On September 16, 2024 Alligator Bioscience AB ("Alligator") (Nasdaq Stockholm: ATORX) and Aptevo
Therapeutics ("Aptevo") (Nasdaq: APVO) reported positive interim data from the dose escalation phase of their Phase 1 trial evaluating ALG.APV-527 for the treatment of solid tumors likely to express the tumor antigen 5T4 (Press release, Alligator Bioscience, SEP 16, 2024, View Source [SID1234646643]). The results, which include clinical activity, safety, tolerability outcomes, pharmacokinetics and pharmacodynamics were presented in a poster session on Saturday, September 14, 2024, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress in Barcelona, Spain.

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ALG.APV-527 is a first-in-class bispecific antibody that targets 4-1BB and the tumor antigen 5T4. The compound is being evaluated in a multi-center, dose escalation trial that has 18 patients included in the safety analysis. These patients received multiple prior rounds of therapy for the treatment of solid tumor types. The trial is approaching full enrollment and interim results include:

Clinical Activity/Efficacy

Nine of 15 efficacy evaluable patients (60%) have a best overall response to date of stable disease (SD)
The longest SD duration was in a breast cancer patient who entered the study with progressive disease, achieved stable disease and remained on study for >11 months. This patient successfully transitioned to a higher dose level twice
One colon cancer patient with sustained SD remains on study for more than four months
Safety and Tolerability

ALG.APV-527 demonstrated positive safety and tolerability across all cohorts
A maximum tolerated dose has not been identified
Evidence of favorable pharmacokinetics and biological activity of ALG.APV-527

ALG.APV-527 could be measured in all patients with serum concentration of ALG.APV-527 consistent with the administered dose and preclinical predictions.
Biomarker analyses confirm biological activity of ALG.APV-527
"4-1BB has been a target of interest—though with excess toxicity—for decades, and novel bispecific approaches like this will enable us to maximize anti-tumor immunity while limiting the systemic toxicity concerns that have plagued this key immune costimulatory receptor. With this backdrop, these Phase 1 interim results are very encouraging, with ALG.APV-527 showing a positive safety profile with 60% of evaluable patients achieving stable disease, meaning not progressing for variable time frames including one breast cancer patient being treated with monotherapy on study with SD for more than 11 months. We are excited to see signs of clinical activity, underscoring the potential of the drug to benefit patients with solid tumors in the clinical setting, supported by a positive safety and tolerability profile," stated Thomas Marron, MD, PhD, Professor in Immunology & Immunotherapy and in Medicine, Hematology and Medical Oncology at Icahn School of Medicine at Mount Sinai, participating Investigator of the trial.
Trial Overview
The ALG.APV-527 Phase 1 trial is a multi-center, multi-cohort, open-label dose-escalation trial that includes administration of ALG.APV-527 in up to six escalating dose levels in a 3+3 design*. The trial is enrolling adult patients with multiple solid tumor types/histologies likely to express the 5T4 antigen. ALG.APV-527 will be given intravenously once every two weeks. The trial is assessing the safety and tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ALG.APV-527.

*The 3+3 design proceeds in cohorts of three patients treated at increasing dose levels. Dose escalation stops when at least two out of three or six patients experience dose limiting toxicities (DLTs) at that dose level.

About ALG.APV-527
ALG.APV-527 is a bispecific conditional 4-1BB agonist, only active upon simultaneous binding to 4-1BB and 5T4. This has the potential to be clinically important because 4-1BB can stimulate the immune cells (antitumor-specific T cells and NK cells) involved in tumor control, making 4-1BB a particularly compelling target for cancer immunotherapy. 5T4 is an oncofetal tumor associated antigen overexpressed on numerous solid tumors including non-small-cell lung carcinoma (NSCLC), breast, head and neck, cervical, renal, gastric, and colorectal cancer.

Preclinical studies, highlighting the differentiated design of the molecule that minimizes systemic immune activation, allowing for highly efficacious tumor-specific responses as demonstrated by potent activity in preclinical models, has been published in the peer-reviewed publication, Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

On September 16, 2024 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported new ADG126 clinical data presented at the ESMO (Free ESMO Whitepaper) Congress, taking place in Barcelona, Spain, September 13-17 (Press release, Adagene, SEP 16, 2024, View Source [SID1234646641]).

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The poster, titled Increased Therapeutic Index of Muzastotug (ADG126), a Masked Anti-CTLA-4 Antibody, in Combination with Pembrolizumab (Pembro) Enables Significant Clinical Benefits and Supports Further Clinical Development in Patients with Metastatic MSS CRC, reports data from an ongoing phase 1b/2 trial of Adagene’s masked anti-CTLA-4 SAFEbody in combination with Merck & Co., Inc., Rahway, NJ, USA’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) (ADG126-P001; NCT05405595).

"I am delighted that the ESMO (Free ESMO Whitepaper) data show a promising overall response rate, progression-free survival (PFS) and early survival benefit from treatment with the immunotherapy (IO) doublet of ADG126 in combination with pembrolizumab for patients with advanced/metastatic MSS CRC, the largest segment of colorectal cancer with few treatment options," said Daneng Li, MD, Associate Professor in the Department of Medical Oncology & Therapeutics Research at the City of Hope Comprehensive Cancer Center, and a study investigator. "With a much higher dosing level than available anti-CTLA-4 therapies, these data reinforce the encouraging safety and efficacy profile for ADG126 administered repeatedly in MSS CRC."

Dr. Li continued, "Given the best-in-class potential for ADG126, this combination with pembrolizumab could address even broader patient populations, such as those with liver metastases, particularly if combined with standard of care to control early disease progression. Further, the safety profile of this immunotherapy doublet enables repeat cycles to achieve and sustain sufficient drug exposure that maximizes potential for a long-term survival benefit."

ADG126 is a masked anti-CTLA-4 SAFEbody targeting a unique epitope of CTLA-4 on regulatory T cells (Tregs) in tumor tissue which shows potential best-in-class safety and efficacy profiles in combination with pembrolizumab. The unique epitope of ADG126 alone has shown enhanced antibody-dependent cell mediated cytotoxicity without Fc engineering, which is associated with significantly increased toxicity. Further, it has shown minimal immunogenicity and anti-drug antibodies, with no impact on its pharmacokinetic (PK) profile.

Key highlights from the poster (July 30, 2024 data cutoff) include:

· ADG126 in combination with pembrolizumab continued to demonstrate a differentiated safety profile in dose escalation and dose expansion cohorts for heavily pre-treated advanced/metastatic patients with solid tumors (n=66):

o No dose-limiting toxicities (DLT) or Grade 4 or 5 TRAEs were observed at any dose up to 20 mg/kg Q3W, which was evaluated in dose escalation (n=6) to support an ongoing loading dose cohort.

o No Grade 3 colitis was observed at any dose, with limited use of infliximab to manage immune-mediated diarrhea/colitis in no more than 10% of patients.

o No significant late-onset toxicities were observed after repeat dosing at the 10 mg/kg dose level. TRAEs by week from treatment start are summarized in the poster.

o Grade 3 TRAEs occurred in only 6% of patients at the 10 mg/kg Q6W dose (1/17) and 16% of patients at the 10 mg/kg Q3W dose (6/37). Standard of care treatments are associated with higher rates of toxicities.

o Seven patients developed treatment related SAEs; however, the discontinuation rate remains low at 8% (5/66).

· ADG126 administered at 10 mg/kg Q6W or Q3W in combination with pembrolizumab (200 mg/Q3W) demonstrated an encouraging efficacy signal, durable disease control and an early survival benefit in MSS CRC patients, with dose-dependent efficacy and objective responses per RECIST criteria observed for the Q3W schedule:

o In the subset of efficacy evaluable patients without liver and peritoneal metastases (n=17) who received ADG126 10 mg/kg Q3W, an ORR of 24% was observed, including four confirmed PRs. These results are consistent with earlier ORR data published at ASCO (Free ASCO Whitepaper) GI 2024. Response rates for current standard of care treatments range from 1% to 6.3%*.

o An additional 11 patients had stable disease (SD) for an overall disease control rate (DCR) of 88% (15/17).

o Further, a median PFS of 8.5 months was observed in the subset at the ADG126 10 mg/kg Q3W dose and median PFS was 5.9 months for patients at the ADG126 10 mg/kg Q6W dose.

o The 12-month OS rates were 74% for those patients without liver metastases (n=36), and 82% in those without liver and peritoneal metastases (n=24) in the combined 10 mg/kg Q6W and Q3W cohorts.

o While the 10 mg/kg Q3W cohort demonstrated efficacy with RECIST responses and the Q6W did not, early OS rates appear comparable for both doses. This suggests that the Q6W could be used as a starting point for future combination trials, or as a dose modification strategy for safety management.

o Additionally, results in patients without liver metastases who received at least four cycles of the combination showed comparable OS rates to those without liver and peritoneal metastases, highlighting the importance of early disease control with standard of care to enable the IO doublet to drive a long-term survival benefit.

· In dose escalation, the 20 mg/kg Q3W dose level was tolerable for the initial cycle (n=6). Based upon the safety profile of the initial dose, 20 mg/kg is being evaluated as a loading dose in an expansion cohort that has enrolled 12 patients. This cohort is evaluating a single dose of ADG126 at 20 mg/kg followed by a 10 mg/kg Q3W maintenance dose in combination with pembrolizumab. Initial data for this cohort are expected later this year.

· Comprehensive PK and exposure response analyses were also conducted to provide insight on various dosing regimens and their correlation to safety and efficacy of the combination. These results reinforce the increased therapeutic index of ADG126, underscoring a key advantage of the SAFEbody precision masking technology. The extensive PK data also guide future clinical development and dose selection to meet FDA’s Project Optimus dose optimization requirements.

Commenting on these promising results, Peter Luo, Adagene’s CEO and President of R&D said, "We are thrilled that today’s update continues to reinforce the clinical benefits of the best-in-class therapeutic potential for ADG126 at the 10 mg/kg dose level in combination with pembrolizumab in MSS CRC. Armed with these results and the anticipated findings from our ongoing 20 mg/kg loading dose regimen, we are moving ahead with plans to evaluate ADG126 in MSS CRC at 10- to 20-fold higher doses than ipilimumab in a randomized, registration-oriented clinical program. With safety comparable to historical data for pembrolizumab monotherapy, these data provide a solid foundation for the potential of an IO doublet targeting CTLA-4 and PD-1 to move into earlier lines of therapy and broader patient populations, particularly when combined with standard of care aiming for a transformational improvement in patient outcomes."

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

SAFEbody is a registered trademark in the United States, China, Australia, Japan, Singapore, and the European Union.

On September 16, 2024 Exact Sciences Corp. (NASDAQ: EXAS), a leading provider of cancer screening and diagnostic tests, reported performance data for its blood-based colorectal cancer (CRC) screening test (Press release, Exact Sciences, SEP 16, 2024, View Source [SID1234646634]). Results show sensitivities of 88.3% for CRC and 31.2% for advanced precancerous lesions at specificity of 90.1% for negative samples confirmed by colonoscopy. Results were presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in an oral presentation titled, "Organ-specific performance of a multi-analyte, multi-cancer early detection (MCED) blood test in a prospectively-collected cohort."

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"The Exact Sciences team is constantly innovating to help close the screening gap," said Kevin Conroy, chairman and CEO, Exact Sciences. "The insights that led to this innovation reflect our understanding of the biology of cancer and the power of our scientific capabilities. We took a unique scientific approach to developing this test by combining a novel panel of markers. This led to data that improve upon what we previously thought was possible with a blood-based colorectal cancer screening test."

To optimize the final test algorithm, Exact Sciences designed a study to simulate the screening population in the United States and better predict real-world, prospective performance of a novel test. The study consisted of more than 3,000 blood samples, including approximately 2,900 blinded, prospectively collected samples from the pivotal BLUE-C study. This analysis was prespecified with the U.S. Food and Drug Administration (FDA) and the samples will be excluded from the final clinical validation. The study also included more than 90 advanced precancerous lesions, the majority of which were prospectively collected, and 60 case-collected colorectal cancer samples. In the pivotal BLUE-C study results, performance degradation is expected for advanced precancerous lesion sensitivity and overall CRC sensitivity.

Results of this study show the potential of a novel, highly discriminate blood-based panel of methylated DNA markers and an impactful, new marker class to detect advanced precancerous lesions and cancers at an attractive cost profile. The company will implement the innovative marker class on a new testing platform and complete additional analytical studies to support an FDA submission.

"A blood-based colorectal cancer screening test that can detect advanced precancerous lesions at a level comparable to the FIT test would be a breakthrough in this field," said Paul Limburg, MD, MPH, AGAF, chief medical officer for Screening, Exact Sciences. "Results from this large, well-designed study show progress toward that goal and move us one step closer toward providing average-risk patients with another non-invasive screening option."

BLUE-C results for Exact Sciences’ blood-based CRC screening test are now expected in the first half of 2025. Exact Sciences plans to use these results to support an FDA submission and approval and to make the blood-based CRC screening test available broadly. If approved, the blood-based CRC screening test could provide another testing option for 60 million unscreened people1 in the United States. It would be supported by Exact Sciences’ commercial infrastructure and ExactNexus technology platform, making electronic ordering and resulting seamless for more than 350 health systems.

The company also presented data from its multi-cancer early detection (MCED) blood test, assessing organ-specific performance of methylation and protein biomarkers in a prospectively collected cohort of samples from its ASCEND 2 study. The analysis indicated an overall sensitivity of 54.8% with 98.5% specificity in cancers without standard-of-care screening options (excluding lung) and 63.7% in the six most aggressive cancers with the shortest survival rates (esophagus, liver, lung, ovarian, pancreatic, and stomach). These findings highlight the potential clinical value of using multiple biomarkers to detect various cancer types, including the most aggressive and those without recommended screening options.

On September 16, 2024 TME Pharma N.V., a clinical-stage biotechnology company focused on developing novel therapies for treatment of cancer by targeting the tumor microenvironment (TME), reported an oral presentation by Dr. Frank A. Giordano, lead investigator of the NOX-A12 GLORIA Phase 1/2 trial in first-line brain cancer (glioblastoma), taking place on Sunday, September 15, 2024, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Barcelona, Spain (Press release, TME Pharma, SEP 16, 2024, View Source [SID1234646633]). The presentation provided the updated results and key conclusions from the combined therapy with NOX-A12 and bevacizumab in newly diagnosed glioblastoma patients resistant to standard chemotherapy (MGMT unmethylated) with residual detectable tumor after surgery.

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In the presentation, Dr. Giordano highlighted that inhibition of two paths of brain tumor revascularization after radiation – vasculogenesis with NOX-A12 and angiogenesis with bevacizumab – resulted in deeper clinical responses, i.e. stronger shrinkage of tumor size compared to NOX-A12 therapy alone. The research showed a significant decrease in tumor perfusion which supports the suggested mode of action of the combination therapy. The presentation also reveals that the deeper responses to the combination therapy with NOX-A12 and bevacizumab translate to significantly longer median progression free survival (mPFS: 9.1 months, p=0.003) and median overall survival (mOS: 19.9 months, p=0.005) compared to a matched SOC reference cohort (mPFS: 4.0 months; mOS: 9.5 months) or to NOX-A12 alone (mPFS: 5.7 months; mOS: 12.7 months). Two out of the six glioblastoma patients in the NOX-A12 + bevacizumab arm of the GLORIA trial survived for more than 26 months since the start of therapy.

"The median OS of 19.9 months achieved in patients receiving combination therapy in the GLORIA study is especially exciting when considering the prognosis this chemotherapy-refractory patient population with residual detectable tumor after surgery would otherwise face on current standard of care, notably survival of approximately 10 months," said Aram Mangasarian, CEO of TME Pharma. "What further strengthens our confidence in our dual inhibition approach is the tumor tissue analysis showing spatially distinct expression patterns of NOX-A12’s target CXCL12 and VEGF. This indicates that the two different ways of growing blood vessels occur in different tumor structures: vasculogenesis driven by NOX-A12’s target, and angiogenesis driven by bevacizumab’s target. This helps explain why combined inhibition of both pathways is needed to effectively prevent tumor vasculature restoration after radiotherapy."

Details of the oral presentation at the ESMO (Free ESMO Whitepaper) Congress 2024 are as follows:

Title: Dual inhibition of postradiogenic angio-vasculogenesis in glioblastoma: Results of the phase 1/2 GLORIA trial
Presenter: Dr. Frank A. Giordano, Chair of the Department of Radiation Oncology, University Medical Center Mannheim, Germany
Session: Mini oral session: CNS tumors
Time and Date: 08.30-8.35 a.m. CEST, Sunday, September 15, 2024

On September 16, 2024 Johnson & Johnson (NYSE: JNJ) reported interim data from the ongoing Phase 2 SunRISe-4 study showing neoadjuvant treatment with investigational TAR-200 plus cetrelimab (CET) achieved nearly double the pathological complete response (pCR) rate compared to CET alone in patients with muscle-invasive bladder cancer (MIBC) who are ineligible or refuse neoadjuvant platinum-based chemotherapy and scheduled for radical cystectomy (RC) (Press release, Johnson & Johnson, SEP 16, 2024, View Source [SID1234646627]). These data were featured as a late-breaking oral presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2024 Congress (Abstract #LBA84).

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"These findings from the SunRISe-4 study show for the first time that an intravesical treatment with TAR-200, combined with a systemic PD-1 inhibitor, could potentially result in a complete pathological response in a high proportion of patients, as well as allowing a tolerable approach," said Andrea Necchi, M.D., of Italy’s Vita-Salute San Raffaele University and the IRCCS San Raffaele Hospital and Scientific Institute and a presenting author of the study. "These preliminary findings show a potential for a future change in the local treatment of muscle-invasive bladder carcinoma using TAR-200."

In the interim analysis of the SunRISe-4 study, neoadjuvant TAR-200 plus CET (n=53) showed overall efficacy with a centrally confirmed pathologic complete response (pCR, [T0]) rate of 42 percent compared to 23 percent (95 percent CI, 28-56; 10-41, respectively) with CET alone (n=31) in patients with histologically proven, non-metastatic MIBC. The pathological overall response (pOR) rate (defined as the proportion of patients ≤ pT1) was 60 percent compared to 36 percent, respectively (CI 95 percent, 46-74; 19-55).1

In a subgroup analysis of patients with organ-confined disease (cT2), those treated with TAR-200 plus CET (n=40) showed a 48 percent pCR rate compared to 23 percent pCR with CET alone (n=26, 95 percent CI, 32-64; 9-44, respectively) and 68 percent were downstaged (≤ pT1) at the time of radical cystectomy, potentially improving surgical outcomes and reducing risk of recurrence.1

"With these promising results, TAR-200 plus cetrelimab as a neoadjuvant therapy before radical cystectomy could potentially alter how bladder cancer is treated," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Innovative Medicine, Johnson & Johnson. "This investigational innovative approach may offer a possible alternative for many patients who are not eligible for the current standard of pre-operative treatments."

Treatment-related adverse events (TRAEs) occurred in 72 percent of patients treated with TAR-200 combined with CET and 44 percent of patients treated with CET alone, with the majority being Grade 1-2. Nine percent of patients discontinued treatment with TAR-200 and eight percent discontinued treatment with CET in the combined treatment cohort due to TRAEs; no patients discontinued treatment due to TRAEs when treated with CET alone.1

Bladder cancer is the ninth most common cancer in the world.2 Although BCG immunotherapy has been accepted as the standard of care for nearly five decades, 30-40 percent of patients do not respond to BCG and experience disease recurrence or progression.3 In such scenarios, radical cystectomy (removal of the bladder and neighboring structures and organs) emerges as the primary treatment option. This major abdominal procedure requires a urinary diversion to be created to collect and store urine.4

TAR-200 is an investigational targeted releasing system designed to provide extended local release of gemcitabine into the bladder. It is installed in a physician’s office setting during a 2-3 minute procedure with no anesthesia. In December 2023, the FDA granted TAR-200 Breakthrough Therapy Designation (BTD) for the potential future treatment of patients with BCG-unresponsive HR-NMIBC, who are ineligible for or elected not to undergo radical cystectomy (surgical removal of the bladder).

About SunRISe-4
SunRISe-4 (NCT04919512) is an open-label, multicenter, randomized Phase 2 study assessing the efficacy and safety of neoadjuvant TAR-200 + cetrelimab (CET) (anti-programmed death-1 antibody) or neoadjuvant CET alone in patients with MIBC scheduled for RC who are ineligible for or refuse neoadjuvant platinum-based chemotherapy.

About TAR-200
TAR-200 is an investigational targeted releasing system, enabling extended release of gemcitabine into the bladder, increasing the amount of time the drug delivery system spends in the bladder and sustaining local drug exposure. The safety and efficacy of TAR-200 are being evaluated in Phase 2 and Phase 3 studies in patients with MIBC in SunRISe-2 and SunRISe-4, and NMIBC in SunRISe-1, SunRISe-3 and SunRISe-5.

About Cetrelimab
Cetrelimab is an investigational programmed cell death receptor-1 (PD-1) monoclonal antibody being studied for the treatment of bladder cancer, prostate cancer, melanoma, and multiple myeloma as part of a combination treatment. Cetrelimab is also being evaluated in multiple other combination regimens.

About Muscle-Invasive Bladder Cancer
Muscle-invasive bladder cancer (MIBC) is a severe form of bladder cancer where the tumor penetrates the muscular layer of the bladder wall, significantly increasing the risk of metastasis.5 Approximately 25 percent of bladder cancer cases are diagnosed as MIBC at the time of initial presentation.6 Early detection and timely intervention are crucial for managing MIBC, as delayed treatment can lead to poor prognosis.