On May 25, 2023 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC) reported positive results from BRACELET-1, a randomized phase 2 trial in HR+/HER2- metastatic breast cancer (Press release, Oncolytics Biotech, MAY 25, 2023, View Source [SID1234632099]). The results are published in an abstract accepted for an oral presentation at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, taking place from June 2 – 6, 2023 in Chicago, Illinois and online. The abstract is available on the ASCO (Free ASCO Whitepaper) Annual Meeting website.

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BRACELET-1 enrolled 48 patients randomized and well-balanced across three cohorts evaluating: (1) paclitaxel monotherapy; (2) paclitaxel in combination with pelareorep; and (3) paclitaxel plus pelareorep in combination with the anti-PD-L1 checkpoint inhibitor, avelumab (Bavencio). All participants enrolled in the trial previously progressed on at least one hormone-based therapy with a CDK 4/6 inhibitor.

Compared to the paclitaxel monotherapy cohort, the cohort evaluating the combination of paclitaxel plus pelareorep showed ≥50% improvements on the trial’s primary endpoint of overall response rate (ORR) at week 16 (31.3% vs. 20%) as of the ASCO (Free ASCO Whitepaper) abstract cut-off date (October 2022). This cohort also reported median progression-free survival (mPFS) of 9.6 months vs. 6.4 months as of the cut-off date. Overall survival data from the trial continue to mature. Data from this study validate the results of IND-213, a prior phase 2 trial that showed a statistically significant near doubling of median overall survival in HR+/HER2- metastatic breast cancer patients treated with pelareorep combined with paclitaxel (21.0 months, n = 28) vs. those treated with paclitaxel alone (10.8 months, n = 29).

"BRACELET-1 substantially de-risks our HR+/HER2- breast cancer program by providing a second randomized dataset showing pelareorep plus paclitaxel outperforming paclitaxel alone," said Dr. Matt Coffey, President and Chief Executive Officer. "Importantly, evidence of pelareorep’s ability to synergistically enhance paclitaxel’s efficacy has now been seen consistently across multiple clinical efficacy endpoints of overall survival, progression-free survival, and ORR. With these data, our program is phase 3-ready, and efforts to expeditiously advance to a two-arm registrational study of pelareorep-paclitaxel combination therapy are well underway. I would like to thank BRACELET-1’s participants as well as our collaborators at Pfizer, Merck KGaA, Darmstadt, Germany, and PrECOG, all of whom contributed to an important trial that will inform and accelerate pelareorep’s path to approval."

A detailed summary of BRACELET-1’s data are shown below. Updated results as of a May cut-off date will be featured in an oral presentation at the ASCO (Free ASCO Whitepaper) meeting on June 3, 2023.

Response and Progression-free Survival (October 2022 data cut-off):

Paclitaxel (PTX) Monotherapy (n=15)

PTX + Pelareorep (n=16)

PTX + Pelareorep + Avelumab (n=17)

ORR at Week 161

3 (20 %)

5 (31.3 %)

3 (17.6 %)

Disease Control Rate at Week 16 (CR+PR+SD)

7 (46.7 %)

10 (62.5 %)

12 (70.6 %)

mPFS (months)1

6.4

(95% CI: 2.0, NR)

9.6

(95% CI: 6.5, NR)

7.5

(95% CI: 3.8, NR)

6-month PFS Rate

62.5%

(95% CI: 27.6%, 84.2%)

92.9%

(95% CI: 59.1%, 99%)

73.2%

(95% CI: 42%, 89.4%)

1. Three patients who withdrew consent prior to starting therapy and two patints who discontinued treatment after week 1 were considered non-responders and censored for PFS

CI: Confidence interval; CR: Complete response; PR: Partial response; SD: Stable disease; NR: Not reached

Biomarker and Safety

A statistically significant increase in T cell fraction, a measure of T cell expansion, was observed in cohort 2 (paclitaxel + pelareorep) but not cohort 3 (paclitaxel + pelareorep + avelumab)
Pelareorep displayed an acceptable safety profile consistent with what has been observed in prior clinical trials that have collectively treated over 1,100 patients
Dr. Thomas Heineman, Chief Medical Officer, commented, "BRACELET-1 was a well-conducted study in a randomized setting that included a control arm that performed as expected and a test arm that provides significant evidence of pelareorep’s ability to provide additional meaningful clinical benefit in HR+/HER2- breast cancer patients. Mechanistic data from prior clinical trials indicate pelareorep’s anti-cancer effects are derived from its ability to reverse immunosuppressive tumor microenvironments and stimulate the expansion of anti-cancer T cells. These prior data align with BRACELET-1’s results that show an association between T cell expansion and efficacy."

Andrew de Guttadauro, President of Oncolytics Biotech U.S. and Global Head of Business Development, added, "BRACELET-1’s data greatly enhance our pipeline’s value proposition, bringing our breast cancer program to pivotal trial-readiness and confirming pelareorep’s potential to address large markets by synergistically combining with other anti-cancer agents. Looking ahead, we believe our data in breast cancer, together with the second registration opportunity offered by our pancreatic cancer program, leave us well-positioned as we continue to execute our business development efforts. To ensure we maximize value for shareholders, we remain committed to taking a disciplined and methodical approach as we further discussions with our potential partners in the biopharma community."

Details on the upcoming ASCO (Free ASCO Whitepaper) oral presentation on BRACELET-1 are shown below.

Title: BRACELET-1 (PrE0113): Inducing an Inflammatory Phenotype in Metastatic HR+/HER2- Breast Cancer with the Oncolytic Reovirus Pelareorep in Combination with Paclitaxel and Avelumab

Abstract Number: 1012

Session Type: Clinical Science Symposium

Session Title: The Dr. Bernard Fisher Memorial Annual Clinical Science Symposium Supported by the Breast Cancer Research Foundation: Harnessing the Breast Cancer Immune Response

Session Date and Time: June 3, 2023 | 1:15 p.m. – 2:45 p.m. CT

A copy of slides from the ASCO (Free ASCO Whitepaper) presentation will be available on the Posters & Publications page of Oncolytics’ website (LINK) following the conclusion of the meeting.

About BRACELET-1

The BRACELET-1 (BReast cAnCEr with the Oncolytic Reovirus PeLareorEp in CombinaTion with anti-PD-L1 and Paclitaxel) study is an open-label, phase 2, randomized study in patients with HR+/HER2-, endocrine-refractory metastatic breast cancer being conducted under a co-development agreement with Pfizer Inc. and Merck KGaA, Darmstadt, Germany. PrECOG LLC, a leading cancer research network, is managing the study. The study randomized 45 patients 1:1:1 into three cohorts. A three-patient safety run-in was also conducted with patients receiving pelareorep, paclitaxel, and avelumab prior to randomization. The three cohorts are treated as follows:

Cohort 1: paclitaxel
Cohort 2: paclitaxel + pelareorep
Cohort 3: paclitaxel + pelareorep + avelumab (Bavencio)
Patients in cohort 1 receive paclitaxel on days 1, 8, and 15 of a 28-day cycle. Patients in cohort 2 receive the same paclitaxel regimen as cohort 1, plus pelareorep on days 1, 2, 8, 9, 15 and 16 of the 28-day cycle. Patients in cohort 3 receive the same combination and dosing regimen as cohort 2, plus avelumab on days 3 and 17 of the 28-day cycle. The primary endpoint of the study is overall response rate at week 16. Exploratory endpoints include progression-free survival, peripheral and tumor T cell clonality, inflammatory markers, and safety and tolerability assessments.

On May 25, 2023 Dizal (688192.SH) reported that data from its oncology portfolio will be presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, June 2-6, 2023 in Chicago (Press release, Dizal Pharma, MAY 25, 2023, View Source [SID1234632098]). The data which include updated analyses of Dizal’s two leading assets – sunvozertinib (a selective EGFR TKI targeting a wide spectrum of EGFR mutations) and golidocitinib (a highly selective JAK1 inhibitor), underscore Dizal’s dedication to developing and delivering innovative medicines that will make a meaningful difference to people living with cancer.

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Presentation Highlights

Sunvozertinib

Dizal will present updated results of WU-KONG6, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR Exon20ins mutations in an oral session.

Patients treated with sunvozertinib (n = 97) achieved a confirmed objective response rate (cORR) of 60.8% assessed by independent review committee (IRC). Anti-tumor efficacy was observed across a broad range of EGFR Exon20ins subtypes, and tumor response was also observed in patients with pretreated and stable brain metastasis. Sunvozertinib showed significant anti-tumor efficacy and well tolerated safety profiles. These data suggest that sunvozertinib could be an effective and safe treatment option for this unmet medical need.

Golidocitinib

The clinical data of JACKPOT8 Part B, a multinational pivotal study of golidocitinib in relapsed or refractory peripheral T-cell lymphoma (r/r PTCL) will make its debut at the meeting.

PTCL is a group of heterogenous and rare non-Hodgkin lymphoma originating from mature T cells. There is no consensus on the standard treatment for r/r PTCL. Golidocitinib demonstrated promising and durable anti-tumor efficacy, making it a superior treatment option to fight against this devastating disease. This data was also accepted as an encore presentation at the 17th International Conference on Malignant Lymphoma Lugano (ICML) and will be presented orally.

In addition, two abstracts about sunvozertinib in the first line setting and heavily pretreated EGFR mutant NSCLC, respectively, were selected as poster presentations in ASCO (Free ASCO Whitepaper) 2023 annual meeting, including:

The "best-in-class" potential of sunvozertinib as a first line treatment for NSCLC patients with EGFR Exon20ins mutations.
Promising anti-tumor efficacy of sunvozertinib with median PFS of close to 6 months in heavily pretreated NSCLC patients with EGFR sensitizing mutations who failed standard EGFR TKI treatment (median 5 lines of prior therapies).
The updated data will be presented at the meeting.

"We are thrilled to have a robust presence at this year’s ASCO (Free ASCO Whitepaper) meeting, showcasing our strong portfolio and rapid acceleration of our pipeline in oncology and hematological malignancies." said Xiaolin Zhang, Ph.D., Chairman and CEO of Dizal, "Sunvozertinib has further reinforced its best-in-class position with an even higher ORR, while golidocitinib will debut its global pivotal study results, demonstrating its superior efficacy. These presentations reflect the high quality of our science and our unwavering commitment to advance cancer research and improve patient outcomes."

Select studies, along with the dates, times and locations of their data sessions, are highlighted below.

Lead Author

Abstract Title

Presentation Details

Prof. Mengzhao
Wang

Sunvozertinib for the treatment of
NSCLC with EGFR Exon20 insertion
mutations: The first pivotal study results

Abstract #9002

Session Type: Oral

Oral Abstract Session

Lung Cancer – Non-Small Cell Metastatic

Session

Date and Time: June 6, 2023, 10:09 AM-10:21AM CDT

Venue: Hall D1

Prof. Qingqing
Cai

Golidocitinib in treating refractory or
relapsed peripheral T-cell lymphoma:
Primary analysis of the multinational
pivotal study results (JACKPOT8)

Abstract #7503

Session Type: Oral

Oral Abstract Session

Hematologic Malignancies – Lymphoma and Chronic Lymphocytic Leukemia

Session

Date and Time: June 6, 2023, 10:45 AM-10:57 AM CDT

Venue: S100a

Prof. Yan Xu

Efficacy and safety of sunvozertinib
in treatment naïve NSCLC patients
with EGFR exon20 insertion mutations

Abstract #9073

Poster Session

Lung Cancer – Non-Small Cell Metastatic

Session

Date and Time: June 4, 2023, 08:00 AM-11:00 AM CDT

Venue: Hall A

Prof. James
Chih-Hsin Yang

Anti-tumor activity of sunvozertinib
in NSCLC with EGFR sensitizing
mutations after failure of EGFR TKI
treatment

Abstract #9103

Poster Session

Lung Cancer – Non-Small Cell Metastatic

Session

Date and Time: June 4, 2023, 08:00 AM-11:00 AM CDT

Venue: Hall A

About sunvozertinib (DZD9008)

Sunvozertinib was designed with the goal to address the limitations of existing NSCLC therapies. It is a rationally designed, irreversible EGFR inhibitor targeting various EGFR mutations with wild-type EGFR selectivity. The first pivotal study WU-KONG6 of sunvozertinib has achieved its primary objective, demonstrating superior anti-tumor efficacy in pretreated NSCLC patients with EGFR Exon20ins. The confirmed objective response rate (cORR) at 300 mg was 60.8% assessed by IRC (Data cut-off date: October 17, 2022). Anti-tumor efficacy was observed across a broad range of EGFR Exon20ins subtypes, and in patients with pretreated and stable brain metastasis. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins mutations.

Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. Two multinational pivotal studies are ongoing in ≥ 2nd line (WU-KONG1) and 1st line settings (WU-KONG28), respectively, in NSCLC patients with EGFR Exon20ins mutations.

Pre-clinical and Phase 1 clinical results of sunvozertinib were published in peer-reviewed journal Cancer Discovery (IF:39.397) in April 2022. The China NMPA has accepted NDA filing and granted priority review for sunvozertinib for the treatment of advanced NSCLC with EGFR Exon20ins mutations after platinum-based chemotherapy.

About Golidocitinib (DZD4205)

Golidocitinib (DZD4205) is an oral, potent, JAK1 selective inhibitor. It is the first JAK inhibitor which has moved into the stage of pivotal clinical development. In phase 1 study (Data cut-off date: May 31, 2021), golidocitinib showed encouraging anti-tumor activity in patients with r/r PTCL, with an ORR of 42.9%, and among those responders, more than 50% achieved complete response. The longest duration of response was longer than 14 months.

Golidocitinib was granted Fast Track Designation by US FDA in February 2022.

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.