On June 6, 2023 Memgen, Inc., a clinical-stage biotechnology company reported updated clinical data from its first-in-human study of MEM-288, an oncolytic viral therapy, in patients with advanced/metastatic refractory non-small cell lung cancer (Press release, Memgen, JUN 6, 2023, View Source [SID1234632537]). Dr. Andreas Saltos, the lead study investigator at Moffitt Cancer Center, presented the poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2023 Annual Meeting in Chicago.

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Dr. Saltos noted that "We looked at biopsies and blood samples for patients on the study and see encouraging signs of an anti-tumor immune response being generated. We’ve demonstrated that MEM-288 can powerfully shrink tumors and increase immune response even for patients with stage 4 tumors who had multiple prior treatments."

This MEM-288 dose-escalation, monotherapy study has now completed patient accrual of fourteen patients with advanced/metastatic non-small cell lung cancer (NSCLC) refractory to standard therapies including anti-PD(L)1.

The study’s primary safety endpoint was achieved with no dose limiting toxicities at any dose level, and no patients stopped treatment due to toxicity. Treatment-related adverse events consisted mostly of mild and transient injection-site reactions and flu-like symptoms.

Four patients had significant shrinkage (range -26% to -54%) of injected lesions, which correlated with strong remodeling of the tumor microenvironment and infiltration of CD8+ T-cells, and significant necrosis and apoptosis of tumor cells measured in tumor biopsies.

Systemic immune activation was clearly noted in multiple patients, with increases in IFN-gamma in the majority of patients as well as increased T-cell clonotype diversity in both tumor biopsies and peripheral blood following MEM-288 treatment.

Two patients have had ongoing durable responses after completing MEM-288 treatment and then receiving salvage chemotherapy. Both had previously relapsed on chemo/immunotherapy prior to MEM-288. One patient has had a complete response greater than 9 months and the other a partial response. Mark Cantwell, Memgen’s CSO, noted, "We continue to follow these patients and implications for expanded avenues to use MEM-288 in combination with multiple therapeutic strategies."

On June 6, 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 for the second consecutive year, it has released updated data of APG-2449, a novel FAK/ALK/ROS1 tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma, in patients with non-small cell lung cancer (NSCLC), in a Poster Discussion session at the 59th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Ascentage Pharma, JUN 6, 2023, View Source;ascentage-pharma-releases-updated-data-showing-apg-2449s-potential-as-a-new-treatment-for-drug-resistant-nsclc-301843129.html [SID1234632536]).

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Showcasing progress in clinical development at the ASCO (Free ASCO Whitepaper) Annual Meeting for six consecutive years, Ascentage Pharma had clinical results from four clinical studies of four of the company’s lead drug candidates selected for presentations in 2023. Among these results, the updated clinical data of APG-2449 showed the potential as a new treatment option that can effectively overcome drug resistance through the targeted inhibition of FAK. These data indicated efficacy and safety of APG-2449 in patients with NSCLC, with 8 partial responses (PRs) in the 28 patients who had failed treatment with the second-generation ALK TKIs.

Developed by Ascentage Pharma, APG-2449 is an orally available, small-molecule FAK/ALK/ROS1 TKI and the first China-developed third-generation ALK inhibitor entering clinical development.

"APG-2449 is an effective multi-targeted inhibitor targeting FAK/ALK/ROS1. Compared to data released at the ASCO (Free ASCO Whitepaper) Annual Meeting last year, the updated results reported this year continuously indicated favourable safety and promising antitumor activity in patients with NSCLC, and the preliminary efficacy observed in patients who were resistant to second-generation ALK inhibitors was particularly encouraging," said Prof. Li Zhang, the Principal Investigator of this study from Sun Yat-Sen University Cancer Center. "We believe that FAK inhibition could be a new treatment strategy for patients with NSCLC resistant to second-generation ALK inhibitors."

"We are excited by the results presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting as they demonstrated APG-2449’s therapeutic option in advanced NSCLC and the drug’s potential in offering a safe and effective novel therapy to this underserved patient population," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Moving forward, we will expedite this clinical development program, which hopefully can yield a safe and effective new treatment option to patients, fulfilling our mission of addressing unmet clinical needs in China and around the world."

* APG-2449 is an investigational drug that has not been approved in any country and region.

Highlights of the poster on APG-2449 presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting:

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
Session Title: Lung Cancer—Non-Small Cell metastatic
Key Results:
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, 136 patients were enrolled and treated with APG-2449 at dose levels from 900 to 1,500 mg. The median (range) age of these patients was 53 (21-78) years, and 54.4% 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+ 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 28 patients with ALK+ NSCLC that was resistant to second-generation ALK inhibitors, 8 achieved PR (8/28; 28.6%) when treated with APG-2449 at the RP2D.
Analysis of FAK Expression: Among the 48 patients with ALK+ NSCLC who were previously treated with second-generation ALK inhibitors, compared to baseline, those who experienced PR showed greater reduction in phosphorylated FAK (pFAK) levels in peripheral blood mononuclear cells (PBMCs) by Day 28 than patients who experienced SD and progressive disease (PD), thus suggesting that patients with higher FAK expression at baseline were likely to achieve deeper clinical responses to APG-2449.
Safety Results: A total of 123 (90.4%) patients experienced treatment-related adverse events (TRAEs), with the most frequent TRAEs (>20%) being elevated blood creatinine (46.3%), elevated alanine aminotransferase (ALT) (40.4%), and elevated aspartate aminotransferase (AST) (33.1%), as well as gastrointestinal disorders that included nausea (27.2%), vomiting (22.8%), and diarrhea (21.3%). A total of 19 (14%) patients experienced grade ≥ 3 TRAEs.
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.
Appendix: The four posters on Ascentage Pharma’s four lead drug candidates, including APG-2449, presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting.

Drug Candidates

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

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).

#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

On June 6, 2023 Acepodia, a clinical stage biotechnology company developing first-in-class cell therapies with its unique Antibody-Cell Conjugation (ACC) and allogeneic gamma delta 2 T-cell platforms to address gaps in cancer care, reported a $100 million Series D financing led by Digital Mobile Venture with participation from additional existing investors (Press release, Acepodia, JUN 6, 2023, View Source [SID1234632535]). The funds will be used to progress the company’s pipeline of enhanced cell therapies for solid tumors and hematologic cancers, including ACE1831 and ACE2016. ACE1831 is an anti-CD20 armed allogeneic gamma delta 2 T-cell therapy currently being studied in a Phase 1 trial for patients with non-Hodgkin Lymphoma. ACE 2016 is an anti-EGFR armed allogeneic gamma delta 2 T-cell therapy targeting EGFR-expressing solid tumors.

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"This financing illustrates the confidence of Acepodia’s current investors in our team, our mission, and our differentiated platform, and we are extremely grateful for their support," said Sonny Hsiao, Ph.D., chief executive officer of Acepodia. "These funds will directly promote the progression of our clinical and pre-clinical candidates and also continue the validation of our ACC and allogeneic gamma delta 2 T-cell platforms to advance the development of innovative, effective, and importantly affordable off-the-shelf allogeneic cell therapies."

Acepodia has raised $259 million to date in venture capital financing, including a $109 million Series C round completed in December 2021. Returning investors in the Series D included Digital Mobile Venture as the lead investor.

The company’s first-in-class ACC technology is based on click chemistry applied to live cells, the foundational work for which Dr. Carolyn Bertozzi was awarded the 2022 Nobel Prize in Chemistry. Antibody-cell conjugation supports the connection of tumor-targeting antibodies to a variety of immune cells including gamma delta T cells. Acepodia’s novel technology pairs the precision of targeted monoclonal antibodies and cancer-killing immune cells into a powerful cell therapy that is differentiated from viral vector-delivered gene transductions or genetic engineering that CAR-based cell therapies require. This approach allows for the development of off-the-shelf allogeneic cell therapies that are more broadly accessible for cancer patients.

"We continue to believe in the strength and potential of Acepodia’s platform, and the ability of the team that is well-positioned to advance new therapies through the clinic and to patients," said Samuel Chen, Director at Digital Mobile Venture. "We are thrilled to continue to partner with Acepodia and support the ongoing advancement of their important research as the company works to demonstrate the potential of antibody-cell conjugation and advance the next generation of cell therapies."

On June 6, 2023 Linnaeus Therapeutics, Inc. (Linnaeus), a privately held clinical-stage biopharmaceutical company focused on the development and commercialization of novel small-molecule oncology therapeutics, reported the presentation of clinical data from its phase 1 dose-expansion study of LNS8801 as a monotherapy and in combination with pembrolizumab in metastatic uveal melanoma at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Linnaeus Therapeutics, JUN 6, 2023, View Source [SID1234632534]).

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The poster is entitled "The effect of LNS8801 alone and in combination with pembrolizumab in patients with metastatic uveal melanoma" (Abstract 9543).

LNS8801 alone and in combination with pembrolizumab was tolerable without unanticipated toxicities. LNS8801 demonstrated encouraging anti-tumor activity in patients with metastatic uveal melanoma, overall 50% of patients had disease control. These data support further development of LNS8801 alone and in combination with pembrolizumab as a therapeutic approach to treat metastatic uveal melanoma patients.

"We are extremely pleased to showcase these data at ASCO (Free ASCO Whitepaper)," commented Patrick Mooney, MD, CEO of Linnaeus. "The data from this study demonstrate that LNS8801 is extremely safe and well tolerated and shows very promising signs of clinical benefit and preliminary efficacy alone and in combination with pembrolizumab in patients with metastatic uveal melanoma. We look forward to further exploring LNS8801 alone and in combination with pembrolizumab in other currently open expansion cohorts."

This study was supported by Linnaeus Therapeutics Inc. and NCI SBIR Phase 2B 5R44CA228695.

About LNS8801

LNS8801 is an orally bioavailable and highly specific and potent agonist of GPER whose activity is dependent on the expression of GPER. GPER activation by LNS8801 rapidly and durably depletes c-Myc protein levels. In preclinical cancer models, LNS8801 displays potent antitumor activities across a wide range of tumor types, rapidly shrinking tumors and inducing immune memory.

In the ongoing clinical study in humans, LNS8801 monotherapy has been safe and well tolerated. Additionally, LNS8801 has demonstrated target engagement, c-Myc protein depletion, and clinical benefit in patients with advanced cancers, and a predictive biomarker has been identified.

About Metastatic Uveal Melanoma
Although uveal melanoma is a rare cancer, it is the most common primary intraocular malignancy in adults. Up to 50% of people with primary uveal melanoma will eventually develop metastatic disease. Unresectable or metastatic uveal melanoma typically has a very poor prognosis.

On June 6, 2023 Bold Therapeutics, a clinical-stage biopharmaceutical company developing first-in-class oncology therapeutics, reported positive interim results in advanced gastric and biliary tract cancer at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Bold Therapeutics, JUN 6, 2023, View Source [SID1234632533]).

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Bold Therapeutics’ BOLD-100 is a first-in-class ruthenium-based small molecule therapeutic that (1) alters the unfolded protein response (UPR) through selective GRP78 inhibition; and (2) induces reactive oxygen species (ROS) which causes DNA damage and cell cycle arrest. Collectively, these effects result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anticancer therapies ranging from traditional chemotherapies to targeted therapies and immuno-oncology agents.

Bold Therapeutics’ ongoing multinational Phase 1b/2 trial (NCT04421820) evaluates BOLD-100 in combination with FOLFOX (folinic acid / leucovorin, fluorouracil, and oxaliplatin) in patients with advanced gastrointestinal cancers. The trial has enrolled 110 patients with advanced gastrointestinal (biliary tract, colorectal, gastric, and pancreatic) cancers at sites in Canada, the United States, Ireland and South Korea, and the primary endpoints for the trial are progression-free survival (PFS), with overall survival (OS) and overall response rate (ORR) as secondary endpoints. Disease control rate (DCR) was also captured. Data from the full Phase 2 trial, which will include an additional 20 patients with advanced colorectal cancer, should be available in late 2023.

Data from 13 patients with advanced gastric cancer and 22 patients with biliary tract cancer was presented in the Gastrointestinal (Gastroesophageal, Pancreatic and Hepatobiliary) Cancer session as Poster 4098: "BOLD-100-001 (TRIO039): A Phase 1b/2a Study of BOLD-100 in Combination with FOLFOX Chemotherapy in Patients with Pre-Treated Advanced Gastric and Biliary Tract Cancer: Efficacy and Safety Analysis." 13 advanced gastric cancer patients (median 4th line) showed a median PFS of 5.5 months, OS of 15.0 months, ORR of 22%, and DCR of 89%, substantially higher than the most comparable benchmark values in a much earlier (median 2nd line) population of a median PFS of 4.6 months, OS of 7.1 months, ORR of 40%, and DCR of 69%. Mature data in an additional 8 advanced gastric cancer patients will be available in late 2023. 22 advanced biliary tract cancer patients (median 3rd line) showed a median PFS of 5.0 months, OS of 7.3 months, ORR of 6%, and DCR of 83%, substantially higher than the most comparable benchmark values in an earlier (true 2nd line) population from the ABC-06 FOLFOX study with a median PFS of 4.0 months, OS of 6.2 months, ORR of 5.0%, and DCR of 33%. Consistent with prior data, BOLD-100 in combination with FOLFOX proved to be exceptionally well-tolerated, with no new safety signals, and with patients remaining on therapy for up to 25 treatment cycles. Treatment-emergent adverse events (TEAEs) were observed in 33 (94%) of patients, with the most common TEAEs being decreased neutrophil count (43%), nausea (29%), and fatigue (20%) – rates comparable to FOLFOX.

Previously, interim data in metastatic colorectal cancer presented at AACR (Free AACR Whitepaper) 2023 indicated that patients treated with BOLD-100 and FOLFOX showed a median PFS of 4.7 months, OS of 9.8 months, ORR of 13%, and DCR of 87%, substantially higher than standard-of-care data for a similar patient population which showed a median PFS of up to 2.0 months, OS of up to 7.1 months, ORR of up to 1.6%, and DCR of up to 44%.

"Our presentation at ASCO (Free ASCO Whitepaper) marks a critical milestone for BOLD-100, with Bold Therapeutics successfully generating positive proof-of-concept data in three different difficult-to-treat gastrointestinal cancer indications where existing therapies are largely ineffective," stated Jim Pankovich, EVP of Clinical Development. "Importantly for patients, BOLD-100 achieves these improved outcomes safely, even in heavily pre-treated patients."

Bold Therapeutics is preparing to initiate a pivotal Phase 3 trial for BOLD-100 in the treatment of advanced colorectal cancer in 2024 and is currently evaluating potentially synergistic development and commercialization partnerships to support these efforts. Concurrently, Bold Therapeutics is exploring additional development indications for BOLD-100 while also advancing its pipeline of other novel metallotherapeutics.

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