On June 6, 2022 Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported that it presented updated preliminary Phase I data on TG4050, its individualized neoantigen cancer vaccine, in a poster session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, Transgene JUN 6, 2022, View Source [SID1234615638]). TG4050 is based on Transgene’s myvac platform and powered by NEC’s cutting-edge AI capabilities.

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These additional positive initial data, including molecular (ctDNA) response, have been generated from the first patients with ovarian cancer and HPV-negative head and neck cancer enrolled in the two ongoing Phase I trials assessing TG4050. They were presented in-person in Chicago, IL, June 5, 2022.

"These new results, though early, are very encouraging" said Dr. Maud Brandely, MD, PhD, Chief Medical Officer of Transgene. "So far we accumulated promising preliminary data with TG4050: good tolerability, consistent immunogenicity and encouraging molecular response. We are particularly impressed by the effective priming of the immune system and the early signs of clinical activity. These results suggest that our individualized vaccine, TG4050, has the potential to extend the remission period, thus providing a new hope for cancer patients. In addition, the information we gather from the two ongoing Phase I studies will be pivotal in designing the Phase II trial of TG4050 which could start as early as 2023."

Prof. Jean-Pierre Delord, MD, PhD, General Manager of IUCT Oncopole of Toulouse and first author of the poster, added: "Neoantigen vaccination such as TG4050 is a relevant strategy for the treatment of patients with high risk of cancer relapse for whom the medical need is particularly high. In this setting, the vaccine is expected to deliver clinical benefit by controlling the residual disease. To date, this non-invasive treatment is well tolerated by the patients and although preliminary, the data presented at ASCO (Free ASCO Whitepaper) clearly suggest that TG4050 could become a new treatment option for cancer patients. I am looking forward to seeing this potential game-changing therapy moving forward."

For the first time, ctDNA data were generated following treatment with TG4050

Liquid biopsies were performed to measure the circulating tumor DNA (ctDNA) levels. ctDNA is an emerging modality that is used to detect subclinical disease or asymptomatic relapse in an increasing number of indications. Use of such highly sensitive and specific marker seeks to identify patients whose disease is very likely to relapse in the near future, before their disease becomes detectable with current standard methods such as imaging. Moreover, it allows a non-invasive monitoring of treatment effectiveness. For instance, in at least one ovarian cancer patient in the study, a decline in ctDNA was concomitant with CA-125 normalization and disease control. Analyses are ongoing in more recently included patients.

Clinical follow-up data continue to demonstrate the potential of TG4050 in ovarian and head and neck cancer patients

In the head and neck cancer trial, patients were randomized to immediately receive vaccination with TG4050 (early treatment arm, arm A) or at relapse (delayed vaccination arm, arm B). All evaluable patients randomized to arm A (n=8) are still in complete response as of mid-May 2022. In arm B (n=8), two patients have experienced relapse.

In the ovarian cancer trial (n=5), a fifth patient initiated her treatment with TG4050 recently. One patient treated after an elevation of CA-125 experienced a normalization of CA-125 without clinical progression for 9 months until death from an unrelated chronic illness. Another patient was treated upon onset of radiological evidence of relapse and remained stable for 11.4 months.

To date, the vaccine has been well tolerated and no related Serious Adverse Events have been reported across the two studies.

In both clinical studies, enrollment and patient dosing are progressing in line with our expectations. Overall, Transgene plans to treat 13 patients in the ovarian cancer trial and 30 patients in the head and neck cancer trial.

Immune cell response data demonstrated an effective priming of the immune system which is associated with disease regression

Transgene presented a comprehensive set of immunological data at ASCO (Free ASCO Whitepaper). Circulating immune cells quantification (in particular monocytes, DC, NK cells, subcells of CD8, CD4, Treg) and expression of immune checkpoints (ICOS and PD1) suggest that the vaccine is able to effectively induce innate and adaptive immune responses in patients.

In an ovarian cancer patient, clinical resolution and biological responses (CA-125 and ctDNA responses) were concomitant to an immune response against multiple epitopes and to the onset of markers of an effective immune response (switch in circulating CD4 and CD8 cells toward an effector phenotype, increase in CD16neg NK cells; peak in circulating cytokines).

All evaluable patients developed a robust T-cell response against multiple targeted neoantigens (median of 10 positive responses per patient). T-cell responses were observed for class I and class II epitopes, they consisted of de novo responses and amplifications of preexisting responses.

Poster title: Phase 1 studies of personalized neoantigen vaccine TG4050 in ovarian carcinoma (OC) and head and neck carcinoma (HNSCC)

Abstract number: 2637
Session title: Developmental Therapeutics—Immunotherapy
Authors: J.P. Delord, M. Block, C. Ottensmeier, G. Colon-Otero, C. Le Tourneau, A. Lalanne, O. Lantz, KL. Knutson, G. Lacoste, A. Tavernaro, M. Brandely, N. Silvestre, B. Grellier, Y. Yamashita, O. Kousuke, N. Yamagata, Y. Tanaka, B. Malone, E. Quemeneur, K. Bendjama

About the clinical trials

TG4050 is being evaluated in two Phase I clinical trials for patients with ovarian cancer (NCT03839524) and HPV-negative head and neck cancers (NCT04183166).

In a first Phase I trial, TG4050 is being administered to patients with HPV-negative head and neck cancer. A personalized treatment is created for each patient after they complete surgery and while they receive an adjuvant therapy. Half of the participants receive their vaccine immediately after they complete their adjuvant treatment. The other half is given TG4050 as an additional treatment at the time of recurrence of the disease as an additional treatment to SoC. This randomized study is evaluating the treatment benefits of TG4050 in patients who have a high risk of relapse. Up to 30 patients will receive TG4050 in France, in the UK and in the USA. The principal investigator of the trial is Prof. Christian Ottensmeier, MD, PhD, Consultant Medical Oncologist at the Clatterbridge Cancer Centre and Professor of Immuno-Oncology at the University of Liverpool. In France, the clinical trial is being conducted at Institut Curie, Paris by Prof. Christophe Le Tourneau, MD, PhD, Head of the Department of Drug Development and Innovation (D3i), and at the IUCT-Oncopole, Toulouse by Prof. Jean-Pierre Delord, MD, PhD. In the USA, the trial is being led by Yujie Zhao, MD, PhD, at the Mayo Clinic. Endpoints of the trial include safety, feasibility and biological activity of the therapeutic vaccine.

In parallel, a Phase I clinical trial of TG4050 is enrolling patients with ovarian cancer. This second trial is including patients at the time of asymptomatic relapse after surgery and first-line chemotherapy. Matthew Block, MD, PhD, Consultant Medical Oncology, Consultant Immunology and Associate Professor of Oncology at the Mayo Clinic (USA) is the principal investigator of the trial; in France, the trial is being conducted by Prof. Le Tourneau, MD, PhD, at Institut Curie and by Alexandra Martinez, MD, Associate Head of Surgical Department, at IUCT-Oncopole. Endpoints of the trial include safety, feasibility and biological activity of the therapeutic vaccine.

The first preliminary clinical data generated from the first patients treated with TG4050 were very encouraging.

About myvac

myvac is a viral vector (MVA – Modified Vaccinia Ankara) based, individualized immunotherapy platform that has been developed by Transgene to target solid tumors. myvac-derived products are designed to stimulate the patient’s immune system, recognize and destroy tumors using the patient’s own cancer specific genetic mutations. Transgene has set up an innovative network that combines bioengineering, digital transformation, established vectorization know-how and unique manufacturing capabilities. Transgene has been awarded "Investment for the Future" funding from Bpifrance for the development of its platform myvac. TG4050 is the first myvac-derived product being evaluated in clinical trials.

Click here to watch a short video on myvac.

About TG4050

TG4050 is an individualized immunotherapy being developed for solid tumors that is based on Transgene’s myvac technology and powered by NEC’s longstanding artificial intelligence (AI) expertise. This virus-based therapeutic vaccine encodes neoantigens (patient-specific mutations) identified and selected by NEC’s Neoantigen Prediction System. The prediction system is based on more than two decades of expertise in AI and has been trained on proprietary data allowing it to accurately prioritize and select the most immunogenic sequences.

TG4050 is designed to stimulate the immune system of patients in order to induce a T-cell response that is able to recognize and destroy tumor cells based on their own neoantigens. This individualized immunotherapy is developed and produced for each patient.

On June 6, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported results of a prospective analysis from the Phase 1b cohort of the KRYSTAL-1 study evaluating intracranial (IC) responses of adagrasib in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC) with active and untreated central nervous system (CNS) metastases (Press release, Mirati, JUN 6, 2022, View Source [SID1234615636]). This is the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC with active and untreated CNS metastases. Findings show that approximately one third of the patients had an IC response in patients with CNS metastases, consistent with what was observed systemically in this cohort.

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The data will be presented today as a late-breaking oral presentation in the session titled, "Clinical Science Symposium/Including the Excluded: Advancing Care for All Patients With Lung Cancer" at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from 5:30 to 5:42 PM ET/4:30 to 4:42 PM CT (Abstract #LBA9009).

"We are proud to share the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC," said Charles Baum, M.D., Ph.D., president, founder and head of research and development, Mirati Therapeutics, Inc. "Central nervous system metastases disproportionately affect patients with NSCLC and should be carefully considered as part of the treatment approach. Adagrasib showed CNS penetration and intracranial responses in patients with active and untreated CNS metastases, demonstrating potential as a treatment option for this underserved patient population."

Results of Prospective Analysis

With a median follow up of 6.6 months (data cutoff date December 2021), 25 patients with active, untreated CNS metastases were enrolled in the study and treated with adagrasib 600 mg BID.

Of the radiographically evaluable patients (n=19), results showed an IC objective response rate of 32% (6/19) by modified response assessment in neuro-oncology-brain metastases (modified RANO-BM) by blinded independent central review.

In this analysis, three patients achieved a complete response and three patients achieved a partial response. The IC disease control rate was 84% (16/19, including 10 patients with stable disease). The median IC duration of response was not reached (95% confidence interval: 4.1 – not evaluable). Concordance of disease control between systemic and IC responses was 88% (14/16). For all patients enrolled, median overall survival was not reached.

Cerebrospinal fluid (CSF) samples were obtained from two patients for whom regression of CNS metastases was observed; adagrasib CSF/free plasma concentration ratios (Kp,uu: 0.47) were consistent with other agents with known CNS penetration and activity.

The safety profile of adagrasib in this study was consistent with the overall population with no new safety signals observed. Grade 1 and 2 treatment related adverse events (TRAEs) occurred in 60% of patients. Grade 3 TRAEs occurred in 36% of patients, and there were no Grade 4/5 TRAEs.
"Central nervous system metastases occur in 27% to 42% of patients with KRASG12C-mutated NSCLC at diagnosis. These patients have a median overall survival of approximately five months, posing a serious clinical challenge," said Joshua K. Sabari, M.D., assistant professor of medicine, medical oncology at Perlmutter Cancer Center, NYU Langone Health. "With a median follow up of 6.6 months, these early and positive data show adagrasib demonstrated a meaningful overall intracranial response rate with early indications for overall survival. Adagrasib warrants further investigation on its potential to improve clinical outcomes for NSCLC patients harboring a KRASG12C-mutation who have active and untreated CNS metastases, including opportunities through Mirati’s Expanded Access Program."

Mirati also presented results from the registration-enabling Phase 2 cohort of the KRYSTAL-1 study evaluating adagrasib in patients with pre-treated NSCLC harboring a KRASG12C mutation during the Lung Cancer–Non-Small Cell Metastatic session at ASCO (Free ASCO Whitepaper) on June 3, 2022.

Virtual Investor Event

Mirati Therapeutics will host an Investor Event on Monday, June 6, 2022, at 8:00 PM ET/ 7:00 PM CT.

Company executives will provide an overview of the adagrasib clinical data presented at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting and the Company’s broader lung cancer strategy, including in earlier lines of therapy.

Investors and the general public are invited to register and listen to a live webcast of the event through the "Investors and Media" section on Mirati.com. A replay of the event will be available shortly after the conclusion of the event.

Central Nervous System (CNS) Metastases in KRAS-Mutated Lung Cancer

The brain, along with the bone, adrenals, and liver are common sites of extra-thoracic metastases in NSCLC.[1]−3 CNS metastases occur in 27−42% of patients with KRASG12C-mutated NSCLC at diagnosis.1,4−6 Additionally, patients with CNS metastases and KRAS-mutated NSCLC may have poor outcomes, with median overall survival ranging of approximately five months. 7-9

About Adagrasib (MRTX849)

Adagrasib is an investigational, highly selective, and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24–48 hours. Adagrasib is being evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer and pancreatic cancer. For more information visit Mirati.com/science.

Mirati has an Expanded Access Program (EAP) for investigational adagrasib for the treatment of eligible patients with KRASG12C-mutated cancers, regardless of tumor type, including patients with treated or untreated CNS metastases, in the U.S. Learn more about the EAP at Mirati.com/expanded-access-policy.

On June 6, 2022 Enlivex Therapeutics Ltd. (Nasdaq: ENLV, the "Company"), a clinical-stage macrophage reprogramming immunotherapy company targeting diseased macrophages in patients with sepsis and solid tumors, reported that the Israeli Ministry of Health (MOH) authorized the initiation of a company-sponsored Phase I/II clinical trial evaluating Allocetra combined with chemotherapy in patients with peritoneal metastases arising from solid cancer (Press release, Enlivex Therapeutics, JUN 6, 2022, View Source [SID1234615635]).

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Peritoneal cancer, whether originating from a primary tumor within the peritoneum or from a metastatic tumor elsewhere in the body, is a terminal disease with a poor prognosis. Patients with peritoneal metastases are in urgent need of novel treatment options, as standard-of-care (SOC) chemotherapy provides only modest survival benefits. The median survival of patients with peritoneal metastases differs based on the location of the primary tumor but is frequently poor, with survival rates of 2.9 months, 6.5 months, and 6.9 months reported for cancers of pancreatic, gastric, and colorectal origins, respectively.

The planned Phase I/II trial is an open-label dose escalation and expansion trial that is expected to enroll a total of approximately 12 patients across four cohorts. It is designed to evaluate the safety and potential preliminary efficacy of Allocetra combined with SOC chemotherapy in patients with peritoneal metastases arising from solid cancer. The study will begin with two cohorts of intra-patient and intra-cohort dose escalation to determine the maximum feasible dose (MFD) of Allocetra in this population, followed by two additional cohorts comparing administration of Allocetra at the selected dose either before or after administration of SOC via a pressurized intraperitoneal aerosol chemotherapy procedure (PIPAC; a technique applied when patients are not eligible to receive the standard treatment due to a considerable tumor load, or large quantities of persistent ascites and other circumstances).

Intraperitoneally delivered Allocetra and SOC chemotherapy administered via PIPAC will be given to patients every six weeks. Systemic chemotherapy will also be administered per the treating oncologist’s plan. The primary endpoint is the number and severity of Allocetra-related adverse events and serious adverse events during the 16-week period, starting from the first administration of study treatment. Secondary endpoints include efficacy assessments, such as best overall response rate (ORR), progression-free survival, and overall survival. Changes from baseline in macrophage and immune cell characteristics in peritoneal fluid and tissues will also be assessed as an exploratory endpoint.

Currently, the efficacy of many anti-cancer agents is hampered by the body’s tumor defense mechanisms that facilitate the recruitment of macrophages which become "pro-tumor" tumor associated macrophages (TAMs) rather than "anti-tumor" macrophages. The TAMs typically form a physical layer on top of the solid tumor and induce immunosuppression in the solid tumor microenvironment. This in-turn promotes tumor growth and metastasis and contributes to poor clinical outcomes and response to therapy. Previously reported preclinical data from solid tumor models suggest that Allocetra has the potential to reprogram pro-tumor macrophages back to their homeostatic state and may thereby promote disease resolution and provide patients that do not respond well to existing FDA-approved therapies with an effective treatment option.

Einat Galamidi, M.D., Vice President, Medical of Enlivex, stated: "Receiving this authorization from the MOH is an important step toward expanding Allocetra’s potential therapeutic impact into oncology. Our preclinical studies suggest Allocetra may enhance the efficacy of a broad range of therapeutic agents by weakening tumor defense mechanisms through a novel mechanism of action that drives macrophage populations towards a more anti-cancer state. We look forward to beginning the clinical evaluation of this hypothesis through both this chemotherapy combination study and an additional planned solid tumor study that will evaluate Allocetra combined with a checkpoint inhibitor."

Enlivex plans to initiate the Phase I/II trial evaluating Allocetra in combination with chemotherapy in patients with peritoneal metastases arising from solid cancer in Q3 2022. The Company also expects to initiate a Phase I/II trial evaluating Allocetra in combination with an immune checkpoint inhibitor in late 2022.

ABOUT ALLOCETRATM

Allocetra is being developed as a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. Diseases such as solid cancers, sepsis, and many others reprogram macrophages out of their homeostatic state. These non-homeostatic macrophages contribute significantly to the severity of the respective diseases. By restoring macrophage homeostasis, Allocetra has the potential to provide a novel immunotherapeutic mechanism of action for life-threatening clinical indications that are defined as "unmet medical needs", as a stand-alone therapy or in combination with leading therapeutic agents.

On June 6, 2022 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of MasterKey therapies, reported that its President and Chief Executive Officer, David M. Epstein, Ph.D., will present an update on the Company’s progress at the Jefferies Global Healthcare Conference on Wednesday, June 8, 2022, at 3:00pm ET in New York, NY (Press release, Black Diamond Therapeutics, JUN 6, 2022, View Source [SID1234615634]).

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A live webcast of the presentation can be accessed by visiting the investor relations section of the Company’s website, www.blackdiamondtherapeutics.com. A replay of the webcast will also be available and archived for 90 days following the event.

On June 6, 2022 Ayala Pharmaceuticals, Inc. (Nasdaq: AYLA), a clinical-stage oncology company focused on developing and commercializing small molecule therapeutics for patients suffering from rare and aggressive cancers, primarily in genetically defined patient populations, reported that data on AL101 from the Phase 2 ACCURACY study in a poster at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place June 3-7, 2022 in Chicago, Illinois (Press release, Ayala Pharmaceuticals, JUN 6, 2022, View Source [SID1234615633]).

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The poster at ASCO (Free ASCO Whitepaper) provides updated data from the 4mg and 6 mg AL101 cohorts in the ACCURACY study of the AL101, a selective gamma-secretase inhibitor, in subjects with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch activating mutations (Notchmut) (NCT03691207). The most recent safety efficacy, PK, and PD data from the study is presented. The abstract from this study has been released on the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting website (View Source).

"We are excited to have AL101 featured in the 2022 ASCO (Free ASCO Whitepaper) meeting and are pleased with the very promising safety and efficacy data from ACCURACY," said Gary Gordon, M.D., Ph.D., Chief Medical Officer of Ayala. "ACC is an orphan disease with no approved therapies and patients with Notch mutations have a more aggressive disease course and poorer survival outcomes as compared to patients with Notch wild-type. If approved, we see strong potential for AL101 to provide a much needed treatment option for R/M ACC patients and look forward to further advancing this clinical program."

ACCURACY is an open-label, single-arm, multicenter Phase 2 study to assess the clinical activity of AL101 using radiographic assessments of patients with R/M ACC demonstrating disease progression within 6 months prior to dosing. It is the first ACC study selecting subjects with ACC bearing defined NOTCH-activating mutations. A total of 87 patients were enrolled (all with RECIST v1.1 evaluable disease or bone exclusive disease deemed evaluable by MD Anderson Bone Response criteria) and of these, 77 were evaluable for efficacy. Approximately 90% of the patients had metastatic disease at screening. This was a heavily pretreated patient population with over half having previously received some form of systemic therapy. Preliminary data from the study were announced by Ayala in 2021.

Efficacy Results

In the 4mg dose group, 6 patients (14.6%) had a partial response, 23 (56.1%) had stable disease, for an overall disease control rate of 70.7%
In the 6mg dose group, 3 patients (8.3%) had a partial response, 21 (58.3%) had stable disease and for an overall disease control rate of 66.7%
Fifty six percent of the 4mg cohort patients and 36% of the 6mg cohort patients experienced some degree of tumor regression.
The median progression free survival (PFS) in each of the 4mg and 6mg dose cohorts was 3.7 months but was 6.7 months among the patients who had a partial response
Median overall survival (OS) was 9.3 months in the overall group but 12.1 months among the patients who had a partial response.
Both dose regimens demonstrated substantial inhibition of the NOTCH pathway consistent with previous studies, but the higher dose did not improve the observed outcomes
Safety

AL101 was adequately tolerated with most adverse events being Grade 1 or 2
Among all 87 patients, 54 or 62% had treatment related grade 3 or 4 AEs (49% in the 4mg cohort and 76% in the 6mg cohort).
Dr. Renata Ferrarotto, Associate Professor and Director of Head and Neck Oncology Clinical Research at M.D. Anderson Cancer Center and the principal investigator of the study commented "The anti-tumor activity of AL101 in the ACCURACY study suggests that it is providing benefit to a subset of patients with ACC carrying Notch-activating mutations. We are presenting data for the first time showing that subjects who had a partial response to AL101 had progression free survival that was approximately double that of the group as a whole. This result, together with the high disease control rate observed, underscores the clinical relevance of the outcomes, given the aggressive disease course associated with Notch mutations and the fact that the majority of subjects in this trial were heavily pretreated."

Poster presentation details:

Abstract Title: Results of ACCURACY: A phase 2 trial of AL101, a selective gamma secretase inhibitor, in subjects with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch activating mutations (Notchmut)
Abstract Number: 6046
Session Title: Head and Neck Cancer
Session Date and Time: Monday, June 6, 2022, 1:15 PM-4:15 PM CDT
A copy of the poster will be available on the Ayala corporate website, following the presentation at ASCO (Free ASCO Whitepaper) on June 6.

About Adenoid Cystic Carcinoma (ACC)

ACC is a rare malignancy of the secretory glands including salivary glands, accounting for about 10% of all salivary gland tumors with an annual incidence of 3,400 in the U.S. There is currently no approved standard of care for patients with recurrent/metastatic ACC. Patients with locoregional disease undergo surgery and radiation therapy, with recurring disease treated by chemotherapy. ACC is an immunologically "cold" tumor that is refractory to chemotherapy, with a recurrence rate of about 60% after initial surgery. The Notch pathway has been determined to be an oncogenic driver of ACC and its dysregulation plays a key role in tumorigenesis and correlates with a distinct pattern of metastasis and a poor prognosis.

About AL101

AL101 is an investigational small molecule Gamma Secretase Inhibitor (GSI) that is designed to potently and selectively inhibit Notch 1, 2, 3 and 4, and is currently being evaluated in the Phase 2 ACCURACY clinical studies in patients with adenoid cystic carcinoma (ACC). AL101 is designed to inhibit the expression of Notch gene targets by blocking the final cleavage step by the gamma secretase required for Notch activation. Ayala obtained an exclusive, worldwide license to develop and commercialize AL101 from Bristol-Myers Squibb Company in November 2017. AL101 was granted U.S. FDA Fast Track Designation and Orphan Drug Designation for the treatment of ACC.