On June 6, 2022 Enterome, a clinical stage biopharmaceutical company developing first-in-class immunomodulatory drugs based on its bacterial Mimicry drug discovery platform, reported proof-of-concept immune response data and first clinical data from its Phase 1/2 clinical trial of EO2401 in combination with an immune checkpoint inhibitor (nivolumab, Opdivo) +/- an anti-VEGF therapy (bevacizumab, Avastin), for the treatment of patients with first progression/recurrence of glioblastoma (the ROSALIE trial, EOGBM1-18, NCT04116658) (Press release, Enterome, JUN 6, 2022, View Source [SID1234615607]). The data1 were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, on June 5, 2022 in Chicago and virtually.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

EO2401 is Enterome’s first-in-class off-the-shelf OncoMimics cancer immunotherapy. It combines three OncoMimics peptides that closely mimic IL13Ra2, BIRC5 and FOXM1, all of which are known driver antigens present on aggressive solid tumors. In addition, EO2401 contains a CD4 helper peptide UCP2. Enterome selected these OncoMimics using its Mimicry platform, which applies best-in-class biocomputational tools and bioassays to identify novel therapeutics from its proprietary database of 20+ million bioactive gut microbiome peptides and proteins.

Key highlights from the EO2401 poster presentation covering the Phase 1/2 ROSALIE trial were:

Proof-of-concept immune response data

Immune monitoring demonstrated the ability of the individual microbiome-derived peptides that comprise EO2401 to induce a strong CD8+ T cell response in patients with strong cross-reactivity against the human tumor antigens that they mimic.

Positive responses against the three OncoMimics peptides were demonstrated for 26 of the 27 patients investigated, and sustained for more than 44 weeks in the longest-followed patient.

Promising clinical outcomes

The combination of EO2401 plus nivolumab in study part 1 (Cohorts 1/2a/2b, n=29), despite short treatment durations, showed promising survival with a possible plateau at around 30% after 1 year. The short treatment durations were thought to be a result of a higher than expected rate of "pseudoprogression" leading to neurological symptoms (infiltration of tumor by immune cells and edema).

In study part 2, the addition of time-limited, low-dose bevacizumab as a symptom-driven anti-edema treatment (to counteract edema due to tumor infiltration of immune cells) supported prolonged treatment durations, which could also potentially impact efficacy (efficacy not yet presented due to short follow-up).

The triple combination of EO2401 plus nivolumab and bevacizumab (Cohort 3, n=11) demonstrated interesting directly measurable anti-tumor efficacy (objective tumor shrinkage) as compared with that observed in Cohort 1/2a/2b from study part 1 (EO2401 plus nivolumab without any bevacizumab) (below), and also with previous results shown with a checkpoint inhibitor (pembrolizumab or nivolumab) plus bevacizumab in contemporary trials2,3:

Objective response rates (ORR) – Cohort 3: 54.5% (95% CI 23.4; 83.3) vs Cohorts 1/2a/2b: 3% (95% CI 2.2; 27.4)

Disease control rates (DCR) – Cohort 3: 81.8% (95% CI 48.2; 97.7) vs Cohorts 1/2a/2b: 5% (95% CI 17.9; 54.3)
The encouraging efficacy seen with the triplet, including longer treatment durations, supports the hypothesis that the addition of symptomatic anti-edema treatment with time-limited, low-dose bevacizumab to the EO2401 plus nivolumab combination might influence efficacy positively.

Safety

The combination of EO2401, administered sub-cutaneously with the adjuvant Montanide ISA 51 VG, with nivolumab +/- bevacizumab was well tolerated. The safety profile was consistent with the profile of nivolumab, and, when applicable, the profile of bevacizumab, except the addition of local administration site reactions (occurring in 48% of patients, all Grade 1-2).

Professor Wolfgang Wick, Universitätsklinikum Heidelberg and German Cancer Research Center, Heidelberg, Germany commented, "I am pleased to be part of the ROSALIE trial, the first clinical study to evaluate Enterome’s novel therapeutic vaccine EO2401, which is based on the OncoMimics concept. In contrast to tumor antigens, the OncoMimic peptides in EO2401 are recognized by the immune system as "non-self" and, as we have seen in this study, generate strong human cytotoxic CD8+ responses. Based on the immune response and early clinical data that we have seen so far in this extremely challenging patient propulation, I am hopeful that more mature data from the trial might support further development steps in glioblastoma."

Jan Fagerberg, Chief Medical Officer of Enterome said, "I am very pleased that we have been able to present these very encouraging data from the ROSALIE trial, evaluating EO2401 in combination with checkpoint blockade, and checkpoint blockade plus anti-VEGF therapy. Most importantly, this first presentation of data from a clinical trial of EO2401 show proof-of-concept with regard to immune response, and also encouraging clinical data. We are looking forward to sharing a more mature set of data from ROSALIE at ESMO (Free ESMO Whitepaper) in September, which we hope will reinforce the positive findings that we have communicated at ASCO (Free ASCO Whitepaper)."

EO2401 in adrenal malignancies

At ASCO (Free ASCO Whitepaper), and separately announced today, Enterome presented the first clinical data from its Phase 1/2 clinical trials of EO2401 in combination with nivolumab for the treatment of patients with adrenal tumors (the SPENCER trial, EOADR1-19). View press release here.

About ROSALIE

ROSALIE (EOGBM1-18, NCT04116658) is a multicenter, open-label, Phase 1/2 trial investigating EO2401 in combination with nivolumab, and in combination with nivolumab/bevacizumab in patients with glioblastoma at first progression/recurrence after surgery and adjuvant radiotherapy/temozolomide. The trial is assessing safety, tolerability, immunogenicity and preliminary efficacy in approximately 80 patients at centers in the US and Europe

On June 6, 2022 Clarity Pharmaceuticals (ASX: CU6) ("Clarity"), a clinical-stage radiopharmaceutical company developing next-generation products to address the growing needs in oncology, reported the approval of its Investigational New Drug (IND) application by the United States Food and Drug Administration (US FDA) to evaluate its SAR-Bombesin product as an imaging agent in prostate cancer patients that are Prostate-Specific Membrane Antigen (PSMA)-negative (Press release, Clarity Pharmaceuticals, JUN 6, 2022, View Source [SID1234615624]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Clarity’s Executive Chairman, Dr Alan Taylor, commented, "Receiving clearance from the FDA on the imaging trial with SAR-Bombesin is yet another significant milestone for Clarity. It shows our ability to develop cutting-edge theranostics from the lab, through preclinical studies and into clinical trials, with SAR-Bombesin being Clarity’s fourth IND across five products which are clear for investigation in the US."

This IND gives Clarity clearance to proceed with a US-based Phase II 64Cu SAR-Bombesin Positron Emission Tomography (PET) imaging trial in participants with PSMA-negative biochemical recurrence (BCR) of prostate cancer following definitive therapy (such as surgery or radiation).

SABRE, which derives from "Copper-64 SAR-Bombesin in Biochemical REcurrence of Prostate Cancer trial", is a multi-center, single arm, non-randomised, open-label trial in up to 50 PSMA-negative patients with known or suspected prostate cancer. The primary objectives of the trial are to investigate the safety and tolerability of 64Cu SAR-Bombesin, as well as its ability to correctly detect the recurrence of prostate cancer.

The SABRE trial builds upon the promising clinical data from the pilot trial assessment of 64Cu SAR-Bombesin in breast cancer led by Prof Louise Emmett of St Vincent’s Hospital Sydney. The data from this trial was recently presented at the prestigious American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting. The SABRE trial was developed in response to the strong demand for this product from clinicians with prostate cancer patients whose cancer was not visible with currently approved PSMA diagnostic agents or conventional imaging (such as CT and/or MRI). Their patients were successfully imaged with 64Cu SAR-Bombesin under a Special Access Scheme.

Approximately 20% of prostate cancers with BCR are PSMA-PET negative1-4. These patients are therefore unlikely to respond to therapeutic PSMA-targeted products and currently have few treatment options available to them. Given the prostate cancer indication is one of the largest in oncology, there is a significant unmet medical need in this segment. The SAR-Bombesin product targets the Gastrin Releasing Peptide receptor (GRPr) found on prostate and many other cancers. As such, the product could offer valuable imaging and therapeutic options for not only PSMA negative patients, but also the large number of patients that have the target receptor on their cancers.

"We look forward to further progressing the development of SAR-Bombesin and hope it will provide a new and effective diagnostic option for prostate cancer patients. Building on the promising clinical and preclinical data acquired to date, we are also planning an IND submission for a theranostic trial in prostate cancer participants, using 67Cu SAR-Bombesin therapy paired with the imaging agent, 64Cu SAR-Bombesin. Combined with the clinical, environmental and logistical benefits enabled by the copper isotope pairing, SAR-Bombesin has potential to provide this large patient population with accurate and precise detection and treatment of prostate cancer. We anticipate the SABRE trial to commence shortly and the theranostic trial to commence in 2023," Dr Taylor added.

This announcement has been authorised for release by the Executive Chairman.

On June 6, 2022 Novartis reported Tafinlar (dabrafenib) + Mekinist (trametinib) significantly improved efficacy in patients ages 1 to 17 years old with BRAF V600 pediatric low-grade glioma (pLGG) requiring first systemic treatment compared to chemotherapy, the current standard-of-care for these patients1 (Press release, Novartis, JUN 6, 2022, View Source [SID1234615640]). In this study, patients randomized to receive Tafinlar + Mekinist experienced a statistically significant overall response rate (ORR) of 47% (CI: 35-59%) compared to 11% (CI: 3-25%, p<0.001) for those randomized to receive chemotherapy. A new liquid formulation of Tafinlar + Mekinist that can be easier to administer than chemotherapy was used in this trial. The data will be highlighted today as part of an official press briefing and oral presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #LBA2002).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These results show dabrafenib and trametinib demonstrate an improvement over chemotherapy for children and adolescents with BRAF V600 low-grade gliomas," said Eric Bouffet, MD, FRCPC, Senior Associate Scientist Emeritus at The Hospital for Sick Children (SickKids) in Toronto, Canada. "This work highlights the importance of testing for mutations like BRAF in patients with low-grade gliomas."

LGG is the most common pediatric brain cancer and BRAF V600 mutations are present in 15-20% of pLGGs2,5. Currently, standard chemotherapy is associated with poor outcomes and a high burden of care6.

Additional results from the Phase II/III trial showed at a median follow-up of 18.9 months, median progression-free survival (PFS) was 20.1 months with Tafinlar + Mekinist (CI: 12.8 months-not estimable) compared to 7.4 months with chemotherapy (CI: 3.6-11.8 months, hazard ratio=0.31 [CI: 0.17-0.55] [p<0.001])1. Additionally, tumors shrank or remained stable in 86% of patients in the Tafinlar + Mekinist arm (n=73; CI: 76-93%) compared to 46% of patients in the chemotherapy arm (n=37; CI: 30-63%). After one year of follow-up, nearly all patients on Tafinlar + Mekinist (89%) had a reduction in tumor size compared with baseline versus 70% of patients in the chemotherapy arm. Results from a quality-of-life analysis favored Tafinlar + Mekinist compared to chemotherapy at all time points1.

"These young patients and their families experience a heavy burden of care as BRAF V600 low-grade glioma poses a risk of neurological impairment and current standard-of-care treatment is intravenous and associated with frequent trips to the cancer clinic or hospital," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development at Novartis. "Tafinlar + Mekinist has shown unprecedented efficacy, and we will work with health authorities to bring these children the possibility of a more effective and easier to administer liquid oral treatment option as quickly as possible."

The safety profile of Tafinlar + Mekinist was generally consistent with established safety observed in previous studies. Patients in the Tafinlar + Mekinist arm had fewer grade 3 or higher adverse events (AEs; 47% vs 94%) and fewer discontinuations due to AEs (4% vs 18%) than patients in the chemotherapy arm evaluated for safety (n=33)1. The most frequent AEs in the Tafinlar + Mekinist arm were pyrexia, headache and vomiting1.

In a separate single-arm cohort of this study evaluating pediatric patients with relapsed or refractory BRAF V600 high-grade gliomas (HGG), treatment with Tafinlar + Mekinist showed an independently assessed ORR of 56.1% [CI: 39.7%-71.5%] and generally consistent safety results4. These data were presented in a poster discussion at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting (Abstract #2009).

Tafinlar + Mekinist was granted Breakthrough Therapy designation by the US Food and Drug Administration for the treatment of pediatric patients one year of age and older with LGG with a BRAF V600E mutation who require systemic therapy.

About the TADPOLE trial
This global Phase II/III, multicenter, open-label trial is evaluating patients aged 1 to 17 with BRAF V600 LGG (n=110) or relapsed or refractory HGG (n=41)1. Tafinlar + Mekinist is administered orally either as new liquid formulations, or as capsules and tablets, respectively. The primary endpoint in both cohorts is overall response rate. Secondary outcome measures include duration of response, progression-free survival, overall survival and other endpoints1.

About pediatric gliomas
Gliomas are the most common pediatric central nervous system tumor type, representing about half of all pediatric brain cancers5,7,8. Gliomas are classified as either low-grade (grades 1 and 2) or high-grade (grades 3 and 4)7.

Pediatric low-grade gliomas positive for the BRAF V600E mutation have been associated with worse survival outcomes (OS/PFS) and are found in approximately 15-20% of pLGG2,3. BRAF mutations are found in approximately 3% to 7% of people with HGG (all ages combined)9,10.

BRAF mutations have been identified as drivers of cancer growth across a wide range of solid tumors and often have limited treatment options11,12.

About Tafinlar + Mekinist
The combination of Tafinlar + Mekinist, the worldwide targeted therapy leader in BRAF/MEK-inhibition research and patients reached, may help to slow tumor growth by blocking signals associated with the BRAF and MEK kinases, which are implicated in the growth of various types of cancer11-15. Tafinlar + Mekinist has been studied in more than 6,000 BRAF-positive patients in more than 20 ongoing and completed trials and has been prescribed to more than 200,000 patients worldwide15.

Tafinlar + Mekinist is currently not approved for pediatric patients with LGG or HGG. These results will form the basis of regulatory discussions with global health authorities.

On June 6, 2022 AnHeart Therapeutics ("AnHeart"), a clinical-stage global biopharmaceutical company committed to developing novel precision oncology therapeutics, and Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that updated efficacy and safety data from the Phase 2 TRUST clinical trial of taletrectinib in patients with ROS1-positive non-small cell lung cancer (NSCLC), at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, AnHeart Therapeutics, JUN 6, 2022, View Source [SID1234615657]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Efficacy and Safety of Taletrectinib in TKI-naïve or Crizotinib-pretreated ROS1-positive Non-Small Cell Lung Cancer (NSCLC) Patients

Poster Presentation, Abstract #: 8572

The ongoing TRUST study (NCT04395677) is a multicenter, open-label, single-arm, Phase 2 study of taletrectinib in Chinese ROS1-positive NSCLC patients who are ROS1 tyrosine kinase inhibitor (TKI)-naive or crizotinib-pretreated.

As of February 23, 2022, the Phase 2 TRUST study has enrolled 67 TKI-naive and 42 crizotinib-pretreated patients. The patients were treated with taletrectinib 600 mg once daily and evaluated by independent review committee (IRC) for key efficacy endpoints including objective response rate (ORR), duration of response (DOR), disease control rate (DCR), intracranial objective response rate (IC-ORR), intracranial disease control rate (IC-DCR), progression-free survival (PFS), overall survival (OS), and safety.

In ROS1 TKI-naïve patients, the cORR was 92.5% (62/67), including 2 confirmed complete response (cCR); and DCR was 95.5% (64/67).
In crizotinib-pretreated patients, the cORR was 50% (19/38), DCR was 78.9% (30/38).
Of the 5 crizotinib-pretreated patients who had ROS1 G2032R mutation, 4 achieved cPR, and 1 achieved SD.
Of the 12 patients with brain metastasis and measurable brain lesions at baseline, the IC-ORR and IC-DCR were 91.7% and 100%, respectively. The brain tumors disappeared completely in one patient who had only non-measurable brain lesions at baseline.
Taletrectinib was generally well tolerated. Most treatment emergent adverse events (TEAEs) were Grade 1 or 2. The most frequently reported treatment-related adverse events (TRAEs) for patients on taletrectinib were low-grade diarrhea and transient AST/ALT elevation without increase in bilirubin. Low incidence of neurological AEs was reported. The selective inhibition of ROS1 over TRKB by taletrectinib may help significantly reduce TRKB-related CNS adverse events. Some common adverse events that are frequently reported in other ROS1 inhibitors, such as vision disorders, edema, headache, dizziness, and musculoskeletal disorders were observed less frequently in taletrectinib.
"Taletrectinib is a potential best-in-class next-generation ROS1 inhibitor that is a much-needed new option to treat both ROS1-TKI-naïve and pre-treated NSCLC patients," said Dr. Caicun Zhou, primary investigator and chief oncologist at Shanghai Pulmonary Hospital. "The TRUST study showed high objective response rates in both the first-line and second-line settings in ROS1-positive NSCLC, with excellent potency against crizotinib-resistant mutations, including G2032R solvent front mutation. We’re excited to see that taletrectinib has also demonstrated intracranial antitumor activity in patients with brain metastases."

"Taletrectinib reported better brain penetration and intracranial activity in reference to other ROS1 inhibitors, with a favorable safety profile," said Dr. Bing Yan, Global Chief Medical Officer and Co-Founder of AnHeart. "We look forward to advancing taletrectinib, as we believe it is a potential best-in-class next-generation ROS1 inhibitor for both ROS1 TKI-naïve and ROS1 TKI-pretreated NSCLC patients, who are in need for new therapeutic options that have antitumor activity against resistant mutations and brain metastases."

"The updated ORR and DCR data of taletrectinib demonstrated its potential superior benefits in terms of both efficacy and safety for Chinese patients with ROS1-positive NSCLC," said Dr. Hui Zhou, Senior Vice President of Innovent. "We are encouraged by the results and will move towards further clinical development of taletrectinib to explore the potential of the next-generation ROS1 inhibitor and benefit more NSCLC patients in the future."

ROS1 oncogenic fusions are observed in ~1-2% NSCLC patients as well as in cholangiocarcinoma, glioblastoma, ovarian, gastric, and colorectal cancers. CNS metastasis occurs in 20-30% ROS1 TKI-naïve and in up to 50% of crizotinib-pretreated ROS1-positive NSCLC patients. Resistance to first-generation ROS1 inhibitors often occurs with secondary mutations such as ROS1 G2032R solvent front mutation, for which no FDA-approved therapy is available.

Taletrectinib is a next-generation, CNS-penetrant, selective ROS1 inhibitor. In March 2022, the NMPA grants Breakthrough Therapy Designation (BTD) to taletrectinib for both first-line TKI-naïve and second-line TKI-pretreated patients with ROS1-positive NSCLC.

A separate global Phase 2 trial TRUST-II (NCT04919811) is actively enrolling patients at clinical sites in North America, Europe and Asia. The design of the TRUST-II study is presented in the poster (#TPS8601) at ASCO (Free ASCO Whitepaper) 2022.

ABOUT TALETRECTINIB

Taletrectinib1 is a novel best-in-class next-generation ROS1 inhibitor designed to effectively target ROS1 fusions with potential to treat both TKI-naïve and pre-treated patients. ROS1 rearrangement is estimated to be an oncogenic driver in approximately 1 to 2 percent of patients with NSCLC. ROS1 fusions are also observed in several other cancers such as cholangiocarcinoma, glioblastoma, ovarian, gastric, and colorectal cancers. Taletrectinib has demonstrated excellent potency against crizotinib resistance, good brain penetration and intracranial antitumor activity, and favorable safety profiles in ROS1 fusion-positive NSCLC patients. In these patients, few neurological adverse events were observed, which likely benefits from the selective inhibition of ROS1 over TRKB by taletrectinib. More information about the ongoing China TRUST (Taletrectinib ROS1 LUng STudy) phase 2 trial and the global TRUST-II phase 2 trial may be found by searching clinical trial identifiers NCT04395677 and NCT04919811, respectively at View Source For questions about the ongoing trials, please contact [email protected].

On June 6, 2022 CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, reported that at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, the Company presented two posters with study results for CT041, an autologous CAR T-cell product candidate against protein Claudin18.2 (CLDN18.2) (Press release, Carsgen Therapeutics, JUN 6, 2022, View Source;301561407.html [SID1234615673]). The two posters included (1) results from the multicenter Phase 1b CT041 trial in the U.S. for patients with advanced gastric and pancreatic adenocarcinoma and (2) the safety and preliminary efficacy results from the Phase Ib/II CT041 study in China for patients with advanced gastric/gastroesophageal junction adenocarcinoma.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The abstracts of the posters are listed below:

Abstract #2538: Multicenter Phase 1b Trial of Salvage CT041 CLDN18.2 – specific Chimeric Antigen Receptor T Cell Therapy for Patients with Advanced Gastric and Pancreatic Adenocarcinoma

A single-arm, open-label, Phase 1b trial (NCT04404595) was conducted in six centers in the U.S. CLDN18.2 positive patients who had gastric cancer or gastroesophageal junction cancer (GC/GEJ) with ≥ 2 prior lines of systemic therapy or pancreatic cancer (PC) with ≥ 1 prior line were eligible for the study. A preconditioning regimen with fludarabine, cyclophosphamide, and nab-paclitaxel (100 mg or 100 mg/m2; FNC) was given prior to CT041 infusion. Adverse events (AEs) were graded per CTCAE v5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by ASTCT criteria. Tumor response was assessed per RECIST 1.1.

As of May 6, 2022, 14 patients had enrolled (5 GC/GEJ, 9 PC) with a median of 3 prior lines of therapy (range 1-5) and had received 18 total cycles of CT041. Fourteen patients were given by three dose levels (DL) including DL1 of 2.5-3.0×108 cells (n=6), DL2 of 3.75-4.0×108 cells (n=6) and DL3 of 6.0×108 cells (n=2).

Safety

No dose-limiting toxicities or treatment-related deaths were observed. No ≥ Grade 3 CRS or ICANS was observed. No gastrointestinal bleeding or acute gastric mucosal injury were reported. One patient did not have CRS. Among the 13 patients with CRS, 11 patients had Grade 1 and 2 patients had Grade 2.

Efficacy

In a subgroup of patients with GC/GEJ, an objective response rate (ORR) of 60% was reported, and one patient achieved complete response (CR). Additionally, tumor shrinkage was observed in 80% (4 of 5) of patients with stable disease (4 patients with PC). Median duration of response (mDOR) and progression-free survival (mPFS) have not been reached. Two patients who received DL3 did not have tumor response assessments by the data cutoff date. Dose-dependent responses were observed in DL1 and DL2. An ORR of 16.7% and a disease control rate (DCR) of 50% was observed in DL1. An ORR of 33.3% and a DCR of 83.3% were observed in DL2. Tumor response details are listed in the table below.

Tumor response by tumor type

GC/GEJ (n=5)

n (%)

PC (n=7)

n (%)

Complete response

1 (20)

0 (0)

Partial response

2 (40)

0 (0)

Stable disease

1 (20)

4 (57.1)

Progressive disease

1 (20)

3 (42.9)

Note: GC/GEJ= gastric cancer or gastroesophageal junction cancer; PC=pancreatic cancer.

Conclusion

In heavily pre-treated gastric cancer, CT041 CLDN18.2 CAR T cells may have significantly improved antitumor activity compared to historical treatment regimens.

Abstract #4017 Safety, Tolerability and Preliminary Efficacy Results in Patients with Advanced Gastric/Gastroesophageal Junction Adenocarcinoma from a Phase Ib/II Study of CLDN18.2 CAR T-cell Therapy (CT041)

This multicenter, open-label, Phase Ib/II study (NCT04581473) was conducted to evaluate the safety and efficacy in Chinese patients with GC/GEJ. In Phase Ib, CT041 dose levels of 2.5×108 and 3.75×108 cells were investigated using a 3 + 3 design.

Key eligibility criteria for the Phase Ib study: patients with CLDN18.2-positive expression confirmed by immunohistochemistry (IHC) staining (2+/3+ in ≥40% tumor cells), advanced GC/GEJ adenocarcinoma who were refractory to or intolerant of at least 2 prior treatments are eligible for this study. HER2–positive patients should have received standard anti–HER2 therapy.

As of December 22, 2021, 14 eligible patients with GC/GEJ were enrolled in Phase Ib, among which 57.1% had ≥ 3 metastatic organs and 92.9% had peritoneal dissemination. Most of the patients (85.7%) had received 2 prior treatments or a triple combination of fluoropyrimidine, oxaliplatin and paclitaxel. 35.7% of the patients had been exposed to PD-1/PD-L1 inhibitor. The baseline characteristics are shown in the table below.

Demographics and baseline characteristics

Total (N = 14)

Median age (range), year

44.5 (23–71)

Male, n (%)

6 (42.9%)

Eastern Cooperative Oncology Group performance status=1, n (%)

12 (85.7%)

Lauren classification, n (%)

Intestinal type

3 (21.4%)

Diffuse type

9 (64.3%)

Mixed type

2 (14.3%)

Signet ring cell carcinoma, n (%)

9 (64.3%)

Claudin18.2 staining, n (%)

2+

2 (14.3%)

3+

12 (85.7%)

HER2 expression, n (%)

Positive

1 (7.1%)

Negative

12 (85.7%)

Unknown

1 (7.1%)

Numbers of metastatic organs, n (%)

< 3

6 (42.9%)

≥ 3

8 (57.1%)

Peritoneal metastasis, n (%)

13 (92.9%)

Liver metastasis, n (%)

3 (21.4%)

Numbers of prior lines, n (%)

2*

12 (85.7%)

≥ 3

2 (14.3%)

Prior systemic therapies, n (%)

Fluorouracil

14 (100%)

Platinum

14 (100%)

Paclitaxel / nab–paclitaxel

13 (92.9%)

PD–1/PD-L1 inhibitor

5 (35.7%)

Tyrosine–kinase inhibitor

2 (14.3%)

* Five patients received a triple combination of fluoropyrimidine, oxaliplatin and paclitaxel as first line treatment.

All 14 patients received 1 cycle of bridging chemotherapy determined by the investigators, including 13 patients (92.9%) received FOLFIRI, and only 1 received 5–FU plus intraperitoneal nab–paclitaxel. All patients received preconditioning treatment (fludarabine 25 mg/m2 on d1–2, cyclophosphamide 250 mg/m2 on d1–3 and nab–paclitaxel 100 mg on d2) before CT041 infusion. All patients received at least one infusion (11 received 2.5×108 cells and 3 received 3.75×108 cells) of CT041 and 7 patients received two infusions. For the 7 patients who received two infusions, the median interval between infusions was 132 days (range 49–252 days).

Safety

No patients had dose–limiting toxicities or AEs leading to death. Thirteen patients had Grade 2 CRS, and only one patient had Grade 4 CRS, which was related to the patient’s disease burden, who fully recovered after corticosteroid treatment. No ICANS or gastrointestinal mucosal injury were reported.

Efficacy

Thirteen patients were evaluable and one patient withdrew from the study before any tumor assessment was performed. Eight of 14 (57.1%) patients achieved partial response at the first tumor assessment after the first CT041 infusion. Based on the investigators’ assessment, the ORR and DCR were 57.1% and 78.6% respectively.

While the median follow-up time was 8.8 months, the mPFS and median overall survival were 5.6 months and 10.8 months respectively. Seven patients were still alive by the cutoff date.

Conclusion

These preliminary results suggest that CT041 had manageable safety/tolerability profile and promising efficacy in patients with previously treated advanced GC/GEJ adenocarcinoma. This study is ongoing with further investigation of CT041 in confirmatory Phase II underway.

Dr. Raffaele Baffa, Chief Medical Officer of CARsgen Therapeutics Holdings Limited, said, "Solid tumors, including gastric cancer, are of high incidence globally. As treatment options for gastric cancer are still limited, there is a strong need for more innovative therapies. The updated clinical data of CT041 at ASCO (Free ASCO Whitepaper) 2022 are very encouraging in pre-treated GC/GEJ and PC patients, demonstrating significant efficacy and excellent tolerability, including the impressive ORR of 60% and a case of CR. We look forward to the continuing development of CT041 and we believe it can help more patients."

Dr. Zonghai Li, Founder, Chairman of the Board, Chief Executive Officer, and Chief Scientific Officer of CARsgen Therapeutics Holdings Limited, said, "It is the first time that we presented the data for CT041 from registrational trials in China and the U.S. Following the publication of the results of an investigator-initiated trial of CT041 in Nature Medicine earlier in May, the updated results announced at ASCO (Free ASCO Whitepaper) 2022 further demonstrated the promising therapeutic efficacy and favorable safety of CT041. CT041 is currently the only CAR T-cell product candidate entering a confirmatory Phase II clinical trial for the treatment of solid tumors. We will spare no efforts to continue driving the global clinical development of CT041 to benefit more cancer patients worldwide."

About CT041

CT041 is an autologous CAR T-cell product candidate against the protein CLDN18.2 that has the potential to be the first-in-class globally. CT041 targets the treatment of CLDN18.2 positive solid tumors with a primary focus on GC/GEJ and PC. CT041 has demonstrated promising therapeutic efficacy and favorable safety in ongoing clinical trials. CARsgen believes that CT041 has the potential to become a backbone therapy for GC/GEJ and PC in the future and benefit a large population of patients worldwide.

As of the date of the announcement, CT041 is the only CLDN18.2-targeted CAR T-cell product candidate globally that is being studied in clinical trials with IND/CTA approvals from the FDA, the NMPA and Health Canada.

Active trials in CARsgen include investigator-initiated trials, a Phase Ib clinical trial for advanced GC/GEJ and PC and a confirmatory Phase II clinical trial for advanced GC/GEJ in China (CT041-ST-01, NCT04581473), and a Phase 1b/2 clinical trial for advanced gastric or pancreatic adenocarcinoma in North America (CT041-ST-02, NCT04404595). CARsgen also intends to conduct a pivotal Phase 2 clinical trial in North America in 2022.

In May 2022, the phase I trial interim results of an investigator-initiated trial of CT041 have been published in Nature Medicine. In this largest clinical trial for solid tumors to date, the CAR T-cell therapy showed unprecedented efficacy against solid tumors.

In 2020 and 2021, CT041 received Orphan Drug designation from the U.S. FDA for the treatment of GC/GEJ and Orphan Medicinal Product designation from the EMA for the treatment of advanced gastric cancer. In November 2021, CT041 was granted PRIME Eligibility by the EMA for the treatment of advanced gastric cancer. In January 2022, CT041 was granted Regenerative Medicine Advanced Therapy (RMAT) Designation by U.S. FDA for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma with CLDN18.2 positive tumors.