On June 1, 2024 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with cancer, reported additional data from the Phase 1 dose escalation trial of BDTX-1535 in patients with recurrent glioblastoma (GBM), and initial data from a phase 0/1 "trigger" ("window of opportunity") investigator-sponsored trial at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Black Diamond Therapeutics, JUN 1, 2024, View Source [SID1234643922]). Clinical data from these trials in patients with recurrent GBM demonstrated brain penetrance of BDTX-1535, as well as safety and tolerability data similar to what has been previously described for patients with non-small cell lung cancer (NSCLC). In addition, the Phase 1 trial demonstrated encouraging anti-tumor activity and duration of treatment for patients with previously treated GBM.

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"The Phase 1 dose escalation results in patients with recurrent GBM show promising duration of treatment beyond two to four months typically expected in the recurrent setting, along with good safety and tolerability at therapeutic doses," said Patrick Wen, M.D., Director of The Center for Neuro-Oncology at Dana-Farber Cancer Institute. "Ultimately, the optimal point of intervention with an EGFR TKI may be upon initial diagnosis given the potential loss of EGFR as an oncogenic driver following chemotherapy and radiation."

In the poster titled "Phase 1 Study of BDTX-1535, an Oral 4th Generation Covalent EGFR Inhibitor, in Patients with Recurrent Glioblastoma: Dose Escalation Results," patients with EGFR alterations at initial diagnosis were enrolled upon recurrence. Patients received increasing doses of BDTX-1535 in 21-day cycles to assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. As of the data cutoff date of January 20, 2024:

Safety/tolerability was consistent with BDTX-1535 clinical data in NSCLC previously presented in October 2023 at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper).

Treatment-related adverse events (TRAEs) were primarily mild to moderate; the most common events included rash, diarrhea, stomatitis, paronychia, nausea, and fatigue.
No grade 3 TRAEs were reported at doses of BDTX-1535 ≤100 mg/day, one grade 3 rash was observed at 200 mg, and no grade 4/5 TRAEs were observed.
Among 19 efficacy evaluable patients, several experienced stable disease with promising durability.

One confirmed partial response was observed and eight patients experienced stable disease.
Five patients remained on BDTX-1535 treatment for ≥4 months, 1 patient for ≥6 months, and 3 patients for ≥10 months.
Longest duration of treatment was a patient who remained on therapy beyond 16 months.
Longer duration of treatment with BDTX-1535 appeared to be associated with a shorter duration of prior treatment with temozolomide.
A second poster titled "A Phase 0/1 ‘Trigger’ Trial of BDTX-1535 in Recurrent High-Grade Glioma (HGG) Patients with EGFR Alterations or Fusions," is an investigator-sponsored trial conducted at the Ivy Brain Tumor Center in Arizona. Patients with recurrent HGG with EGFR alterations and/or fusions at initial diagnosis were dosed with either 200mg BDTX-1535 daily for five days prior to brain tumor resection or 400mg administered three times per week prior to resection. A pre-specified PK threshold of 4.1nM unbound drug concentration was established, representing exposure that is 5-fold above the IC50 of BDTX-1535 for EGFR alterations and amplifications found in patients with GBM. Initial results from the trial demonstrated that BDTX-1535 exceeded the pre-specified threshold for drug concentration in the brain tumor tissue. In addition, both dosing regimens were generally well tolerated with expected EGFR-mediated side effects.

"We are very pleased with these initial results from our study showing that BDTX-1535 achieves levels in brain tumor tissue needed to observe a therapeutic effect," said Nader Sanai, M.D., Director of the Ivy Brain Tumor Center. "Clinical activity in these patients with further follow-up could support an additional trial of BDTX-1535 in newly diagnosed patients with confirmed EGFR mutations."

As of the data cutoff date of May 3, 2024, nine patients were evaluable:

BDTX-1535 generally well tolerated and achieved target drug concentration in tumor tissue.

BDTX-1535 was generally well tolerated with no serious adverse events related to BDTX-1535.
Eight of nine (88.9%) patients exceeded the PK threshold of 4.1nM unbound drug concentration, with average unbound drug concentration in Gadolinium (Gd) non-enhancing tumor tissue of 11.9 nM (for the 200mg dose) and 18.8nM (for the 400mg dose).
BDTX-1535 was associated with suppression of EGFR-mediated signaling as determined by several pharmacodynamic markers.
Patients achieving the PK threshold were enrolled in the post-resection component of the study with an update expected in the fourth quarter of 2024.
About BDTX-1535
BDTX-1535 is an oral, brain-penetrant MasterKey inhibitor of oncogenic epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), including classical driver mutations, non-classical driver mutations, and the acquired resistance C797S mutation. BDTX-1535 is a fourth-generation tyrosine kinase inhibitor (TKI) that potently inhibits, based on preclinical data, more than 50 oncogenic EGFR mutations expressed across a diverse group of patients with NSCLC in multiple lines of therapy. Based on preclinical data, BDTX-1535 also inhibits EGFR extracellular domain mutations and alterations commonly expressed in glioblastoma (GBM) and avoids paradoxical activation observed with earlier generation reversible TKIs. A "window of opportunity" trial of BDTX-1535 in patients with GBM is ongoing (NCT06072586) and a Phase 2 trial is ongoing in patients with NSCLC (NCT05256290).

On June 1, 2024 Genmab A/S (Nasdaq: GMAB, "Genmab") and BioNTech SE (Nasdaq: BNTX, "BioNTech") reported initial data from the ongoing Phase 2 trial (NCT05117242) evaluating acasunlimab (DuoBody-PD-L1x4-1BB), an investigational bispecific antibody also known as GEN1046/BNT311, as monotherapy and in combination with pembrolizumab in patients with PD-L(1)-positive metastatic non-small cell lung cancer ("mNSCLC") who had disease progression following one or more prior lines of anti-PD(L)1-containing treatment (Press release, BioNTech, JUN 1, 2024, View Source [SID1234643921]). The results showed a 12-month overall survival ("OS") rate of 69%, a median overall survival ("mOS") of 17.5 months, and a 30% overall response rate ("ORR") (confirmed ORR 17%) at the time of data cut-off in patients treated with the combination of acasunlimab and pembrolizumab every six weeks. The findings were presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") Annual Meeting held in Chicago, IL from May 31-June 4, 2024.

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The Phase 2 study randomized a total of 113 patients in three arms, evaluating acasunlimab alone (Arm A) and in combination with pembrolizumab (Arms B and C). The objective response analysis was conducted for 62 centrally confirmed PD-L1-positive efficacy-evaluable patients. The OS was evaluated in all centrally confirmed PD-L1-positive patients (n=80). Arm A showed a mOS rate of 5.5 months, a 50% disease control rate (DCR) and a 31% ORR (confirmed ORR 13%) in patients treated with acasunlimab alone. An 8.6 months mOS, a 59% DCR and a 21% ORR (confirmed ORR 18%) for treatment of acasunlimab in combination with pembrolizumab every three weeks (Arm B) and a 17.5 months mOS, a 75% DCR and a 30% ORR (confirmed ORR 17%) when the combination was administered every six weeks (Arm C). Anti-tumor activity was observed in patients with a tumor proportion score ("TPS") of 1–49% and ≥50%, in patients with <6 months and ≥6 months of previous immune checkpoint inhibitor ("CPI") treatment, and in patients with squamous and non-squamous histology.

Adverse events were consistent with the safety profiles of the individual drugs and treatment related adverse events ("TRAEs") were primarily grade 1 and 2. The most common TRAEs (all grades) in Arm A were asthenia (22.7%), diarrhea (18.2%), nausea (18.2%), anemia (13.6%), and liver-related events (13.6%). In the combination arms (Arms B and C), the most common TRAEs were liver-related events (28.6%, 18.4%), fatigue (21.4%, 8.2%), asthenia (12%, 12.2%), and diarrhea (12%, 10.2%). Overall, a lower incidence of grade ≥3 TRAEs, treatment-related liver-related events and lower discontinuation rates were observed with the combination regimen therapy administered every six weeks. Transaminase elevations were generally asymptomatic and manageable with the administration of steroids and/or treatment delay and resolved more rapidly in patients treated with the combination therapy administered every six weeks.

"We are encouraged by the findings of this ongoing Phase 2 study. The initial results of acasunlimab in combination with pembrolizumab administered every 6 weeks suggest a potential meaningful impact on patients with metastatic non-small cell lung cancer," said Judith Klimovsky, Executive Vice President & Chief Development Officer at Genmab. "We will continue to evaluate these data to inform further development of acasunlimab including a planned Phase 3 trial as we remain committed to investigate acasunlimab as a potential treatment option."

"Most patients with mNSCLC have limited treatment options following progression on first-line checkpoint inhibitor therapy. For these patients, chemotherapy remains the main treatment despite limited efficacy and considerable toxicity," said Prof. Özlem Türeci, M.D., Chief Medical Officer and Co-Founder at BioNTech. "The data of our Phase 2 trial show that the combination of acasunlimab with PDL1-blockade may be a suitable approach in this heavily pretreated patient population."

About the GCT1046-04 Clinical Trial

The GCT1046-04 trial (NCT05117242) is a randomized, open-label trial evaluating the safety and efficacy of acasunlimab in patients with relapsed/refractory metastatic non-small cell lung cancer ("mNSCLC") after treatment with standard of care therapy containing immune checkpoint inhibitor therapy. Patients with stage IV NSCLC with at least one prior line of systemic therapy containing an anti-PD-1/PD-L1 and a tumor PD-L1 expression in ≥1% of the tumor cells are included in the study. The primary endpoint of the trial is the overall response rate ("ORR"). Key secondary endpoints include overall survival ("OS"), progression free survival ("PFS"), time to response ("TTR"), duration of response ("DOR"), and safety. More information on this trial can be found at clinicaltrials.gov.

About Non-small Cell Lung Cancer (NSCLC)

Non-small cell lung cancer ("NSCLC") is the most common type of lung cancer, accounting for about 85% of all reported cases. NSCLC starts in cells that line the airways and can grow into nearby tissues or spread to other parts of the body. NSCLC is often diagnosed at an advanced stage, when it is hard to treat and has a poor prognosis. The survival rate of patients with NSCLC varies depending on the stage at diagnosis.i,ii,iii,The treatment of NSCLC depends on the stage, subtype, and biomarker status of the disease, and may include surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or a combination of these modalities.

About Acasunlimab (GEN1046/BNT311)
Acasunlimab (GEN1046/BNT311) is an investigational PD-L1x4-1BB bispecific antibody fusing Genmab’s proprietary DuoBody technology platform and BioNTech’s proprietary immunomodulatory antibodies. Acasunlimab is designed to elicit an antitumor response via conditional activation of 4-1BB on T cells and natural killer cells, which is strictly dependent on simultaneous binding of the PD-L1 arm. Acasunlimab is being developed in collaboration by BioNTech and Genmab under a license and collaboration agreement. The candidate is currently being investigated in three clinical trials: (1) a Phase 1/2 safety trial in patients with multiple solid tumors, (2) a Phase 1 dose escalation trial in patients with advanced solid tumors in Japan, and (3) a randomized Phase 2 safety and efficacy trial with acasunlimab as a monotherapy and in combination with pembrolizumab in patients with NSCLC who have failed previous standard of care treatments with immune checkpoint inhibitors. Please visit www.clinicaltrials.gov for more information.

On June 1, 2024 Sairopα, a clinical-stage developer of innovative cancer therapies, reported updated results from its dose-escalation phase of the ongoing Phase 1 study evaluating safety, pharmacokinetics and clinical efficacy of ADU-1604 (anti-CTLA4 antibody) in advanced PD-1 relapsed/refractory melanoma patients at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2024 in Chicago (Press release, Sairopa, JUN 1, 2024, View Source [SID1234643919]).

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Data from the completed dose-escalation study (n=20) in PD-1 relapsed/refractory melanoma patients shows that ADU-1604 is well tolerated at dosages of 25, 75, 225 and 450 mg Q3W, demonstrating a mild safety profile and no dose-limiting toxicities. Early signs of clinical efficacy were observed in three patients (two patients at 225 mg and one patient at 450 mg). Dose-dependent increase of pharmacodynamic biomarkers was detected, including strong increase of CD8+ T-cell proliferation in patients that showed tumor reduction.

The currently ongoing dose-expansion phase will treat an additional 20 patients (n=20) at the recommended Phase 2 dose (RP2D) of 225mg to support potential future combination therapies.

On May 31, 2024, Propanc Biopharma, Inc. (the "Company") reported to have entered into and closed a securities purchase agreement (the "Purchase Agreement") with an investor (the "Investor"), pursuant to which the Investor agreed to purchase a convertible promissory note from the Company in the aggregate principal amount of $49,200 (the "Note"), for a purchase price of $41,000 (Filing, 8-K, Propanc, MAY 31, 2024, View Source [SID1234644136]). The Company intends to use the net proceeds therefrom for general working capital purposes.

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The maturity date of the Note is March 30, 2025 and the Note bears a one-time interest charge of fifteen percent (15%) (the "Interest Rate") that shall be applied on the Issuance Date to the Principal ($49,200.00 * fifteen percent (15%) = $7,380.00). Accrued, unpaid interest and outstanding principal, subject to adjustment, shall be paid in five (5) payments, with the first on November 30, 2024 for $28,290.00, and the other four payments on December 30, 2024, January 30, 2025, February 28, 2025, and March 30, 2025, each for $ 7,072.50 (a total payback to the Holder of $56,580.00). The Company shall have a five (5) day grace period with respect to each payment. The Company has right to prepay in full at any time with no prepayment penalty.

The Investor is entitled, at its option, at any time after an Event of Default (as defined in the Note), to convert any or all or any amount of the principal face amount of the Note then outstanding into shares of the Company’s common stock (the "Common Stock") at a price for each share of Common Stock at a price ("Conversion Price") of 65% multiplied by the lowest Trading Price for the Common Stock during the ten (10) Trading Days prior to the Conversion Date (representing a discount rate of 35%).

The Note contains certain events of default, including failure to pay principal and interest when due, failure to timely issue the Conversion Shares, failure to maintain the listing of the Common Stock on at least one of the OTC markets (which specifically includes the quotation platforms maintained by the OTC Markets Group) or an equivalent replacement exchange, failure to comply with its reporting requirements with the U.S. Securities and Exchange Commission, a breach of certain covenants in the Purchase Agreement, default by the Company under any other note issued to the Investor, as well as certain customary events of default set forth in the Note, including, among others, breach of covenants, representations or warranties, insolvency, bankruptcy, and liquidation. Upon an event of default, the Note will become immediately due and payable by the Company.

The foregoing descriptions of each of the Purchase Agreement and the Note do not purport to be complete and are qualified in their entirety by reference to the full text of each of the Purchase Agreement and the Note, which are filed as Exhibits 10.1 and 4.1, respectively, to this Current Report on Form 8-K (this "Form 8-K") and are incorporated herein by reference.

On May 31, 2024 Agendia, Inc. reported that it will present new data characterizing the immune biology of MammaPrint High Risk tumors in an oral session at the 2024 Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting, taking place in Chicago, IL. on June 3rd, 2024 (Press release, Agendia, MAY 31, 2024, View Source;Early-Stage-Breast-Cancer-at-2024-ASCO [SID1234643918]).

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The study presented by Erin Cobain MD, Associate Professor in the Division of Hematology/Oncology at the University of Michigan Medical School, Ann Arbor and co-Principal Investigator of the SWOG S2206 Trial, titled Elucidating the immune active state of HR+HER2- MammaPrint High 2 early breast cancer [Cobain, E., et al.] characterizes the underlying immune biology that mediates immune therapy response in early stage hormone receptor-positive (HR+), Human Epidermal Growth Factor Receptor negative (HER2-) breast cancer, categorized as MammaPrint High Risk 2 (MP H2) in patients enrolled in the prospective, observational FLEX Study (NCT03053193). This study builds upon the findings from the I-SPY 2 Trial, which showed that patients with MP High-2, HR+HER2- tumors have improved response rates when immunotherapy is added to standard neoadjuvant chemotherapy.

Using whole transcriptome analysis, researchers evaluated relative frequency of immune cell types, expression level of genes involved in antigen processing and presentation, and expression of immune checkpoint genes PD-1 and PD-L1. Results of the analysis showed that MP High-2 tumors had a significantly higher frequency of antigen presenting cells (APCs) (including activated dendritic cells and macrophages, CD4+ memory T cells, CD8+ T cells, memory B cells and antibody producing plasma cells) relative to High-1 tumors, highlighting an increased immune active state in High-2 tumors. The increased antigen presentation and presence of APCs, which are critical in activating T- and B-cells, may explain why High-2 tumors display improved response rates to immunotherapy. The data from this study suggests that early stage HR+HER2- High-2 tumors might benefit from the addition of immunotherapy to their chemotherapy treatment regimens. These findings support the rationale for the ongoing SWOG S2206 (NCT06058377) Trial, which is utilizing MP High-2 as a biomarker to select patients for neoadjuvant chemo-immunotherapy treatment.

"There is a great need for biomarkers beyond PD-L1 and tumor mutational burden that may predict clinical benefit from immunotherapy-based treatments. The recent CheckMate 7FL and KEYNOTE-756 studies demonstrated that there is a subset of patients with HR+HER2- early breast cancer that will benefit from immunotherapy, as both trials demonstrated an improvement in likelihood of pathologic complete response rates for those patients receiving neoadjuvant chemo-immunotherapy compared to chemotherapy alone," said Dr. Cobain. "However, we are aiming to take this a step further and refine the biomarkers that will allow for us to identify those patients most likely to benefit from this approach and avoid overtreatment. This is particularly important given the potential serious toxicities that can result from immunotherapy treatment."

"This study highlights the importance of understanding how the classification of tumors may determine different response rates to treatment and how this will inform breast cancer care going forward. With the FLEX Study, we are now able to not only look at clinical outcomes but also analyze whole transcriptome data to better understand how women with breast cancer respond to different treatment regimens and use this information to customize breast cancer treatment," said William Audeh, MD, MS, Chief Medical Officer of Agendia. "The data we’re sharing at 2024 ASCO (Free ASCO Whitepaper) further validates MammaPrint utility in identifying not only the question of chemo vs. no chemo, but also illustrates the ability of MammaPrint to identify tumors with increased immune activation, supporting the rationale for using MammaPrint High 2 as a selective biomarker for immunotherapy in SWOG S2206."