On April 17, 2023 Corvus Pharmaceuticals, Inc. (Nasdaq: CRVS), a clinical-stage biopharmaceutical company, reported new data for CPI-818, the Company’s ITK inhibitor, demonstrating its potential to treat a variety of solid and hematological cancers based on a novel immunotherapy mechanism of action (Press release, Corvus Pharmaceuticals, APR 17, 2023, View Source [SID1234630147]). The data will be presented today in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is taking place April 14-19, 2023 in Orlando, FL.

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"The preclinical and laboratory data presented at AACR (Free AACR Whitepaper) demonstrates the potential of targeting ITK with CPI-818 to modulate T cell differentiation and enhance the immune system’s ability to kill both solid and hematological cancers," said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. "CPI-818 inhibited tumor growth in five different tumor models including colon, renal and melanoma cancers, and in both T and B cell lymphomas. This work builds upon the immunologic properties and anti-tumor activity already seen in our ongoing Phase 1/1b clinical trial in T cell lymphoma, and we now believe we can extend this approach to a wide range of solid tumors. Our data presented at AACR (Free AACR Whitepaper) shows that CPI-818’s novel mechanism of action involves multiple synergistic features including Th1 skewing, increases in T cell cytolytic capacity and reduction in T cell exhaustion. These properties are a result of the myriad of functions that ITK plays in T cell biology. Together, we believe these characteristics position CPI-818 to potentially lead the next generation of tumor immunotherapy if approved."

Dr. Miller added, "We are excited by the long-term potential of CPI-818 across a broad range of cancer indications, but in the near-term our main focus is continuing enrollment in our T cell lymphoma (TCL) Phase 1/1b clinical trial and meeting with the FDA to discuss a potential registration randomized Phase 3 clinical trial."

CPI-818 Preclinical Data Presented at AACR (Free AACR Whitepaper)
The CPI-818 preclinical data was presented by Lih-Yun Hsu, Ph.D., Director of Immunology, Corvus Pharmaceuticals, in a poster session (abstract #1813) today at the AACR (Free AACR Whitepaper) Annual Meeting. The key highlights from the poster, which is also available on the Publications and Presentations page of the Corvus website, include:

CPI-818 monotherapy (7 days oral administration) provided statistically significant inhibition of growth in established tumors in the following cancer models: CT26 colon cancer, RENCA kidney cancer, B16 melanoma, EL4 TCL and A20 B cell lymphoma.

Mechanism studies revealed that CD8 T cells were primarily involved in inhibiting growth in the CT26 colon cancer model and that CD8, CD4 T cells and NK cells were primarily involved in inhibiting growth in the EL4 TCL model.
Studies also showed that CPI-818 increased the cytolytic capacity of tumor infiltrating lymphocytes. These cells produce interferon gamma, tumor necrosis factor (TNF) and perforin, which are cytokines and effector molecules produced by killer T cells.

The preclinical data demonstrated that CPI-818 enhances the anti-tumor efficacy of anti-PD1 and anti-CTLA4 therapy in animal models, including at suboptimal doses of these therapies. The triplet combination led to complete tumor elimination in 19 of 20 animals with established CT26 colon cancer tumors.

The preclinical data also demonstrated that CPI-818 reduced the expression of T cell exhaustion markers in animals treated with anti-PD1 and anti-CTLA4 therapy. T cell exhaustion is a phenomenon seen in tumors and chronic infections where prolonged exposure to antigens results in exhausted or ineffective T cell function and inability to eliminate tumors or infections. The down-regulation of these T cell exhaustion markers suggests that the inhibition of ITK by CPI-818 potentially produces favorable changes in the tumor microenvironment that could enhance anti-tumor immune system activity.

In vitro studies with normal human naïve CD4+ T cells demonstrated that CPI-818 suppressed T cell differentiation into Th2 cells and their production of Th2 derived cytokines IL4, IL5, IL9, IL10 and IL17, however it did not affect differentiation into Th1 cells or their production of the cytokine interferon gamma (IFNg). These findings were the result of Th1 skewing.

CPI-818 is currently being studied in a Phase 1/1b clinical trial as a single agent therapy in patients with relapsed TCL. The Company recently incorporated a minimum absolute lymphocyte count (ACL) as an eligibility criterion for enrollment in the clinical trial and anticipates presenting updated data from this trial at a medical meeting in the second quarter 2023. Based on the current enrollment rate of this clinical trial, the Company believes that the number of patients treated in this clinical trial would provide adequate safety and preliminary efficacy data to inform the design of a potential registration Phase 3 randomized clinical trial. As recommended by the FDA, the Company plans to meet with the FDA to discuss such a clinical trial; it is anticipated that this meeting will take place later this year.

On April 17, 2023 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported updated preclinical data from the Company’s pipeline programs, including its novel EGFR-sparing brain-penetrant ErbB2 inhibitor and its next-generation selective fibroblast growth factor receptor 2 (FGFR2) program (Press release, Cogent Biosciences, APR 17, 2023, View Source [SID1234630146]). The data are being presented today in poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting. Cogent also announced the initiation of Part 2 of the Company’s ongoing APEX trial with bezuclastinib in Advanced Systemic Mastocytosis (AdvSM).

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"We are pleased to share our progress highlighting the Cogent Research Team in their ongoing effort to discover and advance potential best-in-class novel therapies for rare disease populations with high unmet medical need," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "Separately, based on bezuclastinib’s impressive and consistent clinical activity, safety and tolerability, we are also excited to announce the initiation of Part 2 of the APEX trial in AdvSM at a once-daily dose of 150 mg. We remain on track to provide clinical updates in the second half of 2023 from both APEX and SUMMIT, our trial of bezuclastinib in NonAdvSM patients, as well as updated clinical results from the PEAK lead-in trial in GIST patients this quarter."

AACR Poster Details

Title: Identification of a novel EGFR sparing brain penetrant ErbB2 inhibitor with activity against oncogenic ErbB2 mutations
Session Category: Molecular/Cellular Biology and Genetics
Session Title: Cell Cycle Progression, Checkpoint, and Telomeres
Session Date and Time: Monday Apr 17, 2023 9:00 AM – 12:30 PM ET
Location: Poster Section 10
Poster Board Number: 21
Published Abstract Number: 1440

Cogent is developing a potential best-in-class EGFR-sparing, brain-penetrant ErbB2 inhibitor that includes coverage of key mutations (YVMA, S310F, V842I, L755S) inadequately addressed by currently approved therapies. Activating mutations in the ErbB2 gene have been identified in multiple cancers and demonstrate a tumorigenic role similar to that of ErbB2 amplification. The poster presented today describes a series of novel compounds which potently inhibit several key ErbB2 mutations, including YVMA insertions, while sparing inhibition of EGFR. An exemplar compound from these series demonstrates advantages versus tucatinib, an approved benchmark compound, on tumor growth inhibition in a peripheral ErbB2 L755S driven mutant model, as well as in an ErbB2 driven intracranial model. Recent program advances with a novel chemotype have further improved ErbB2 mutational potency and selectivity, increased estimated brain penetrance to 40% and improved human whole blood stability to nearly 24 hours, suggesting a favorable profile for optimal clinical efficacy.

Title: In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations
Session Category: Molecular/Cellular Biology and Genetics
Session Title: Cell Cycle Progression, Checkpoint, and Telomeres
Session Date and Time: Monday Apr 17, 2023, 9:00 AM – 12:30 PM ET
Location: Poster Section 10
Poster Board Number: 20
Published Abstract Number: 1439

FGFR inhibitors are well-established oncogenic drivers in multiple diseases, but approved medicines fail to capture the full landscape of FGFR altered tumor types, with FGFR1-mediated hyperphosphatemia serving as the most common dose-limiting toxicity for pan-FGFR inhibitors. The poster presented today provides the first published evidence of a reversible, selective FGFR2 inhibitor with coverage of activating and emerging resistance mutations that spares inhibition of FGFR1. Preclinical data demonstrate a profile that delivers equipotent coverage across both key gatekeeper and molecular brake mutations (V564X, N549X) in FGFR2, while avoiding any evidence of FGFR1-linked hyperphosphatemia at efficacious plasma concentrations. In addition, as a reversible inhibitor, the Cogent program retains enzymatic potency against potential cysteine 491 mutations which are known to emerge as key resistance mutations in patients treated with covalent inhibitors.

APEX Part 2 Design Highlights

APEX is an ongoing Phase 2 trial evaluating bezuclastinib in patients with AdvSM. Part 2 will enroll approximately 65 patients treated at a once-daily 150 mg optimized dose and if successful, is designed to support regulatory submission. Enrollment is expected to be complete by the end of 2024. Several additional patient cohorts are anticipated during Part 2 of the APEX trial designed to demonstrate the breadth of AdvSM patients who may benefit from bezuclastinib, including:

Up to 20 patients with systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) treated concomitantly with bezuclastinib and AHN directed therapies, including azacitidine.
Up to 15 patients with inevaluable mIWG disease without C-findings.
Approximately 10 patients at a dose of 300 mg once-daily to explore the effect of exceeding IC90 KIT D816V engagement in AdvSM patients.
The predicted clinical exposure of the optimized 150 mg formulation of bezuclastinib is expected to surpass that of the previous formulation of bezuclastinib dosed at 100 mg twice-daily in APEX Part 1. Clinical data from approximately 30 patients from APEX Part 1 will be included in a presentation at a scientific meeting in the second half of 2023. Currently, clinical activity, safety and tolerability of patients dosed in APEX Part 1 remains consistent with results presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in December 2022.

On April 17, 2023 Cellectis (the "Company") (Euronext Growth: ALCLS – NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, reported preclinical data on TALEN-edited MUC1 CAR T-cells at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Cellectis, APR 17, 2023, View Source [SID1234630145]). The data showed the capability of armored allogeneic MUC1 CAR T-cells to excel in the immune suppressive tumor micro-environment suggesting that they could be an effective option in treating relapsed and refractory triple negative breast cancer (TNBC) patients with limited therapeutic options.

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Tumor-associated MUC1 antigen is overexpressed in a large number of TNBC patients offering an effective discriminatory target for CAR T-cell therapy.

Cellectis’ MUC1 CAR T-cells are allogeneic and target Mucin 1 for TNBC and a variety of epithelial cancers. As other solid tumor targets can be plagued by safety concerns due to off-tumor expression, MUC1 is of high interest as its expression in normal epithelium is restricted to apical membranes. Additionally, MUC1 heavy glycosylation in normal tissue contrasts with Cellectis’ MUC1 CAR that is designed to recognize hypoglycosylated MUC1 present in cancer cells. Cellectis’ MUC1 CAR T-cells incorporate up to four TALEN-mediated knockouts and two knock-ins.

"We are very excited to share these encouraging preclinical data at AACR (Free AACR Whitepaper) that dissect how different attributes (knock-out or knock-in) contribute to the efficacy of our CAR T-cell product candidate" said Laurent Poirot, Ph.D., Senior Vice President Immunology at Cellectis. "We are convinced that allogeneic MUC1 CART-cells can be an effective option in the treatment of relapsed and refractory triple negative breast cancer."

The poster presentation at AACR (Free AACR Whitepaper) highlights the following preclinical data:

Intratumoral delivery of antigen-specific CAR T-cells resulted in effective control of tumor growth.
Results demonstrate superior activity of armored MUC1-CAR T-cells not only in tumor clearance but also in the recovery of normal glands.
Thus, innovative strategies can be used to allow CAR T-cell efficiency in the hostile tumor microenvironment while preserving safety.

Title: Deciphering the benefits of variable delivery routes and molecular armoring to enhance efficacy of MUC1-CAR T-cells in targeting triple-negative breast cancer

Session Title: Adoptive Cell Therapy 1

Presenter: Piril, Erler, Ph.D., Scientist II, Immuno-Oncology, Cellectis

Session Date and time: Sunday April 16, 2023, 1:30-5:00 PM ET
Location: Section 37
Poster Board Number: 14
Abstract Presentation Number: 899

On April 17, 2023 Candel Therapeutics, Inc. (Candel or the Company) (Nasdaq: CADL), a clinical stage biopharmaceutical company focused on developing and commercializing viral immunotherapies to help patients fight cancer, reported that the U.S. Food and Drug Administration (FDA) granted fast track designation for its lead asset CAN-2409, an investigational viral immunotherapy, plus valacyclovir in combination with pembrolizumab in order to improve survival or delay progression in patients with stage III/IV non-small cell lung cancer (NSCLC) who are resistant to first line PD-(L)1 inhibitor therapy and who do not have activating molecular driver mutations or have progressed on directed molecular therapy (Press release, Candel Therapeutics, APR 17, 2023, View Source [SID1234630144]). Fast track designation is a process designed to facilitate the development and expedite the review of medicines to treat serious conditions and fulfill an unmet medical need. An investigational medicine that receives fast track designation may be eligible for more frequent interactions with the FDA to discuss the candidate’s development plan and, if relevant criteria are met, eligibility for accelerated approval and priority review.

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"We are pleased with the FDA’s decision to grant fast track designation for CAN-2409, which reinforces our belief that our investigational medicine has meaningful potential to treat those living with late-stage lung cancer," said Paul Peter Tak, MD, PhD, FMedSci, President and CEO of Candel. "Despite progress made in recent years, there remains a significant unmet need for patients with lung cancer who have an inadequate response to standard of care immune checkpoint inhibitors. Fast track designation is intended to bring promising medicines to patients sooner and the receipt of this designation by the FDA reinforces our belief that CAN-2409 has the potential to improve outcomes for patients who lack other treatment options."

CAN-2409 is an investigational viral immunotherapy designed to stimulate an individualized, systemic immune response to the patient’s specific tumor. CAN-2409 plus valacyclovir in combination with continued PD-1/PD-L1 agents is being evaluated in an ongoing, open-label phase 2 clinical trial (NCT04495153) in patients with late-stage NSCLC.

During its R&D Day in December 2022, the Company reported data from 26 patients with NSCLC in its ongoing phase 2 clinical trial demonstrating evidence of local and systemic anti-tumor activity and showed a disease control rate of 77 percent (20/26) in patients entering the trial with disease progression despite previous immune checkpoint inhibitor treatment. Importantly, CAN-2409 demonstrated a favorable change in the trajectory of tumor growth in all patients for whom pre-enrollment scans were available as of October 21, 2022.

The Company expects to present updated clinical data from its phase 2 clinical trial in the third quarter of 2023.

On April 17, 2023 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage precision oncology medicine company developing MasterKey therapies designed to overcome limitations of existing therapies by targeting families of oncogenic driver mutations in patients with genetically defined cancers, reported the presentation of three posters highlighting the design of the phase 1 clinical study of BDTX-1535 and new preclinical data on BDTX-1535 and BDTX-4933 at the 2023 American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held in Orlando, Florida (Press release, Black Diamond Therapeutics, APR 17, 2023, View Source [SID1234630143]).

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"Black Diamond’s MasterKey approach to precision oncology medicines is grounded in our deep understanding of the characterization of oncogenic mutations, and these presentations highlight the depth of our work to expand the addressable patient population for precision oncology. With an everchanging treatment landscape for genetically defined cancers, we believe that our approach to grouping our targets into druggable oncogene families presents a truly differentiated opportunity to address the continuing unmet need of patients," said Elizabeth Buck, Ph.D., Chief Scientific Officer of Black Diamond. "Our MAP Drug Discovery Engine has enabled us to intricately design MasterKey inhibitors based on extensive preclinical and real-world data, elucidating what we believe to be the necessary attributes for effectively targeting shared, activated conformations used by oncogenic drivers for tumor growth. Our fourth-generation irreversible brain penetrant EGFR MasterKey inhibitor, BDTX-1535, has demonstrated its ability to achieve potent anti-tumor activity against EGFR alterations and amplifications in a broad range of preclinical NSCLC and GBM models and we look forward to continuing to advance its development in the clinic and providing a first clinical update in the second half of this year. Our next most advanced program, BDTX-4933 was designed to be brain penetrant and selectively inhibits aberrant RAF signaling as result of BRAF class I, II, III and RAS oncogenic mutations without inducing paradoxical activation. We are encouraged by the results shared today, which support its potentially best-in-class profile."

BDTX-1535 Program:

Black Diamond presented two posters highlighting BDTX-1535’s preclinical development as well as the ongoing Phase 1 study.

In a poster titled, "Discovery of BDTX-1535, a novel brain penetrant, irreversible, potent, wild type sparing EGFR MasterKey inhibitor that targets oncogenic kinase domain mutations as well as extracellular domain alterations for the treatment of NSCLC and GBM," Black Diamond outlined the unmet need for next generation EGFR inhibitors that target classical driver mutations as well as acquired and intrinsic resistance mutations expressed in the context of EGFR driver mutations in non-small cell lung cancer (NSCLC), and EGFR alterations expressed in glioblastoma multiforme (GBM). Additional highlights include:

While EGFR C797S substitution is a frequently reported post-osimertinib resistance mutation, real world evidence indicates the emergence of other EGFR alterations that lead to resistance to osimertinib including EGFR kinase domain mutations (e.g., S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification.
A family of extracellular domain EGFR alterations occurs in nearly 50% of GBM patients and these alterations are clinically resistant to all current generation inhibitors.
Real world data in GBM demonstrates EGFR alterations often co-occur and persist throughout treatment with current standard of care therapy. Black Diamond observed that the oncogenic isoform of EGFR in GBM is a covalent homo-dimer which can be formed and paradoxically activated by the binding of reversible EGFR inhibitors.
Black Diamond concluded that an effective EGFR inhibitor should meet four design principles and be: 1) potent and selective against a broad family of intracellular, extracellular EGFR oncogenic alterations and amplification, 2) wild type EGFR sparing, 3) irreversible to avoid paradoxical activation, and 4) central nervous system (CNS) penetrant.
In a poster titled, "A Phase 1 Study to Assess BDTX-1535, an Oral EGFR Inhibitor, in Patients with Glioblastoma or Non-Small Cell Lung Cancer," Black Diamond outlined its ongoing Phase 1, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics, CNS penetrance and preliminary antitumor activity of BDTX-1535 in recurrent GBM (rGBM) or locally advanced or metastatic NSCLC with or without CNS disease. Key highlights include:

The monotherapy dose escalation portion will evaluate BDTX-1535 in patients with either rGBM expressing EGFR alterations or locally advanced/metastatic NSCLC harboring sensitizing EGFR mutations with or without CNS disease.
Patients with rGBM must have previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). Eligible NSCLC patients must have EGFR mutated NSCLC that has progressed following standard of care EGFR inhibitor therapy.
Following the establishment of a provisional recommended Phase 2 dose, BDTX-1535 monotherapy will be explored in the following dose expansion cohorts to further evaluate safety, pharmacokinetics (PK), and preliminary assessment of efficacy: 1) rGBM with confirmed EGFR alterations, 2) NSCLC with uncommon EGFR mutations following EGFR inhibitor therapy, and 3) NSCLC with acquired EGFR resistance mutation(s) following a 3rd generation EGFR inhibitor in the first-line setting. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M or MET.
BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with rGBM harboring EGFR mutations or variants.
Enrollment was initiated in 2022 and dose escalation is ongoing. Dose Expansion cohorts are expected to open in 2023.
Black Diamond remains on track to provide a clinical update on BDTX-1535 in the second half of 2023.

BDTX-4933 Program:

In a poster titled, "Preclinical characterization of a brain penetrant RAF inhibitor, BDTX-4933, targeting oncogenic BRAF Class I/II/III and RAS mutation," Black Diamond outlined its approach to characterizing BRAF, RAS and MAPK pathway in addition to the design and preclinical development of BDTX-4933:

Mutations in BRAF and RAS are often oncogenic and lead to a constitutively active MAPK pathway that promotes aberrant cell proliferation and tumor growth.
BDTX-4933 is a potent, reversible, CNS penetrant RAF MasterKey inhibitor designed to target a large family of oncogenic BRAF class I, II, III and RAS mutants.
In a panel of cancer cell lines that endogenously express BRAF or RAS mutations, BDTX-4933 demonstrated inhibition of the MAPK pathway signaling without paradoxical activation, resulting in potent inhibition of cellular proliferation.
In tumor models in vivo, BDTX-4933 showed target engagement, inhibiting ERK phosphorylation, achieving strong anti-tumor activity and tumor regression across tumor models driven by either BRAF or RAS mutations.
BDTX-4933 exhibits high CNS exposure leading to dose-dependent tumor growth inhibition, and survival benefit in an intracranial tumor model harboring oncogenic BRAF mutation.
Based on preclinical data, BDTX-4933 has a potential best-in-class profile to treat cancer patients harboring oncogenic BRAF Class I, II, III and RAS mutations, with or without brain disease.
Black Diamond expects to initiate a Phase 1 clinical trial of BDTX-4933 in patients with tumors harboring all-class BRAF or RAS mutations in the second quarter of 2023.

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