normal, or wild-type, EGFR, which we believe has the potential to improve upon the toxicity profiles of current ErbB kinase inhibitors. Currently, there are no medicines approved by the U.S. Food and Drug Administration (FDA) to target all of these oncogenic mutations with a single therapy.

BDTX-189 is currently being evaluated in a Phase 1/2 clinical trial (MasterKey-01) in adult patients with advanced solid tumors with at least one MasterKey mutation who have no standard therapy available or for whom standard therapy is considered unsuitable or intolerable. In July 2020, the FDA granted Fast Track designation to BDTX-189 for the treatment of adult patients with solid tumors harboring an allosteric HER2 mutation or an EGFR or HER2 Exon 20 insertion mutation who have progressed following prior treatment and who have no satisfactory treatment options.

On April 10, 2021 F-star Therapeutics, Inc. (NASDAQ: FSTX), a clinical-stage biopharmaceutical company dedicated to developing next generation bispecific immunotherapies to transform the lives of patients with cancer, reported that preclinical data from FS222, a potentially best-in-class tetravalent bispecific antibody targeting both CD137 and PD-L1 will be presented in a poster at the 2021 American Academy of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place virtually from April 10-15 and May 17-21 (Press release, F-star, APR 10, 2021, View Source [SID1234578009]). Poster #1864, entitled ‘FS222, a Tetravalent Bispecific Antibody Targeting CD137 and PD-L1, is Designed for Optimal CD137 Interactions Resulting in Potent T cell Activation Without Toxicity’ will be available via on-demand viewing starting today, April 10, at 8:30 a.m. ET.

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FS222 targets PD-L1, the immune checkpoint protein that regulates the balance of activated T cells in the immune system and is overexpressed on many solid tumors and CD137, a co-stimulatory molecule from the tumor necrosis factor receptor superfamily (TNFRSF), which is widely known to be upregulated on tumor-reactive CD8+ T cells or "killer T cells". Currently, only a minority of patients have a long-lasting response to monotherapies that block the PD-(L)1 pathway.

Neil Brewis, Chief Scientific Officer at F-star Therapeutics, said: "We are encouraged by the results of these latest preclinical studies of FS222, our tetravalent bispecific antibody targeting PD-L1 and CD137. This work further demonstrates that FS222’s tetravalent binding mechanism is the most efficient and effective format for bispecific antibodies. The early onset of activity and T cell proliferation gives us confidence that FS222 will allow for a wide range of treatment options."

FS222 was designed to be a potent human CD137/PD-L1 tetravalent conditional agonist with a unique combination of high affinity PD-L1 binding, and moderate affinity, but with high avidity, binding to CD137 on activated T cells to result in optimal receptor clustering. Previously, FS222 has been shown to exhibit a favorable safety profile in preclinical safety studies.

Tetravalent binding by FS222 demonstrated optimal activity in multiple preclinical pharmacology studies, outperforming classic heterodimeric bispecific antibodies. These data showed that there was no evidence of a hook effect, or bell-shaped dose response curve, in vitro, and coupled with FS222’s favorable safety profile, presents a potentially broad and differentiated therapeutic window. A murine surrogate mAb2 for FS222 had peripheral immunopharmacology, as shown by CD8+ T cell proliferation, at high dose levels, mirroring the in vitro data, whereby the tetravalent FS222 surrogate mAb2 outperforms other lower valency formats.

In January 2021, F-star announced that the first patient had been dosed in a Phase 1 clinical trial of FS222, a multicenter, open-label, first-in-human trial to evaluate the safety, tolerability, and early signs of efficacy of FS222 in adult patients diagnosed with advanced malignancies. The adaptive study design will allow for the early exploration of clinical activity of FS222 in a range of selected solid tumors that will guide future targeted clinical development.

On April 10, 2021 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company developing onvansertib to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, pancreatic cancer and castrate-resistant prostate cancer, in collaboration with scientists in the Center for Precision Cancer Medicine at the Massachusetts Institute of Technology (MIT), reported that new gene signature and mechanistic analyses related to its ongoing Phase 2 trial of onvansertib in metastatic castrate-resistant prostate cancer (mCRPC) were featured in a virtual oral poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Cardiff Oncology, APR 10, 2021, View Source [SID1234577879]).

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Analyses presented in the poster suggest that the androgen receptor signaling inhibitor (ARSi) abiraterone sensitizes certain prostate cancer cells to onvansertib by upregulating a set of mitosis related genes and disrupting mitotic spindle orientation. These results are consistent with previous findings showing that onvansertib and abiraterone synergize in an androgen receptor (AR)-independent manner in-vitro and in-vivo.

"The latest results from our collaborative studies with Cardiff Oncology provide important insight into the mechanisms of synergy between onvansertib and abiraterone in mCRPC," said Michael B. Yaffe, M.D., Ph.D., David H. Koch Professor of Science and Professor of Biology and Biological Engineering at the Massachusetts Institute of Technology. "Data showing a cellular mechanism for how these two compounds synergize in an AR-independent manner provide a strong scientific rationale for Cardiff Oncology’s ongoing Phase 2 trial and explain how the addition of onvansertib can improve clinical outcomes in patients showing initial abiraterone resistance. We have also identified a set of genes that appear to drive this mechanism of onvansertib-abiraterone synergy as well as predict patient response and archived clinical trial tissue from patients enrolled in the ongoing trial are being analyzed to confirm this hypothesis."

Mark Erlander, Ph.D., chief executive officer of Cardiff Oncology added, "The identification of a gene signature that appears to predict patient response to onvansertib-abiraterone combination therapy is encouraging, as is the finding that this signature is enriched in mCRPC patients with the known molecular basal tumor subtype. We look forward to continuing to work with our collaborators at MIT and Decipher Biosciences to validate this gene set as a predictive response biomarker. Validation of such a biomarker would be significant, as it would allow us to take a precision medicine approach to future trials by enabling the identification of patients most likely to benefit from therapy with onvansertib."

Highlights from the AACR (Free AACR Whitepaper) presentation include:

Inhibition of polo-like kinase 1 (PLK1) sensitizes CRPC cells to abiraterone, but not the ARSi enzalutamide, indicating that abiraterone and PLK1 inhibitors synergize in an AR-independent manner.
In vitro experiments and RNA sequencing analyses indicate that abiraterone’s AR-independent effects include the disruption of mitotic spindle orientation and the induction of a mitosis related gene signature.
Data suggest that the identified mitosis related gene signature may be predictive of patient response to onvansertib-abiraterone combination therapy, a hypothesis that is being further assessed in an ongoing Phase 2 trial evaluating the all-oral regimen of onvansertib, abiraterone and prednisone in mCRPC patients.
The identified mitosis related gene signature was found to be significantly enriched in the basal molecular subtype of prostate cancer.
The virtual poster, "The selective polo-like kinase (Plk1) inhibitor onvansertib and the antiandrogen abiraterone synergistically kill cancer cells through disruption of mitosis independently of androgen receptor signaling" by Patterson et al, is available for on-demand viewing on the AACR (Free AACR Whitepaper) Annual Meeting 2021 e-poster website and is also posted on the "Scientific Presentations" section of the Cardiff Oncology website at View Source

About the Phase 2 Trial of Onvansertib in Metastatic Castrate-Resistant Prostate Cancer

This trial is a Phase 2 open-label study of onvansertib in combination with abiraterone and prednisone, all administered orally, in patients with metastatic castration-resistant prostate cancer showing signs of early progressive disease (demonstrated by two rising prostate-specific antigen values separated by at least one week with no or minimal symptoms) while on Zytiga/prednisone therapy. The primary efficacy endpoint is the proportion of patients achieving disease control after 12 weeks of study treatment, as defined by a lack of prostate-specific antigen (PSA), radiographic, or symptomatic progression. The trial is being conducted by Beth Israel Deaconess Medical Center (BIDMC), Dana-Farber Cancer Institute (DFCI), and Massachusetts General Hospital Cancer Center (MGH). David Einstein, M.D., Genitourinary Oncology Program at BIDMC, is the principal investigator for the trial. For more information on the trial, please visit View Source