On April 8, 2022 Advaxis, Inc. (OTCQX: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products reported the publication of results of their KEYNOTE-46 Phase 1/2 open-label, double-arm trial of ADXS-PSA with KEYTRUDA (pembrolizumab) in patients with metastatic, castration-resistant prostate cancer (mCRPC) (Press release, Advaxis, APR 8, 2022, View Source [SID1234611717]). The paper, titled "ADXS31­142 Immunotherapy ± Pembrolizumab Treatment for Metastatic Castration-Resistant Prostate Cancer: Open-Label Phase I/II KEYNOTE-046 Study," has been published online in The Oncologist. The article can be found online here.

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The KEYNOTE-46 trial was conducted in conjunction with Merck (known as MSD outside the U.S. and Canada) and evaluated ADXS-PSA, one of Advaxis’ Listeria monocytogenes (Lm)-based immunotherapies, alone and in combination with KEYTRUDA, Merck’s anti-PD-1 therapy.

"The published clinical and immunogenicity data demonstrate that ADXS-PSA in combination with KEYTRUDA has the potential to provide meaningful increases in median overall survival in patients with advanced, metastatic, castration-resistant prostate cancer," said Kenneth A. Berlin, President and Chief Executive Officer of Advaxis. "Furthermore, these demonstrated improvements in survival in an advanced patient population encourage us to continue researching and developing the next generation of Lm-immunotherapies such as our off-the shelf, multineoantigen drug construct, ADXS-504, currently being studied in biochemically recurrent prostate cancer. ADXS-504 is a novel treatment alternative for these earlier stage prostate cancer patients, that has the potential to delay androgen blockade therapy initiation, improve quality of life and increase life expectancy."

As of the January 28, 2020, data cut off, 50 patients with mCRPC were enrolled with evaluable responses in Advaxis’ Ph 1/2 trial of ADXS-PSA alone and ADXS-PSA in combination with KEYTRUDA. The median overall survival (OS) in 13 patients treated with ADXS-PSA alone was 7.8 months (95%CI: 4.4-18.5) with progression free survival (PFS) of 2.2 months (95%CI: 0.8–7.4). The median OS on ADXS-PSA combined with KEYTRUDA was 33.7 months (95%CI: 15.4-NR), while median PFS was 5.4 months (95%CI: 2.3–7.9; n=37). 56.8% (21/37) of patients on combination therapy and 30.8% (4/13) on monotherapy showed stable disease. Robust response was also observed with the combination therapy in patients with prior docetaxel treatment and visceral metastasis. In addition, patients in the combination arm who had prior docetaxel treatment (n=20; 17 of whom had also received 1 or 2 next generation hormonal agent (NGHA) therapies) had an OS of 16.0 months (95%CI: 6.4-34.6), while patients with prior visceral metastasis (n=11; 10 of whom had prior docetaxel and 9 whom had received 1-2 prior NGHA therapies) had an OS of 16.4 months (95%CI: 4.0-NE). Of note, 36 of the 37 patients in the combination arm were tested for microsatellite instability and were all found to be Microsatellite Stable (MSS).

The combination of ADXS-PSA and KEYTRUDA increased T-cell expansion compared to ADXS-PSA alone, suggesting broader immune stimulation. In addition, contraction of T-cell clones was observed in the combination group, which suggests that T-cell clones with lower avidity for PSA (and other prostate-related antigens) were reduced in favor of high-avidity T cells under PD-1 blockade. The combination arm also showed antigen spreading with antigen-specific T-cell responses documented against other relevant prostate cancer antigens.

Naomi B Haas, MD, Director of the Prostate and Kidney Cancer Program and Professor of Medicine at University of Pennsylvania Hospital, and senior author of this publication, said, "Altogether these data are encouraging given the prolonged survival observed in patients in the combination therapy arm regardless of prior therapy with docetaxel, NGHAs or presence of visceral metastasis. It is interesting to see increases in median overall survival to 16.4 months in patients with measurable disease/visceral metastasis as compared to historical data of ≤9.5 months with pembrolizumab alone in this population." She added, "Furthermore, one patient who completed the 2-year study-treatment with ADXS-PSA in combination with KEYTRUDA moved on to a compassionate use protocol and remained with stable disease for yet another 22 months while on combination treatment. These outcomes, delivered with a generally safe and well-tolerated treatment regimen, may warrant additional evaluation of ADXS-PSA in combination with KEYTRUDA or of new generation Lm-immunotherapies in prostate cancer."

The combined therapy was safe and well tolerated in this heavily pretreated population. All patients had more than one treatment-related adverse event, mostly transient Grade 1-2 chills/rigors, fever, hypotension, nausea and fatigue, with no additive toxicity on the combination therapy.

About KEYNOTE-046
KEYNOTE-046 (NCT02325557) was an open-label, multicenter, dose-determining, safety and tolerability Phase 1/2 trial of 50 heavily pretreated patients conducted in two parts (Part A and Part B), with a Phase 2 expansion cohort. While the objective of the study was to evaluate ADXS-PSA as a monotherapy (Part A; n=14 [13 treated]) and in combination with KEYTRUDA (Part B; n= 37) in heavily pretreated patients with progressive and refractory mCRPC, the study was not designed to compare the two treatment regimens. Primary endpoints included safety, tolerability and dosing. Secondary endpoints were anti-tumor activity, progression-free survival and overall survival, and exploratory endpoints included associations between biomarkers of immunologic response (serum PSA) with clinical outcomes.

On April 8, 2022 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that it will hold its first-quarter 2022 sales and earnings conference call with institutional investors and analysts at 8:00 a.m. EDT on Thursday, April 28 (Press release, Merck & Co, APR 8, 2022, View Source [SID1234611716]). During the call, company executives will provide an overview of Merck’s performance for the quarter and outlook.

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Investors, journalists and the general public may access a live audio webcast of the call via this weblink. A replay of the webcast, along with the sales and earnings news release, supplemental financial disclosures and slides highlighting the results, will be available at www.merck.com.

Institutional investors and analysts can participate in the call by dialing (833) 353-0277 or (469) 886-1947 and using ID code number 6647568. Members of the media are invited to monitor the call by dialing (833) 353-0277 or (469) 886-1947 and using ID code number 6647568. Journalists who wish to ask questions are requested to contact a member of Merck’s Media Relations team.

On April 8, 2022 Aadi Bioscience, Inc. ("Aadi") (Nasdaq: AADI), a biopharmaceutical company focused on developing and commercializing precision therapies for genetically-defined cancers with alterations in mTOR pathway genes, reported the presentation of a poster (#5799) at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), being held April 8-13, 2022 in New Orleans, LA (Press release, Aadi Bioscience, APR 8, 2022, View Source [SID1234611715]). The research that was presented quantifies the type and number of advanced cancer patients with malignant tumors carrying TSC1 or TSC2 alterations.

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The study, presented by Gunsagar S. Gulati, M.D., Ph.D., Resident Physician at Brigham and Women’s Hospital (BWH) in Boston evaluated the landscape of TSC1 or TSC2 alterations across 31 solid tumors from The Cancer Genome Atlas (TCGA; n ~10,000 patients), AACR (Free AACR Whitepaper) GENIE database (Memorial Sloan Kettering (MSK): n ~ 15,000 patients, and Dana Farber Cancer Institute (DFCI): n ~ 5,500 patients) and subsequently estimated the annual incidence of patients with these alterations using the Surveillance, Epidemiology, and End Results Program (SEER) database.

The study, which was conducted by additional researchers at BWH, The University of Texas MD Anderson Cancer Center, and Tessellon in Missouri, found that the incidence of advanced cancer patients with TSC1 or TSC2 alterations in 2030 in the U.S. is projected to be approximately 32,000, of which approximately 12,000 patients carry "definite" mutations (frameshift, nonsense, splice-site mutations and deep deletions). TSC1 alterations were most frequent in bladder, kidney, and lung squamous cell cancers, while TSC2 alterations were most frequent in hepatobiliary, ovarian, and soft tissue sarcomas.

Neil Desai, Ph.D., Founder, Chief Executive Officer, and President of Aadi, stated, "Consistent with our expectations, the incidence of patients with TSC1 or TSC2 definite impact alterations is significant, and only exceeded by the incidence of actionable mutations in EGFR, KRAS, HER2, PIK3CA, or BRAF. We are actively enrolling patients into our ongoing pivotal PRECISION 1 trial to evaluate nab-sirolimus in patients harboring TSC1 or TSC2 mutations and look forward to reporting preliminary data in the first half of next year."

On April 8, 2022 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers, reported initial efficacy and safety data from the ongoing Phase 1b trial of ZN-c3 in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian cancer (Press release, Zentalis Pharmaceuticals, APR 8, 2022, View Source [SID1234611712]). Data were reviewed as a clinical poster during the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in New Orleans, Louisiana on April 8-13, 2022.

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"The initial combination clinical activity reported from our ongoing trial supports ZN-c3’s potential best-in-class efficacy and safety profile and for the first time, showcases its synergistic combinability with various chemotherapies," commented Dr. Anthony Sun, Chairman and Chief Executive Officer of Zentalis. "Utilizing a continuous dosing regimen in patients with advanced disease, ZN-c3 demonstrated an Objective Response Rate of 30.2% across all cohorts – achieving up to 62.5% with one cohort – and a markedly better tolerability profile within the Wee1 inhibitor class. Based on these promising initial results, we believe the data support the development of a Phase 3 trial to further investigate this combination’s effect in ovarian cancer patients. We look forward to announcing our future development plans for this program before year-end and are motivated by the opportunity to potentially deliver an improved and best-in-class treatment option to patients."

Initial Efficacy and Safety Data

The ongoing Phase 1b dose-escalation trial is evaluating the safety, tolerability, preliminary clinical activity, pharmacokinetics and pharmacodynamics of ZN-c3 in combination with standard chemotherapies in platinum-resistant or -refractory ovarian cancer. The study consists of four combination dose cohorts: ZN-c3 + PLD, ZN-c3 + carboplatin, ZN-c3 + paclitaxel, and ZN-c3 + gemcitabine, and is enrolling a more advanced patient population, with the inclusion of platinum-refractory patients and higher prior rates of bevacizumab treatment, than similar trials that included a Wee1 inhibitor.

At the time of the data cutoff on January 28, 2022, 56 patients – which were enrolled across three of the cohorts – were evaluated for safety, the primary endpoint, and 43 were response-evaluable. The fourth cohort, ZN-c3 + gemcitabine, had not begun enrollment at the time of the data cutoff. The evaluation of the recommended Phase 2 dose remains ongoing, with the key efficacy data presented at AACR (Free AACR Whitepaper) included in the table below.

Summary of Clinical Activity

ZN-c3 was generally well-tolerated in combination with chemotherapy and exhibited lower hematologic toxicity and a better gastrointestinal tolerability profile in comparison to the Wee1 inhibitor class. As of the cutoff date, the most common treatment-related adverse events at all grades included nausea (48.2% of patients), neutropenia (41.1% of patients), thrombocytopenia (37.5% of patients), vomiting (30.4% of patients) and anemia (26.8% of patients).

"Platinum-resistant and -refractory ovarian cancer are associated with poor prognoses and limited treatment options, with standard of care having an Overall Response Rate of less than 12%," commented Kathleen Moore, MD, Director of the Oklahoma TSET Phase I Program for the Stephenson Cancer Center at the University of Oklahoma College of Medicine. "A treatment option that could elicit a clinically meaningful improvement in efficacy, while being well-tolerated, would make a meaningful difference for patients. In this initial cut of data, ZN-c3 in combination with standard chemotherapies has surpassed this goal, achieving an improved efficacy and tolerability profile in a sicker patient population within the Wee1 inhibitor class. Wee1 inhibition remains a promising therapeutic approach to treating an array of solid tumors, including advanced ovarian cancer, and these results further support the class’ potential in changing the treatment paradigm."

Update on Additional AACR (Free AACR Whitepaper) Presentations

Interim data from the Phase 1 monotherapy USC expansion cohort receiving ZN-c3 ≥300mg QD were also released today. ZN-c3 is potentially a best-in-class Wee1 inhibitor and is in an ongoing potentially registrational Phase 2 trial for USC patients​ (NCT04814108). Updated data from the USC expansion cohort of the Phase 1 monotherapy trial will be presented at the mini symposium on April 11, 2022 at 2:50 p.m. CT.

In addition, Zentalis has three preclinical posters demonstrating the broad potential of ZN-c3 in multiple settings including AML (Abstract #2591), overcoming PARP resistance (Abstract #2606), and in novel biology when combined with our BCL-2 inhibitor, ZN-d5 (Abstract #2605). These findings further support ZN-c3 as a potential cornerstone treatment, creating a significant market opportunity across a broad range of solid and liquid tumors.

The clinical poster, two clinical abstracts and three preclinical posters are currently available on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website at View Source

Updates on ZN-c5

Initial clinical data of ZN-c5 in combination with CDK 4/6 inhibitors demonstrated excellent safety and tolerability. Drug-drug interactions were seen with ZN-c5 doses; however, ZN-c5 is not expected to have DDIs with commonly used medicines or ZN-c3 at relevant doses.

Uniquely among the leading oral SERDs, ZN-c5 demonstrated meaningful bone protectant activity in ovariectomized mice, highlighting a further point of differentiation within the oral SERD class, along with excellent tolerability. Zentalis believes this profile positions ZN-c5 well for an adjuvant setting.

Zentalis plans to initiate a combination study of ZN-c5 + ZN-c3 in ER+/HER2- CDK 4/6i-resistant breast cancer patients in 2022.

KOL Webcast Event:

Zentalis will host a webcast event with key opinion leader, Kathleen Moore, MD, today, Friday, April 8, 2022 at 4:00 p.m. EDT. Dr. Moore is the Associate Professor in the Section of Gynecologic Oncology; the Jim and Christy Everest Endowed Chair in Cancer Research; and the Director of the Oklahoma TSET Phase I Program for the Stephenson Cancer Center at the University of Oklahoma College of Medicine. She has a clinical research interest in drug development and Phase I trials and is a leading expert in gynecological oncology.

To register and access the event, the webcast link is available on the Investors & Media section of the Zentalis website at www.zentalis.com.

About ZN-c3

ZN-c3 is a potentially first-in-class and best-in-class oral inhibitor of Wee1 in development for the treatment of advanced solid tumors. The inhibition of Wee1, a DNA damage response protein, aims to generate sufficient DNA damage in cancer cells, causing cell death, thereby preventing tumor growth and potentially causing tumor regression. ZN-c3 has broad potential as a monotherapy and in combination. We are currently evaluating this candidate in several ongoing and planned studies, including two potentially registrational monotherapy trials in USC and a biomarker-driven setting, as well as combination studies, including in combination with chemotherapy in patients with advanced ovarian cancer. We also received orphan drug and rare pediatric disease designations from the FDA for pediatric osteosarcoma and have initiated a Phase 1/2 trial in combination with chemotherapy.

On April 8, 2022 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported preclinical data showcasing the potential first and best-in-class profile of new antibody candidates (Press release, Adagene, APR 8, 2022, View Source [SID1234611711]). Data are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place in New Orleans, Louisiana from April 8-13, 2022. Posters are available in the Publications section of the company’s website at www.adagene.com.

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"We are encouraged by the preclinical data presented across four posters at AACR (Free AACR Whitepaper), showing the first and best-in-class profiles for our differentiated preclinical candidates, designed to achieve safe, potent and durable responses. These include ADG206, a masked, IgG1 Fc-engineered anti-CD137 therapy and ADG153, a masked anti-CD47 IgG1 antibody, and ADG138, a novel, double masked HER2xCD3 bispecific T-cell engager (TCE) for solid tumors. All three of these candidates are designed for improved efficacy while incorporating precision masking peptides to ensure safety of such powerful modalities," said Peter Luo, Ph.D., Co-founder, Chief Executive Officer and Chairman of Adagene. "Additionally, we are establishing a new paradigm for CD28 TCEs by targeting a unique, highly conserved epitope for local activation, and leveraging SAFEbody to ensure ultimate safety and mitigate known risks of this target. We are very excited to show potential differentiation of these preclinical candidates, and spotlight our ability to create first/best-in-class product candidates that can be safely and effectively combined together as we aspire to cure cancer."

Key takeaways from the four posters include:

ADG206, an anti-CD137 agonistic POWERbody with tailor-made efficacy and safety profiles by strong crosslinking and tumor selective activation for single agent and combinational cancer immunotherapy (#2868)

This masked, IgG1 Fc-engineered anti-CD137 POWERbody combines conditional activation in the tumor microenvironment with strong agonistic activity through heightened FcγR-mediated crosslinking for therapeutic potential in either single agent or combination regimens.
Preclinical data demonstrated that ADG206 was well tolerated and had robust anti-tumor activity as a single agent in multiple tumor models, with 4-fold stronger anti-CD137 agonistic activity of its activated form than a benchmark antibody in development (analog of urelumab) for T cell co-activation.
ADG206 also demonstrated enhanced anti-tumor activity in combination with other checkpoint inhibitors, including anti-PD-1 or anti-CTLA-4 therapy.
Adagene is preparing to submit an IND or equivalent filing for ADG206 during 2022.
ADG153-G1 SAFEbody, a differentiated masked anti-CD47 antibody of IgG1 subclass, demonstrates in vivo anti-tumor activity consistent with enhanced ADCC/ADCP effects and significantly reduced RBC-related and antigen sink liabilities (#4257)

This masked anti-CD47 IgG1 SAFEbody is differentiated by its strong antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activity designed to realize the full potential of anti-CD47 therapy for both hematologic and solid tumor indications.
Preclinical data demonstrated that ADG153 IgG1 was well tolerated, did not induce human hemagglutination and significantly reduced anemia-related and antigen sink liabilities. In particular, ADG153 IgG1 at a 10 mg/kg dose demonstrated only an 8 percent decrease in red blood cell counts, compared to a 49 percent decrease with a benchmark antibody which is in IgG4 format (analogue of magrolimab).
Results also showed that ADG153 IgG1 demonstrated greater anti-tumor activity than the benchmark.
Adagene is preparing to submit an IND or equivalent filing for ADG153 during 2022.
ADG138, A Novel HER2×CD3 POWERbody Integrating Bispecific TCE with Precision Masking to Control Cytokine Release Syndrome and On-Target Off-Tumor Toxicity for Single Agent and Combination Therapies in HER2-Expressing Solid Tumors (#2869)

This novel HER2xCD3 POWERbody is masked on both arms with an impressively high therapeutic index relative to its parental non-masked TCE in both HER2 high and low expressing solid tumors, supporting its development for HER2-expressing solid tumors as a single agent and in combination with other immune modulating agents.
Preclinical data demonstrated the excellent safety profile of ADG138, including 100-fold greater reduction in cytokine release compared to its parental TCE.
Results showed that ADG138 has potent anti-tumor activity in HER2 high and low expressing tumors, as well as resistant/refractory tumors, relative to a benchmark antibody (DS-8201, a HER2 targeting antibody drug conjugate commercially available in specific indications). ADG138 also had synergistic anti-tumor activity in HER2 positive tumors when combined with anti-CD137 or anti-PD-1 therapy, or tumor targeted CD28 bispecific antibody.
ADG138 is currently in IND-enabling studies.
Tumor-targeted CD28 bispecific POWERbody for safe and synergistic T cell-mediated immunotherapy (#2888)

CD28 bispecific POWERbody TCEs exhibit enormous potential to fulfill the promises of safe and durable T cell-mediated synergistic immunotherapies when combined with CD3 bispecific POWERbody TCEs and/or checkpoint inhibitors.
Enabled by Adagene’s suite of antibody platform technologies, preclinical data demonstrated the potential to mitigate the serious safety concerns of CD28 activation and make custom designed antibodies targeting a highly conserved epitope with broad species reactivity.
Multiple tumor associated antigen (TAA)xCD28 POWERbodies are in progress, such as B7-H3xCD28 and HER2xCD28, which can also be combined with the company’s CD3 TCEs to achieve safe, powerful and durable immunotherapy for solid tumors through combination of the fundamental mechanisms and pathways across the cancer immunity cycle.