On November 29, 2023 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, reported positive new data for tabelecleucel (tab-cel or EBVALLO) in patients with relapsed or refractory (r/r) or treatment-naïve Epstein-Barr virus-positive post-transplant lymphoproliferative disease involving the central nervous system (CNS) (EBV+ CNS PTLD) following solid organ transplant (SOT) or hematopoietic cell transplant (HCT) (Press release, Atara Biotherapeutics, NOV 29, 2023, View Source [SID1234638036]). These results will be presented as an oral session at the European Society for Medical Oncology Immuno-Oncology (ESMO I‑O) Annual Congress taking place December 6-8, 2023, in Geneva, Switzerland.

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The clinical experience from this combined analysis of four single-arm, open-label studies, including the multicohort Phase 2 EBVision trial (NCT04554914, n=4) expands on previous data from two single-center, Phase 2 studies (NCT00002663, n=10; NCT01498484, n=2), and multicenter, expanded-access protocol (NCT02822495, n=2).

"EBV+ CNS PTLD is a rare but extremely serious disease, and patients often face a poor prognosis that underscores the urgent medical need," said AJ Joshi, M.D., Executive Vice President, Chief Medical Officer at Atara. "We’re pleased to share new multicenter data, including the first results from our ongoing multicohort EBVision trial and first clinical trial report of treatment with tab-cel in the first line setting. Tab-cel shows a strong objective response rate in these high-risk patients with a favorable safety profile for patients with EBV-driven diseases."

In this pooled analysis, a total of 18 patients, including one previously untreated patient, with EBV+ CNS PTLD received cycles of three weekly infusions of tab-cel at ~2×106 cells/kg. Key endpoints were objective response rate (ORR), overall survival (OS), and safety parameters. Patients received a median (range) of 1 (0 to 5) lines of prior therapy.

An ORR of 77.8% (14/18) was observed in all patients (95% CI: 52.4, 93.6), with a best overall response of Complete Response (CR; 38.9%; n=7) or Partial Response (PR; 38.9%; n=7). The median time to response (TTR) in all patients was 1.8 months (range: 0.7–6.4).

The estimated one-year overall survival (OS) rate was 70.6% (95% CI: 43.0, 86.6) for all patients. The one-year OS rate for responders was 85.7% versus 0% for non-responders.

Tab-cel was well-tolerated. No reports of serious treatment-emergent adverse events, including neurotoxicity, organ rejection, graft versus host disease, or tumor flare reaction of any grade, were identified related to tab-cel.

Detailed results on baseline demographics, disease characteristics, best overall response, OS, and additional safety data including tab-cel exposure details, will be presented on December 7 in the Proffered Paper Session 2.

Oral Presentation Details:
Title: Clinical Experience of Tabelecleucel in Epstein-Barr Virus-Positive Post-transplant Lymphoproliferative Disease (EBV+ PTLD) Involving the Central Nervous System
Presenting Author: John Patton, M.D., Ph.D., James Comprehensive Cancer Center, The Ohio State University, Columbus, OH
Date & Time: December 7, 2023, at 2:15 – 3:45 p.m. CET / 5:15 – 6:45 a.m. PST
Presentation Number: 49O
Session: Proffered Paper Session 2
Location: Palexpo Congress Centre, Room B

On November 28, 2023 Clarity Pharmaceuticals (ASX: CU6) ("Clarity", "the Company"), a clinical stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, reported the successful completion of the first stage of cohort 3 of the Phase I/IIa theranostic trial, SECuRE, evaluating 64Cu/67Cu-SAR-bisPSMA in patients with mCRPC where 3 participants have been treated at the highest dose level of 12GBq of 67Cu-SAR-bisPSMA (Press release, Clarity Pharmaceuticals, NOV 29, 2023, View Source [SID1234638003]). No adverse events were reported in relation to 64Cu-SAR-bisPSMA. Only 1 adverse event was reported and related to the 12GBq cycle of 67Cu-SAR-bisPSMA in 1 of the 3 participants, which was a grade 1 decrease in neutrophil count, and the patient has fully recovered. No ongoing adverse events and no DLTs have been reported and the SRC has recommended the trial progresses with the 3 additional participants as planned in cohort 3.

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The SECuRE trial (NCT04868604)1 is a Phase I/IIa theranostic trial for identification and treatment of Prostate-Specific Membrane Antigen (PSMA) expressing mCRPC using 64Cu/67Cu-SAR-bisPSMA. 64Cu-SAR-bisPSMA is used to visualise PSMA expressing lesions and select candidates for subsequent 67Cu-SAR-bisPSMA therapy. The trial is a multi-centre, single arm, dose escalation trial with a cohort expansion involving up to 44 patients in the US. The aim of the trial is to determine the safety and efficacy of 67Cu-SAR-bisPSMA for the treatment of prostate cancer.

Cohort 3 of the trial has a 3+3 study design with the intent to gather and analyse data from the first 3 participants before progressing with an additional 3 participants. The initial data is very encouraging with no DLTs observed at the highest dose of 67Cu-SAR-bisPSMA (12GBq) and the SRC, responsible for assessing safety of participants and overseeing the general progress of the trial, has assessed the data and recommended the trial continues.

Cohort 3 is the last to assess single doses of 67Cu-SAR-bisPSMA and will be followed by a multi-dose cohort, pending safety evaluation. The initial 3 participants in cohort 3 were heavily pre-treated prior to entering the trial, having received multiple lines of therapy including other investigational products, radioligand therapy and chemotherapy. They continue to be monitored by their physicians for safety and treatment response as per the trial protocol. All 3 participants in cohort 3 remain on the trial following their recent administration of 12GBq of 67Cu-SAR-bisPSMA, with 2 demonstrating a PSA reduction within weeks of dosing, one of which is greater than 90% reduction and the second approximately 40% reduction to date.

Clarity’s Executive Chairperson, Dr Alan Taylor, commented, "We are excited by the PSA declines seen in almost all patients to date in cohorts 2 and 3 from just a single cycle. This result is also seen in patients that have been heavily pre-treated and have failed many other therapies that are either commercial or investigational. Moreover, the safety profile is very favorable and there have been no DLTs reported to date.

"SAR-bisPSMA was designed to be a best-in-class PSMA product as, unlike all other PSMA products in the market, it has dual targeting. The product was optimised to address the challenges of low uptake and retention in lesions that the first generation of PSMA products suffer from, and in both pre-clinical and clinical development to date we have observed two to three times the uptake of SAR-bisPSMA in lesions, followed by retention in lesions out to at least 96 hours. So far, the higher uptake and retention of product, coupled with the advantageous properties of copper-67, has shown quite impressive responses measured by PSA reductions in patients from single cycles of product to date.

"A number of patients from the SECuRE trial have either received, or will soon receive, additional doses of 67Cu-SAR-bisPSMA under the US Food and Drug Administration’s (FDA) Expanded Access Program (EAP). This demonstrates the initial clinical benefit observed in such patients after the administration of a single cycle of the product during the trial.

"As we have seen PSA reductions in the majority of patients after a single cycle of 67Cu-SAR-bisPSMA across all dose levels, which is known to be an independent prognostic indicator of improved overall survival following radio-ligand therapy2,3, we hope to achieve long-term and durable responses once we progress to the multi-dose cohorts of the trial. Furthermore, with commercial quantities of the 67Cu radioisotope now being routinely produced domestically in the US, we see a clear path to commercialisation as we can resolve the supply and manufacturing issues which have plagued the commercial launch of first-generation products. We look forward to sharing more data along with any further updates from patients who may receive single or multiple cycles of 67Cu-SAR-bisPSMA in our programs and bringing this product to the greater prostate cancer patient population," said Dr Taylor.

About SAR-bisPSMA
SAR-bisPSMA derives its name from the word "bis", which reflects a novel approach of connecting two PSMA-targeting agents to Clarity’s proprietary sarcophagine (SAR) technology that securely holds copper isotopes inside a cage-like structure, called a chelator. Unlike other commercially available chelators, the SAR technology prevents copper leakage into the body. SAR-bisPSMA is a TCT that can be used with isotopes of copper-64 (Cu-64 or 64Cu) for imaging and copper-67 (Cu-67 or 67Cu) for therapy.

64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA are unregistered products. Individual results may not represent the overall safety and efficacy of the products. The data outlined in this announcement has not been assessed by health authorities such as the US Food and Drug Administration (FDA). A clinical development program is currently underway to assess the efficacy and safety of these products. There is no guarantee that these products will become commercially available.

About Prostate Cancer
Prostate cancer is the second most common cancer diagnosed in men globally and the fifth leading cause of cancer death worldwide4. The American Cancer Institute estimates in 2023 there will be 288,300 new cases of prostate cancer in the US and around 34,700 deaths from the disease5.

On November 28, 2023 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported program updates for pan-RAF inhibitor naporafenib and central nervous system (CNS)-penetrant EGFR inhibitor ERAS-801, as well as a strategic program prioritization that extends its projected cash runway from H2 2025 to H1 2026 (Press release, Erasca, NOV 28, 2023, View Source [SID1234639351]).

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"We are excited about the recent progress across key clinical programs, including the regulatory alignment with U.S. and European health authorities for our global naporafenib registrational trial which is on track to initiate in the first half of 2024, the establishment of the maximum tolerated dose (MTD) for ERAS-801 in patients with glioblastoma (GBM), and the promising preliminary activity of ERAS-007 plus encorafenib and cetuximab (EC) in EC-naïve patients with BRAF mutant colorectal cancer (CRC) presented at ASCO (Free ASCO Whitepaper)," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "To further maximize resources, we have strategically refined our pipeline to focus on programs with the greatest therapeutic potential for patients with high unmet needs using a data-driven approach. As such, we are deprioritizing our ERAS-601 clinical trial (FLAGSHP-1) and our preclinical ERAS-5 ULK inhibitor and ERAS-10 protein degrader programs. Importantly, this pipeline prioritization extends our cash runway into the first half of 2026 and through key milestones, including important clinical trial readouts for naporafenib, ERAS-801, and ERAS-007."

Recent Program Updates

Naporafenib Plus Trametinib for Patients with NRAS mutant (NRASm) Melanoma in Pivotal SEACRAFT-2 Trial
End of Phase 2 meetings with U.S. Food and Drug Administration (FDA) and European health authorities confirm SEACRAFT-2 Phase 3 trial design and provide clarity on registrational pathway:

Enrollment of patients with high unmet medical need who progressed on, or are intolerant to, standard of care immune checkpoint inhibitor therapy
Comparator arm is physicians’ choice of cytotoxic chemotherapy or trametinib
Dual primary endpoint evaluation of progression free survival (PFS) and overall survival (OS), with PFS acceptable for potential initial approval
The Phase 3 trial consists of two stages: a randomized, controlled, dose optimization stage, for which we expect to have a data readout in 2025, and a randomized, controlled stage to support regulatory approval
Phase 3 SEACRAFT-2 trial initiation remains on track for H1 2024
ERAS-801 for Patients with Recurrent GBM in Phase 1 THUNDERBBOLT-1 Trial
Thirty-three patients with recurrent glioblastoma (rGBM) were enrolled in seven dose escalation cohorts. ERAS-801 monotherapy has been granted Orphan Drug and Fast Track Designations (ODD and FTD) by the FDA. Interest in THUNDERBBOLT-1 from trial investigators continues to be robust.

MTD identified as 240 mg once a day (QD) and MTD-1 identified as 160 mg QD for ERAS-801
ERAS-801 was safe and tolerable at the MTD and MTD-1 dose levels. The adverse event profile was consistent with the mechanism of action and observations in non-clinical studies
ERAS-801 exhibited well behaved pharmacokinetic (PK) characteristics: ERAS-801 showed rapid absorption and had dose-dependent increases in PK exposure. Steady-state PK exposures at doses of 160 mg QD and above exceeded the concentration at which 90% tumor growth inhibition was achieved in the GBM patient-derived orthotopic xenograft (PDOX) mouse model.
Expansion cohorts actively enrolling to collect additional safety, tolerability, and preliminary efficacy data to support dose optimization and selection
Phase 1 dose escalation data to be presented at a scientific meeting in H1 2024; expansion cohort data are anticipated in H2 2024
Shannon R. Morris, M.D., Ph.D., Erasca’s chief medical officer, added, "ERAS-801 is an orally bioavailable CNS-penetrant EGFR inhibitor specifically designed to target the unique EGFR alterations observed in GBM, initially as a monotherapy treatment. Identification of the MTD signals the transition of ERAS-801 to the next stage of development with a focus on characterizing the clinical activity of the molecule in patients with EGFR-amplified rGBM, who may achieve maximum benefit from treatment. Notably, this population represents nearly half of all patients with GBM and 85% of all patients with EGFR-altered GBM."

Prioritized Clinical Programs and Key Upcoming Milestones
Naporafenib – Pan-RAF Inhibitor

Dosing of the first patient in pivotal Phase 3 SEACRAFT-2 trial in patients with NRASm melanoma expected H1 2024
Initial signal-seeking Phase 1b efficacy data in relevant tumor types from patients with RAS Q61X solid tumors in ongoing SEACRAFT-1 trial expected between Q2-Q4 2024
ERAS-801 – CNS-penetrant EGFR Inhibitor

Phase 1 monotherapy dose escalation and expansion data in rGBM expected in 2024
ERAS-007 – ERK1/2 Inhibitor

Initial dose expansion data from Phase 1b/2 HERKULES-3 trial further evaluating encouraging early efficacy data with ERAS-007 in combination with EC in EC-naïve patients with BRAF mutant CRC expected between H2 2023 and H1 2024
Deprioritized Opportunities
Select trials or programs were deprioritized, despite their potential differentiation, to focus the company’s resources on the most promising programs, which is expected to extend the company’s cash runway from H2 2025 to H1 2026:

FLAGSHP-1 – Phase 1b combination trial of ERAS-601 SHP2 inhibitor with cetuximab was deprioritized. Though ERAS-601 achieved confirmed responses as a monotherapy and in combination with cetuximab, preliminary data do not justify further development of this combination in FLAGSHP-1 indications
ERAS-5 – Preclinical ULK inhibitor
ERAS-10 – Preclinical protein degrader

On November 28, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers harboring ESR1 mutations, reported that it had five abstracts accepted as poster presentations at the 2023 San Antonio Breast Cancer Symposium (SABCS), which will be held Dec. 5-9 at the Henry B. Gonzalez Convention Center in San Antonio (Press release, Sermonix Pharmaceuticals, NOV 28, 2023, View Source [SID1234638047]).

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Three posters delve into clinical data tied to Sermonix’s Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) studies. One assesses baseline genomic alterations and the activity of lasofoxifene, Sermonix’s investigational novel endocrine therapy, and Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib during the ELAINE-2 study. A second poster addresses pharmacokinetics of lasofoxifene as a monotherapy and in combination with abemaciclib. The third poster is a trial-in-progress update on ELAINE-3, which is studying the efficacy and safety of lasofoxifene in combination with abemaciclib in treating locally advanced or ER+/HER2- mBC with an ESR1 mutation.

The other two posters address the results of Sermonix’s third ESR1 and Quality of Life Survey (EQUALS 3), which was developed to help inform practicing oncologists about patients’ understanding of ESR1 mutations and the quality of life for metastatic breast cancer (mBC) patients. One poster addresses patient-provider communication challenges with respect to side effects of mBC treatments, and the second discusses how minimizing treatment toxicity and side effects impacts quality of life for ER+/HER2- mBC patients.

"Sermonix looks forward to updating our peers at SABCS 2023 about our growing understanding of lasofoxifene as a monotherapy and combination therapy, our initiated ELAINE-3 study, and our continuing work to learn more about how metastatic breast cancer impacts patient quality of life," said Dr. David Portman, Sermonix founder and chief executive officer. "We are committed to investigating lasofoxifene’s efficacy in combating metastatic breast cancer, as well as observing its impacts on vaginal and sexual health, all issues that affect patients greatly."

Poster sessions details are as follows:

Poster Title: Baseline genomic alterations and the activity of lasofoxifene (LAS) plus abemaciclib (Abema) in patients with ER+/HER2- metastatic breast cancer (mBC): the ELAINE-2 study
Poster ID: P02-14-09
Date: Wednesday, Dec. 6, 2023
Time: 5-7 p.m. CT
Poster Title: Pharmacokinetics (PK) of lasofoxifene (LAS) monotherapy and combined with abemaciclib (Abema)
Poster ID: P03-18-05
Date: Thursday, Dec. 7, 2023
Time: 12-2 p.m. CT
Poster Title: Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE-3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation
Poster ID: P01-18-12
Date: Wednesday, Dec. 6, 2023
Time: 12-2 p.m. CT
Poster Title: Patient (pt)-provider communication challenges about side effects/ from metastatic breast cancer (mBC) treatments]
Poster ID: P03-12-05
Date: Thursday, Dec. 7, 2023
Time: 12-2 p.m. CT
Poster Title: Minimization of treatment toxicity/side effects and their impact on quality of life (QoL) in patients (pts) with ER+/HER2- metastatic breast cancer (mBC)
Poster ID: P03-12-06
Date: Friday, Dec. 8, 2023
Time: 12-2 p.m. CT
To learn more about Sermonix Pharmaceuticals and lasofoxifene, visit View Source For more information about the ELAINE studies, visit View Source

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 a CDK4/6 inhibitor 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 could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

On November 28, 2023 Ribometrix, a biotechnology company developing small molecule therapeutics that modulate RNA biology, reported that it will present preclinical data showing anti-tumor benefit of eIF4E inhibition in Estrogen Receptor-positive (ER+) breast cancer at the annual San Antonio Breast Cancer Symposium, held December 5-9, 2023, in San Antonio, TX (Press release, Ribometrix, NOV 28, 2023, View Source [SID1234638045]).

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Ribometrix is evaluating its portfolio of inhibitors targeting eIF4E in preclinical studies in cancer, including melanoma and breast cancer. eIF4E is both a potent oncogene and a regulator of resistance to therapies targeting common oncogenic drivers, and Ribometrix’s data support the potential efficacy of its eIF4E inhibitors alone or in combination with standard-of-care in treatment naïve and treatment-resistant settings.

Presentation Details
Abstract Title: Pharmacological eIF4E inhibition suppresses anti-tumor activity in ER+ breast cancer
Abstract: PO5-27-09
Presenter: Matthew Friedersdorf, Ph.D., Associate Director, Translational Medicine at Ribometrix
Session: Poster Session 5
Date:  Friday, December 8, 2023
Time:  12:00pm – 2:00pm CT

At the time of presentation, Ribometrix’s poster will be made available on the "Publications" page of the "News" section of its website.

About eIF4E
Eukaryotic translation initiation factor 4E (eIF4E), the main regulatory component of cap-dependent mRNA translation, selectively promotes pro-oncogenic protein synthesis in response to activation of multiple tumor signaling pathways. Interestingly, many pro-oncogenic signaling pathways require eIF4E activity to promote tumor growth. Clinically, eIF4E activity is elevated in many tumor indications and it is typically associated with poor prognosis. Thus, targeting eIF4E has the potential to enhance anti-cancer activity when given in combination with standard-of-care. Additionally, eIF4E is also central to many resistance mechanisms, therefore eIF4E inhibition has the potential to overcome drug resistance and re-sensitize tumors to anti-cancer therapies. Ribometrix is developing eIF4E inhibitors as a promising therapeutic strategy to inhibit oncogene expression to enhance efficacy in combination and overcome resistance to targeted anti-cancer therapies.