On May 25, 2023 Antengene Corporation Limited ("Antengene" SEHK: 6996.HK), a leading innovative, commercial-stage global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for cancer, reported that the latest results from the Phase I/II TORCH-2 study will be presented as a poster at the 2023 American Society for Clinical Oncology Annual Meeting (ASCO 2023) taking place from June 2nd to 6th, 2023 at the McCormick Place Convention Center in Chicago, IL (Press release, Antengene, MAY 25, 2023, View Source [SID1234632097]). Being among the 22 China studies selected for Poster Discussions this year, the abstract will also be presented in a Poster Discussion session on June 3rd.

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"It is our pleasure to have the latest results from the TORCH-2 study selected for Poster Discussion at ASCO (Free ASCO Whitepaper) 2023," said Dr. Amily Zhang, Antengene’s Chief Medical Officer. "Going forward, we will maintain close collaboration with the investigator team of the TORCH-2 study and liaise with regulatory authorities in China and other APAC markets to align on a registration path in cervical cancer and to continue evaluating the combination in additional ongoing studies in other solid tumors."

The TORCH-2 study is a Phase I/II trial of the mTORC1/2 inhibitor ATG-008 plus the Anti-PD-1 monoclonal antibody toripalimab for the treatment of patients with advanced solid tumors. The study enrolled 46 patients, including 21 patients with cervical cancer, to evaluate ATG-008 at three doses (15, 20 and 30 mg) in combination with the standard dose of toripalimab. Study patients had advanced solid tumors with a baseline Eastern Cooperative Oncology Group (ECOG) score of 0-1 (the majority scored 1 on the ECOG scale) and a median of 2 lines of therapy (range:0-7). Median patient age was 53 years. Patients with prior PI3K/AKT/mTOR therapy were excluded. Pharmacokinetics and exploratory biomarkers of drug activity were also evaluated. The data are presented as of the cut-off date of October 21st, 2022.

Poster Details
Title: A phase I/II study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors

Abstract: 2526
Session: Developmental Therapeutics – Immunotherapy
Poster: 368
Poster Discussion Session Date and Time: 3:00 PM – 4:30 PM, June 3, 2023 (Central Time) / 4:00 AM – 5:30 AM, June 4, 2023 (Beijing Time)

52.4% ORR in the Cervical Cancer Cohort: Among the 21 patients in the cervical cancer cohort, 1 patient with negative PD-L1 expression experienced a CR and 9 patients experienced a partial response (PR). Note that the patient who achieved a CR in this cohort remained on treatment for more than 883 days and is on treatment with single agent ATG-008 as of the cut-off date. The mPFS for the cohort was 7.2 months.
Additional Responses in Patients with Nasopharyngeal Carcinoma (NPC): The study reported one additional PR in a patient with NPC; this patient remained on study for over two years.
Recommended Phase II Dose (RP2D) was Defined: The RP2D for ATG-008 was determined to be 15 mg in combination with toripalimab.
Safety Evaluation Did Not Identify any Dose-Limiting Toxicity (DLT) or Maximum Tolerated Dose (MTD) from the Dose Escalation Phase: The study did not identify any DLT or reach the MTD; 97.8% of patients had more than one treatment emergent adverse event (TEAE) and 69.6% of patients had TEAEs > grade 3, most common of which were decreased lymphocytes (23.9%), rash (10.6%) and hyperglycemia (10.9%). Pharmacokinetic profiles of ATG-008 in combination with toripalimab were similar to ATG-008 monotherapy across APAC and US patients. No new safety signals were reported.
About ATG-008

ATG-008 (onatasertib) is an orally available mTORC 1/2 inhibitor. ATG-008 inhibits the activity of mTOR, which may result in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR, a serine/threonine kinase that is upregulated in a variety of tumors, has an important role in the PI3K/AKT/mTOR signaling pathway, which is frequently dysregulated in human cancers. ATG-008 has been studied in clinical trials to treat a broad range of tumor types including multiple myeloma (MM), glioblastoma (GBM), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), diffuse large B-cell lymphoma (DLBCL), etc.

On May 25, 2023 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that 4 of its abstracts were selected for presentations at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Ascentage Pharma, MAY 25, 2023, View Source [SID1234632096]). These studies report on four of the company’s lead drug candidates, including the first and only China-approved third-generation Bcr-Abl inhibitor, olverembatinib (HQP1351), Bcl-2 selective inhibitor, lisaftoclax (APG-2575), MDM2-p53 inhibitor, alrizomadlin (APG-115), and FAK/ALK/ROS1 inhibitor, APG-2449.

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The ASCO (Free ASCO Whitepaper) Annual Meeting showcases the most cutting-edge research in clinical oncology and state-of-the-art advanced cancer therapies and is the world’s most influential and prominent scientific gathering of the clinical oncology community. This year’s ASCO (Free ASCO Whitepaper) Annual Meeting will take place both online and in-person at the McCormick Place, Chicago, IL, United States, on June 2–6, 2023.

"We are pleased to have the opportunity to release the updated clinical results on four of our lead drug candidates and showcase our capabilities in global innovation and clinical development at the ASCO (Free ASCO Whitepaper) Annual Meeting, one of the most prominent medical congresses in the world," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Moving forward, we will continue to accelerate these clinical development programs globally in the hope of benefitting more patients around the world as soon as possible."

These four clinical studies to be presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting are as follows:

Drug Candidate

Abstract Title

Abstract #

Format

APG-2449

FAK inhibition with novel FAK/ALK inhibitor APG-2449 could overcome resistance in NSCLC patients who are resistant to second-generation ALK inhibitors.

#9015

Poster Discussion

Olverembatinib

(HQP1351)

Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)- resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST).

#11540

Poster Presentation

APG-2575

(Lisaftoclax)

Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

#7569

Poster Presentation

APG-115

(Alrizomadlin)

A phase 2 study of alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic cutaneous melanoma that has failed immuno-oncologic (IO) drugs.

#9559

Poster

Presentation

Poster Discussion

APG-2449

FAK inhibition with novel FAK/ALK inhibitor APG-2449 could overcome resistance in NSCLC patients who are resistant to second-generation ALK inhibitors

Abstract#: 9015
Poster Board#: 3
Date and Time: June 4, 2023, Sunday, 4:30 PM – 6:00 PM (Central Time) / June 5, 2023, Monday, 5:30 AM – 7:00 AM (Beijing Time)
Session Title: Lung Cancer—Non-Small Cell Metastatic
Highlights
This open-label, multicenter, Phase I dose-escalation and dose-expansion study was designed to evaluate the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of APG-2449 in patients with ALK/ROS1+ NSCLC or other solid tumors.
As of December 9, 2022, 130 patients were enrolled and treated with APG-2449 at doses ranging from 900 to1,500 mg. The median (range) age of these patients was 53 (21-78) years and 53.8% of them were female. After 1,200 mg daily (QD) was determined as the recommended Phase II dose (RP2D), patients with NSCLC were enrolled into 2 dose-expansion cohorts. Among them, Cohort 1 included patients who were resistant to second-generation ALK/ROS1+ tyrosine kinase inhibitors (TKIs), while Cohort 2 included those who were ALK/ROS1+ TKI-naïve.
Efficacy Results: In the subgroup of patients with TKI-naïve NSCLC (n = 33; 31 were efficacy evaluable), the overall response rate (ORR) and disease control rate (DCR = complete response [CR] rate + partial response [PR] rate + stable diseases [SD] rate) were 70.6% (12/17) and 88.2% (15/17), respectively, in ROS1+ treatment-naïve patients; and were 78.6% (11/14) and 100% (14/14) in ALK+ treatment-naïve patients. Among the 27 patients with ALK+ NSCLC that was resistant to second-generation ALK inhibitors, 7 achieved PR (7/27; 25.9%) when treated with APG-2449 at the RP2D.
Analysis of FAK Expressions: Among the 27 patients with ALK+ NSCLC that was resistant to second-generation ALK inhibitors, compared to baseline, those who experienced PR showed lower phosphorylated FAK (pFAK) levels in peripheral blood mononuclear cells (PBMCs) by Day 28 (24 hours after dosing on Day 28) than patients who experienced SD. Furthermore, patients with progressive disease showed an increase in PBMC pFAK levels on Day 28 compared to baseline, indicating that APG-2449 could inhibit FAK phosphorylation. Meanwhile, patients with higher pFAK expression in tumor tissues at baseline tended to achieve better clinical responses than those with lower pFAK expression after APG-2449 treatment.
Safety Results: A total of 117 (90%) patients experienced treatment-related adverse events (TRAEs) with the most frequent TRAEs being elevated blood creatinine (43.8%), elevated alanine aminotransferase (ALT) (40.8%), and aspartate aminotransferase (AST) (33.1%), as well as gastrointestinal disorders that included nausea (25.4%), vomiting (21.5%), and diarrhea (21.5%). A total of 17 (13.1%) TRAEs were grade≥3.
Conclusions: APG-2449 showed a favourable preliminary safety profile and antitumor efficacy in patients with NSCLC. Preliminary efficacy was observed in patients who were TKI-naïve and resistant to second-generation ALK inhibitors. FAK inhibition could be a novel approach to overcome ALK resistance in patients with NSCLC that is resistant to second-generation ALK inhibitors.
Poster Presentation

HQP1351 (Olverembatinib)

Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor- (TKI)- resistant succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST)

Abstract#: 11540
Poster Board#: 474
Date and Time: June 3, 2023, Saturday, 1:15 PM – 4:15 PM (Central Time) / June 4, 2022, Sunday, 2:15 AM – 5:15 AM (Beijing Time)
Session Title: Sarcoma
Highlights
This open-label, multicenter Phase Ib/II study in China was designed to evaluate the safety, tolerability, PK, and antitumor activity of olverembatinib in patients with TKI-resistant locally advanced or metastatic GIST.
As of January 15, 2023, a total of 20 patients with SDH-deficient GIST were enrolled in the study. The median (range) age of these patients was 30 (14-56) years. Olverembatinib, at doses ranging from 20 to 50 mg (50 mg cohort [n=6]; 40 mg cohort [n=8]; 30 mg cohort [n=6]), was administered once every other day (QOD) in 28-day cycles.
Efficacy Results: The median duration of treatment in the 20 patients with SDH-deficient GIST was 7.8 (1.81-42.3) months. A total of 5 of these patients experienced PRs. Of the 16 evaluable patients who were treated with olverembatinib for 16 weeks or more, the clinical benefit rate (CBR=CR+PR+SD > 16 weeks) was 93.8% (15/16) and the longest treatment duration was 42 months.
Safety Results: All patients experienced at least one treatment-emergent adverse event (TEAE), most of which were grade 1 or 2; 2 patients experienced grade 3 AEs; and the only hematologic AE with an incidence rate≥20% was anemia (55%). A total of 15 (75%) patients experienced TRAEs, including 1 patient who experienced a grade 3 TRAE (neutropenia). No serious TRAEs were reported during the study.
Conclusions: Olverembatinib was well-tolerated up to 50 mg QOD and showed antitumor activity in patients with TKI-resistant SDH-deficient GIST. A total of 5 (25%) PRs were reported among 20 evaluable patients; the 16 patients treated for ≥16 weeks achieved a CBR of 93.8%. These promising findings warrant further investigation.
Lisaftoclax (APG-2575)

Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

Abstract#: 7569
Poster Board#: 120
Date and Time: June 5, 2023, Monday, 8:00 AM (Central Time) / June 5, 2023, Monday, 9:00 PM (Beijing Time)
Session Title: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia
Highlights：
This open-label, multicenter, global Phase Ib/II study was designed to evaluate the safety, tolerability, efficacy, and PK of the orally administered high-selective novel Bcl-2 inhibitor lisaftoclax as monotherapy or in combination with ibrutinib or rituximab in patients with WM.
As of January 25, 2023, a total of 46 patients were enrolled in the study and later enrolled into 3 arms as follows:
Arm A: lisaftoclax monotherapy in patients with WM resistant/intolerant to Bruton tyrosine kinase inhibitors (BTKi) (n=14)
Arm B: lisaftoclax plus ibrutinib in treatment-naïve patients (n=24)
Arm C: lisaftoclax plus rituximab in ibrutinib and other BTKi-naïve relapsed/refractory patients (n=8)

The dose of lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval-2 (mTPI-2) design. Doses in Arms A, B, and C were escalated to up to 1,000 mg, 1,200 mg, and 800 mg, respectively.
Efficacy Results: The ORR (PR and deeper responses) and median time to response (MTTR) for Arms A, B, and C were 25%, 90.9%, and 37.5%; and 4.3, 1.9, and 4.4 months, respectively. The study did not observe any significant difference between patients with and without the CXCR4 mutation.
Safety Results: At 1,200 mg, 1 grade 3 dose-limiting toxicity (DLT) (grade 3 tumor lysis syndrome [TLS]) due to pre-existing renal impairment was observed in Arm B. At 1,000 mg, 1 grade 3 laboratory TLS occurred in Arm B because of dehydration and active symptomatic recurrence. Abnormal electrolytes in this patient was resolved after 1 day of drug intervention and the AE did not recur. Grade≥3 lisaftoclax-related AEs included neutropenia (13%), leukocytopenia (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmias were not observed. The PK data indicated no drug- drug interaction (DDI) between lisaftoclax and ibrutinib.
Conclusions: Lisaftoclax alone or combined with ibrutinib/rituximab demonstrated measurable effects in patients with treatment-naïve or BTKi-refractory WM.
Alrizomadlin (APG-115)

A phase 2 study of alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic cutaneous melanoma that has failed immuno-oncologic (IO) drugs.

Abstract#: 9559
Poster Board#: 322
Date and Time: June 3, 2023, Saturday, 1:15 PM – 4:15 PM (Central Time) / June 4, 2023, Sunday, 2:15 AM – 5:15 AM (Beijing Time)
Session Title: Melanoma/Skin Cancers
Highlights
This open-label, multicenter Phase Ib/II study conducted in the U.S. and Australia was designed to evaluate the safety, tolerability, PK, and antitumor activity of alrizomadlin plus pembrolizumab in patients with unresectable or metastatic cutaneous melanoma or advanced solid tumors. At the meeting, the latest Phase II efficacy and safety results from the cutaneous melanoma subgroup were released.
As of December 12, 2022, a total of 31 patients with cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy were enrolled in the study. The median (range) age of these patients was 65 (27-84) years, 21 （67.7%）of the patients were male, and 10 (32.3%) were female. Alrizomadlin 150 mg was administered QOD for 2 consecutive weeks, with 1 week off, in 21-day cycles. Pembrolizumab 200 mg was administered intravenously on day 1 of the treatment cycles.
Efficacy Results: In 26 efficacy-evaluable patients, 2 achieved CR and, 4 achieved PR, resulting in a confirmed ORR (ORR=CR+PR) of 23.1%. The initial analysis indicated that the ORR observed in patients whose disease had failed IO treatment was primarily attributable to the alrizomadlin plus pembrolizumab regimen, not the delayed effect of prior immunotherapy.
Safety Results: A total of 30 (96.8%) patients reported TRAEs, the most frequent (>10%) being nausea (71%), vomiting (38.7%), fatigue (35.5%), thrombocytopenia (32.3%), diarrhea (25.8%), neutropenia (19.4%), decreased appetite (16.1%), and decreased leukocyte count (12.9%). 4 (12.9%) patients reported serious TRAEs, including anemia, thrombocytopenia, deep vein, thrombosis, joint effusion, pulmonary embolism, and vomiting.
Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and demonstrates clinical efficacy in patients with cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy.

On May 25, 2023 Astrazeneca reported that Positive high-level results from the DUO-E Phase III trial showed Imfinzi (durvalumab) in combination with platinum-based chemotherapy followed by either Imfinzi plus Lynparza (olaparib) or Imfinzi alone as maintenance therapy both demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemotherapy alone in patients with newly diagnosed advanced or recurrent endometrial cancer (Press release, AstraZeneca, MAY 25, 2023, View Source [SID1234632095]). There was a greater clinical benefit observed with the combination of Imfinzi and Lynparza as maintenance treatment.

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Overall survival (OS) data were immature at the time of this analysis however, a favourable trend was observed for both treatment regimens.

Endometrial cancer is the 6th most common cancer in women worldwide, with over 417,000 patients diagnosed and over 97,000 deaths in 2020.1 Diagnoses are expected to rise by almost 40% by 2040.2 The current standard of care for advanced endometrial cancer is chemotherapy.3,4 However, long-term outcomes in 1st-line endometrial cancer remain poor and novel treatment options are needed.5,6

Shannon N. Westin, Professor of Gynaecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center, and principal investigator of the DUO-E trial, said: "These exciting data demonstrate durvalumab immunotherapy can significantly delay disease progression for patients with endometrial cancer and the addition of the PARP inhibitor olaparib can improve the benefit further. These combinations could provide physicians with new treatment approaches to improve outcomes for patients."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These DUO-E data demonstrate for the first time the power of combining immunotherapy and a PARP inhibitor to provide meaningful clinical improvements for patients with endometrial cancer. These results underscore our ambition to redefine cancer care and we hope to bring this innovative Imfinzi and Lynparza combination to endometrial cancer patients as soon as possible."

The safety and tolerability profile of Imfinzi plus chemotherapy and of Imfinzi in combination with Lynparza was broadly consistent with that observed in prior clinical trials and the known profiles of the individual medicines.7,8

These data will be presented at a forthcoming medical meeting, and we look forward to discussing them with health authorities.

Notes

Endometrial cancer
Endometrial cancer is a highly heterogenous disease that originates in the tissue lining of the womb and is most common in women who have already been through the menopause, with the average age at diagnosis being over 60 years old.9-11 Both the incidence and mortality of endometrial cancer are expected to increase from 417,400 cases and 97,400 deaths in 2020 to 608,130 cases and 157,813 deaths in 2040.1,2

The majority of patients with endometrial cancer are diagnosed at an early stage of disease where the cancer is confined to the uterus. They are typically treated with surgery and/or radiation and the 5-year survival rate is high (approximately 95%). However, patients with advanced disease (Stage III-IV) are usually treated with chemotherapy and have a much poorer prognosis, with a 5-year survival rate falling to around 20-30%.4,5,11,12,13

For patients where the disease has already advanced or returned, treatment options are limited as the cancer is not considered likely to respond to hormonal therapy and will be treated with chemotherapy.5,6

DUO-E
The DUO-E trial (GOG 3041/ENGOT-EN10) is a three-arm, randomised, double-blind, placebo-controlled, multicentre Phase III trial of 1st-line Imfinzi in combination with platinum-based chemotherapy (carboplatin and paclitaxel) followed by Imfinzi with Lynparza or Imfinzi alone as maintenance therapy versus platinum-based chemotherapy alone as a treatment for patients with newly diagnosed advanced or recurrent endometrial cancer.

The DUO-E trial randomised 699 patients with newly diagnosed or recurrent Stage III or IV epithelial endometrial carcinoma (excluding sarcomas) to receive either 1120mg of Imfinzi or placebo, given every three weeks in combination with standard-of-care platinum-based chemotherapy. Following cessation of chemotherapy, patients were given either 1500mg of Imfinzi or placebo every four weeks as maintenance, either in combination with 300mg BID (2x150mg tablets, twice a day) of Lynparza or placebo until progressive disease for 24 months.

The dual primary endpoint was PFS. Mismatch repair (MMR) status was one of the stratification factors. Key secondary endpoints included OS, objective response rate (ORR), duration of response (DoR) and safety and tolerability. The trial was conducted in 253 study locations across 22 countries including the US, Europe, South America and Asia.

For more information about the trial please visit ClinicalTrials.gov.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial. Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (SCLC) based on the CASPIAN Phase III trial. Additionally, Imfinzi is approved in combination with a short course of Imjudo (tremelimumab) and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial.

In addition to its indications in lung cancer, Imfinzi is also approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer in the US, EU, Japan and several other countries; in combination with Imjudo in unresectable hepatocellular carcinoma in the US, EU and Japan; and in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 150,000 patients have been treated with Imfinzi. As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal cancers and other solid tumours.

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination-related (HRR) genes, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as new hormonal agents [NHAs]).

Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.

Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA mutation (gBRCAm), HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration-resistant prostate cancer in whom chemotherapy is not clinically indicated (EU only) and as monotherapy for HRR gene-mutated metastatic castration-resistant prostate cancer in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer as well as a 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide. The companies develop Lynparza in combination with their respective PD-L1 and PD-1 medicines independently. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics and Cell Therapies – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On May 25, 2023 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics, reported that it will present additional positive data from the ongoing Phase 1 study of MP0317, a CD40 agonist designed to activate immune cells specifically within the tumor microenvironment by anchoring to fibroblast activation protein (FAP), at the 2023 ASCO (Free ASCO Whitepaper) (American Society of Clinical Oncology) Annual Meeting, held June 2–6 in Chicago, Illinois (Press release, Molecular Partners, MAY 25, 2023, View Source [SID1234632094]).

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The data demonstrate that MP0317 shows evidence of tumor-localized CD40 activation (analyses in paired tumor biopsies). The detection of MP0317 in tumors positively correlated with immune activation when comparing high vs. low doses of MP0317. This detection was associated with a statistically significant CD40-mediated increase of antigen-presenting cells and interferon γ signature. Furthermore, MP0317 has demonstrated a favorable safety profile. The current data support planning of future combination studies.

"These positive data continue to demonstrate that MP0317’s unique mechanism of action has the potential to overcome the limitations of existing therapies that target CD40 by activating only in the tumor microenvironment and therefore avoid systemic toxicities seen by other treatments," said Nicolas Leupin, MD, Ph.D., Chief Medical Officer of Molecular Partners. "MP0317 encapsulates the advantages we believe we can achieve through our DARPin platform: to design candidates to overcome biological challenges that other drug classes like antibodies cannot address. These data of the ongoing study will further support the advancement of MP0317 into later-stage clinical research with partners and highlight the potential of MP0317 for evaluation in combination settings."

"Clinical data from 36 patients with advanced solid tumors, dosed across 8 dose levels, confirms that the tumor-FAP-targeted CD40 agonist MP0317 is safe and well tolerated with limited systemic inflammation compared to other CD40 agonists," said Dr Carlos Gomez-Roca, Head of the Early Phase & Clinical Research Unit at IUCT-Oncopole Claudius Regaud at Toulouse, France, and investigator on the study. "The analysis of paired pre- and on treatment tumor biopsies as well as peripheral biomarkers provides evidence of target occupancy and pharmacodynamic modulation in the tumor microenvironment, consistent with tumor localised CD40 activation. The current data enables further evaluation of MP0317 in combination."

This ongoing first-in-human Phase 1, open-label, dose-escalation study assesses the safety and tolerability as well as pharmacokinetics/pharmacodynamics and antitumor activity of MP0317 monotherapy in patients with refractory/relapsed solid tumors known to express FAP and CD40 (NCT05098405). To date, the 36 patients enrolled in the Netherlands and France across eight dosing cohorts received MP0317 at doses of 0.03–10 mg/kg in every-3-weeks [q3w] and weekly [q1w] schedules (data cut-off 02 May 2023).

MP0317 monotherapy was seen to result in tumor-localized CD40 activation: biomarker data confirmed presence of MP0317 in the tumors of patients with evaluable pre- and on-treatment biopsies as of the cutoff date. This detection of MP0317 in tumors positively correlates when comparing high vs. low doses of MP0317 and was associated with a statistically significant CD40-mediated increase of antigen-presenting cells as well as interferon γ production within the tumor microenvironment. To date, one patient achieved an unconfirmed partial response and stable disease was observed in 5 additional patients.

The observed safety profile of MP0317 monotherapy to date is favorable. A dose-limiting toxicity was reported in one patient (transient asymptomatic Grade 3 elevation of liver enzymes), at the highest planned MP0317 dose of 10 mg/kg administered q3w.

The positive results of this ongoing Phase 1 study in patients with refractory/relapsed tumors support continued clinical evaluation of MP0317 and potential investigation in combination studies. The study continues to enroll one more cohort (q1w). For further information please see clinicaltrials.gov (NCT05098405).

The details of the poster presenting these results from the ongoing Phase 1 study at the ASCO (Free ASCO Whitepaper) 2023 Annual Meeting can be found below. The poster will be made available on Molecular Partners’ website after the presentation.

Title: Phase I study of MP0317, a FAP-dependent DARPin, for tumor-localized CD40 activation in patients with advanced solid tumors
Poster Session: Developmental Therapeutics—Immunotherapy
Abstract number: 2584
Poster number: 426
Location & Timing: Hall A; June 3, 2023; 8:00–11:00am CDT
Authors & Affiliations:
C Gomez-Roca1, N Steeghs2, E Gort3, H De Winter4, E Fernandez 4, V Stavropoulou 4, N Stojcheva 4, P Baverel 4, J Krieg 4, K Ioannou 4, A Florescu 4, P Mossi 4, L Hoenig 4, B Baud-Berthier 4, V Kirkin 4, A Goubier 4, P Legenne 4, P Cassier5

About MP0317
MP0317 targets both the FAP and the immunostimulatory protein CD40 to enable tumor-localized immune activation. Through this proposed mechanism of action, MP0317 is designed to activate immune cells specifically within the tumor microenvironment, potentially delivering greater efficacy with fewer side effects compared to systemic CD40-targeting therapies.

On May 25, 2023 Adaptimmune Therapeutics plc (NASDAQ: ADAP), a leader in cell therapy to treat cancer, reported that it will present data from Cohort 1 of its pivotal trial SPEARHEAD-1 (NCT04044768) for people with advanced synovial sarcoma at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, Adaptimmune, MAY 25, 2023, View Source [SID1234632093]). The poster, titled "The SPEARHEAD-1 trial of afamitresgene autoleucel: Analysis of overall survival in advanced synovial sarcoma," will be presented by Dr. Brian Van Tine of the Washington University School of Medicine at 1:15 p.m. CDT, Saturday, June 3rd, in Hall A, Sarcoma track.

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Dr. John Charlson of the Medical College of Wisconsin and Adaptimmune clinical trial investigator: "Engineered T-cell therapies, like afami-cel, have the potential to change the way we manage difficult to treat late-stage cancers like synovial sarcoma. The current standard-of-care treatments for synovial sarcoma were approved more than two decades ago, have limited efficacy and their dosing schedules, and resulting side effects often negatively impact patients’ lives so there is a tremendous unmet need for novel, effective treatments."

Dennis Williams, Pharm.D., Adaptimmune’s SVP of Late-Stage Development: "There is a high unmet need in late-stage solid tumor cancers and synovial sarcoma is no exception. We have reported an impressive response rate of ~39% among heavily pre-treated patients with advanced synovial sarcoma. We are seeing very meaningful survival data, especially in people who have a response after a single dose of afami-cel. Afami-cel is intended to be our first commercial product and we are developing additional products for other late-stage solid tumors including ovarian, bladder, and head & neck cancers."

Patients with advanced synovial sarcoma who received a single dose of afami-cel had meaningful survival, especially those patients with a RECIST response
There were 44 people with advanced synovial sarcoma who received afami-cel in Cohort 1 of the SPEARHEAD-1 trial. The overall response rate (ORR) by independent review per RECIST v1.1 among people with synovial sarcoma was ~39% (as reported at CTOS 2022) with 17 patients responding. The median duration of response was approximately 12 months (95% CI: 4.44 – not estimable).

An interim analysis was performed on March 29, 2023, when the median (range) follow-up time was 27.8 (16-38) months. The median overall survival was approximately 17 months and overall survival (OS) was significantly longer in patients who had a RECIST response, compared to non-responders, with a 12-month OS probability of 90% and 24-month OS probability of 70%. Median OS among responders has not been reached.

Afami-cel is on path to be Adaptimmune’s first potential commercial product
Adaptimmune has completed submission of the preclinical (Part 1) and clinical modules (Part 2) of the Biologics License Application (BLA) for afami-cel for the treatment of synovial sarcoma, which is targeted for completion in mid-2023. This BLA is supported by data from Cohort 1 of the pivotal SPEARHEAD-1 trial, which has met its primary endpoint for efficacy. For afami-cel, the FDA has provided Orphan Drug Designation (ODD) for the treatment of soft tissues and Regenerative Medicine Advanced Therapy (RMAT) designation for the treatment of synovial sarcoma.

Overview of SPEARHEAD-1 trial design
SPEARHEAD-1 is a Phase 2, open-label trial for people with advanced synovial sarcoma or myxoid/round cell liposarcoma (MRCLS) to evaluate the efficacy, safety, and tolerability of afami-cel. Afami-cel SPEAR T-cells target MAGE-A4+ tumors. MAGE-A4 is highly expressed in synovial sarcoma and MRCLS in the context of HLA-A*02.

Approximately 90 patients were planned to be treated: 45 in Cohort 1 and 45 in Cohort 2. Enrollment in both cohorts is complete. The primary efficacy analysis is for Cohort 1 only. Cohort 2 will strengthen the efficacy and safety database and will aid in descriptive sub-group analyses.

Key eligibility criteria: ECOG performance status of 0 or 1; HLA*02 positive with MAGE-A4 expression in ≥ 30% of tumor cells ≥ 2+ by immunohistochemistry; aged ≥ 16 and ≤ 75 years; and patients must have received either an anthracycline- or ifosfamide-containing regimen. Eligible patients received afami-cel doses between 1-10 × 10^9 transduced T-cells after receiving lymphodepleting chemotherapy.