On April 4, 2023 Absci Corporation (Nasdaq: ABSI), a generative AI drug creation company, and M2GEN, an oncology bioinformatics company with the most advanced lifetime-consented clinicogenomics data to accelerate discovery research, reported a partnership to create new cancer medicines and bring them to market at unprecedented speed (Press release, M2Gen, APR 4, 2023, View Source [SID1234629803]). Absci’s generative AI drug creation platform will tap into M2GEN’s clinical and molecular data set, ORIEN AVATAR (AVATAR), to accelerate the creation of therapeutics for a range of malignancies and patient profiles, bringing AI drug creation to the fight against cancer.

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A key challenge in creating effective cancer treatments is finding specific antigens that can be targeted by immunotherapies. M2GEN’s AVATAR database represents a valuable resource for discovering such antigens. Absci will use its reverse immunology technology to first search the database for antibodies from patients with exceptional immune responses, then computationally re-assemble antigen-antibody pairs as promising starting points for drug development.

This partnership brings together AI drug creation technology and oncology bioinformatics to potentially reduce the time and cost to create better cancer treatments. Absci’s Integrated Drug Creation platform unites generative AI and wet-lab capabilities to screen billions of cells per week, allowing it to go from AI-designed antibodies to lab-validated candidates in as little as six weeks. As the nexus between patients, researchers, and the pharmaceutical industry, M2GEN is uniquely positioned and equipped with the richest clinicogenomic data set, and a lifetime patient-consented Total Cancer Care (TCC) protocol, to accelerate drug discovery and development and transform how cancer is treated. M2GEN’s real-world data set comes from its Oncology Research Information Exchange Network (ORIEN) partners, an alliance of 18 cancer centers across more than a dozen U.S. states.

"M2GEN and its ORIEN partners are premier leaders in the field of oncology data research and bring a wealth of unique data sets to our generative AI platform that may enable us to ultimately shave years off the drug discovery process," said Sean McClain, CEO of Absci. "This is an important leap forward to better understand individualized protein-protein interactions on cancer cells, moving us toward delivering on the promise of personalized medicine."

The cornerstone of ORIEN is the lifetime-consented TCC protocol, one of the first longitudinal cancer patient databases of its kind, with over 360,000 patients enrolled nationwide. TCC enables patient monitoring throughout their treatment journey, with the goal to transform how cancer is treated. M2GEN and ORIEN research-facilitated projects are monitored by a multi-institution governing body, which includes scientists and research leaders from network members, to ensure adherence to privacy protocols and best practices.

"Absci’s recent breakthrough creating de novo antibodies changed the idea of what’s possible for drug discovery," said Jim Gabriele, CEO of M2GEN. "This was just one of the things that excited us about partnering together. Their AI-led approach to targeting biologics to make the drug discovery process more efficient and dramatically impact patients’ lives made them an ideal partner," said Gabriele. "Together, by utilizing our real-world data, we plan to advance personalized cancer treatments in pursuit of a cure."

This partnership maintains Absci’s momentum building one of the largest repositories of patient data in the industry to train its generative AI platform for protein drug creation. The company recently partnered with St. John’s Cancer Institute to train on their datasets to discover medicines faster.

On April 4, 2023 Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA), an oncology-focused drug development company, reported the presentation of new data for both of its pipeline molecules, paxalisib and EVT801, at the upcoming Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), held in Orlando, FL, from 14 – 19 April 2023 (Press release, Kazia Therapeutics, APR 4, 2023, View Source [SID1234629801]).

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In total, there will be five presentations at AACR (Free AACR Whitepaper), four of which build on previous positive data for paxalisib in melanoma and childhood brain cancer. The new data being presented provide significant support and direction for the future development of paxalisib in these expansion indications.

In addition, a presentation by scientists from Kazia’s partner, Evotec, will outline the novel biomarker strategy employed in the phase I study of EVT801, and anticipates the potential initial clinical data from EVT801 in CY2023.

Key Points

Research by Dr Gennie Parkman and colleagues, working in the laboratory of Professor Sheri Holmen at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, shows paxalisib leading to ‘substantially increased overall survival’ in a mouse model of BRAF-driven melanoma.

Further data from Dr Tyler Findlay and Dr Kristen Malebranche in Professor Jeffery Rubens’ team at Johns Hopkins University Medical School has shown compelling evidence of synergy between paxalisib and both gemcitabine, a chemotherapy agent, and mirdametinib, a targeted therapy, in animal models of atypical teratoid / rhabdoid tumors (AT/RT), a childhood brain cancer. This data expands on positive data for paxalisib as monotherapy and in other combination regimens that was presented at AACR (Free AACR Whitepaper) in 2022. The results suggest potential therapeutic approaches for use in clinical trials.

An additional abstract by Dr Hyuk Jean Kwon and colleagues at Professor Rubens’ lab describes in vitro preclinical data for the combination of paxalisib with a dual inhibitor of ACVR1 and MEK in diffuse midline gliomas, a category of childhood brain cancers which includes DIPG. The data showed strong synergy between the two agents, and points to further research in this area.

A poster presentation by Dr Michael Paillaisse and colleagues at Evotec SE describes some of the novel biomarker selection strategies employed in the ongoing phase I study of EVT801 in advanced solid cancers (NCT05114668). The poster outlines the approaches taken by the Evotec team to identify VEGFR3 expression in a range of tissues, potentially allowing for the selection of clinical trial patients who are likely to be more responsive to EVT801.

"The broad range of abstracts presented at AACR (Free AACR Whitepaper) speak to the breadth of work that is ongoing across our pipeline," said Dr James Garner, Chief Executive Officer of Kazia. "The promising new data from Professors Holmen and Rubens, in melanoma and childhood brain cancer respectively, reinforces the significance of these new opportunities for paxalisib. Moreover, Kazia’s ongoing collaboration with Evotec remains extremely fruitful, with excellent work from the biomarker team opening the possibility of rational patient selection in clinical trials. Of note, biomarker strategy is an important area of focus for FDA, and drug candidates with biomarker selection are potentially more likely to achieve approval than those without."

Summary of Abstracts

SESSION PO.ET03.02 – Drug Resistance in Molecular Targeted Therapies 2

April 16, 2023 – 1:30pm-5:00pm

Abstract 427/22 – Newer generation mTOR inhibition represents effective therapeutic strategy for BRAF-mutant melanoma

Gennie L Parkman, Tursun Turapov, David Kircher, William Burnett, Christopher Stehn, Kayla O’Toole, Katie Culver, Ashley Chadwick, Riley Elmer, Ryan Flaherty, Mona Foth, Karly Stanley, Robert Andtbacka, David Lum, Robert Judson-Torres, Martin McMahon, Sheri Holmen

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

University of Minnesota, Minneapolis, MN

SESSION PO.CL09.01 – Combination Therapies for Cancer

April 18, 2023 – 1:30pm-5:00pm

Abstract 5490/8 – Combination of the PI3k inhibitor paxalisib with the nucleoside analog Gemcitabine over-activates the integrated stress response and induces atypical teratoid / rhabdoid tumor cell death

Tyler Findlay, Kristen Malebranche, Anupa Geethadevi, Eric Raabe, Charles Eberhart, Jeffrey Rubens

Johns Hopkins University School of Medicine, Baltimore, MD

Abstract 5509/27 – The PI3K inhibitor paxalisib combines synergistically with the MEK inhibitor mirdametinib to target atypical teratoid / rhabdoid tumors

Kristen J. Malebranche, Tyler Findlay, Anupa Geethadevi, Charles Eberhart, Eric Raabe, Jeffrey Rubens

Johns Hopkins University School of Medicine, Baltimore, MD

SESSION PO.ET01.04 – Targeting Protein Kinases and Phosphatases for Therapy 1

April 18, 2023 – 1:30pm-5:00pm

Abstract 4990/3 – Dual inhibitor of ACVR1 and MEK 1/2 E6201 and PI3K/mTOR inhibitor paxalisib synergistically inhibit cell growth in DMG

Hyuk Jean Kwon, Abigail Tindall, Charles Eberhart, Jeffrey Rubens, Eric Raabe

Johns Hopkins University School of Medicine, Baltimore, MD

SESSION PO.CL01.06 – Diagnostic and Prognostic Biomarkers 1

April 16, 2023 – 1:30pm-5:00pm

Abstract 1015/25 – VEGFR-3 expression profiling by histology to classify patient population for the selective VEGFR-3 inhibitor EVT801

Michael Paillasse, Pierre-Benoit Ancey, Gaelle Badet, Anne Gomez-Brouchet, Janik Selves, Philippe Rochaix, Maxime Battistella, Celeste Lebbe, Philippe Cassier, Carlos Gomez-Roca, Jean-Pierre Delord, Mark Whittaker, Lise Davenne, John Friend, Michael Fitzgerald, James Garner, Pierre Fons

Evotec SE, Toulouse, France & Abingdon, UK

Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France,

Université de Paris Cité, AP-HP Hôpital Saint Louis, Paris, France,

Centre Léon Bérard, Lyon, France

Kazia Therapeutics Ltd, Sydney, Australia

On April 4, 2023 Nexcella Inc., a subsidiary of Immix Biopharma, Inc. (Nasdaq: IMMX) ("ImmixBio", "Company", "We" or "Us") reported that updated NXC-201 clinical data has been selected to be presented at the upcoming 49th annual meeting of the European Society for Blood and Marrow Transplantation (EBMT) to be held in Paris, France, 23-26 April 2023 (Press release, Immix Biopharma, APR 4, 2023, View Source [SID1234629800]).

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"We are delighted to present additional clinical data at the upcoming 49th annual meeting of the European Society for Blood and Marrow Transplantation," said Polina Stepensky, M.D., Director of the Hadassah Medical Organization’s Department of Bone Marrow Transplantation and Immunotherapy for Adults and Children, and principal study investigator. "We are pleased to reach this milestone as we learn more about this promising therapy."

Posters to be presented:

Title: "Point-of-care CART manufacture and delivery for the treatment of multiple myeloma and AL amyloidosis: the experience of Hadassah Medical Center"

Event: European Society for Blood and Marrow Transplantation 49th Annual Meeting

Dates: April 23-26, 2023

Location: Palais des Congrès de Paris, 2 Pl. de la Prte Maillot, 75017 Paris, France

Times: Sunday, April 23 08:30 – 19:20 CEST / Monday, April 24 09:00 – 18:00 CEST / Tuesday, April 25 09:00 – 18:00 CEST / Wednesday, April 26 08:30 – 14:15 CEST

Nexcella, Inc. previously announced that NXC-201 (formerly HBI0101) produced a 90% overall response rate (ORR) and 59% complete response/stringent complete response (CR/sCR) at the therapeutic dose from the first 42 patients in an ongoing phase 1b/2a relapsed/refractory multiple myeloma ongoing clinical trial as of the October 23, 2022 data cutoff. NXC-201 also produced 100% hematologic complete response rate and 100% organ response rate (cardiac, liver, renal) in 5 relapsed/refractory AL Amyloidosis patients as of the October 23, 2022 data cutoff. These data were published in Haematologica View Source (multiple myeloma), Clinical Cancer Research View Source (AL amyloidosis), and presented at the European Society for Blood and Marrow Transplantation and European Hematology Association (EHA) (Free EHA Whitepaper) 5th Annual European CAR T-cell Meeting View Source .

Low-grade (grade 1/2) CRS duration of median 2 days with median onset of 1-day post-dosing (range, 1-5 days) at therapeutic dose in relapsed/refractory multiple myeloma points to NXC-201 potentially becoming the first and only out-patient CAR-T for Multiple Myeloma, AL Amyloidosis and other BCMA-positive malignancies.

About NEXICART-1

NEXICART-1 (NCT04720313) is an ongoing Phase 1b/2, open-label study evaluating the safety and efficacy of NXC-201 (formerly HBI0101) in adults with relapsed or refractory multiple myeloma and AL amyloidosis. The Phase 1b portion of the study has already established an expected recommended Phase 2 dose (RP2D) of 800 million CAR+T cells.

The expected primary endpoint for a pivotal study of NXC-201 will be overall response rate in multiple myeloma, and overall response rate in AL amyloidosis.

To date, 58 patients have been treated with NXC-201, 50 in multiple myeloma, and 8 in AL amyloidosis.

About NXC-201

NXC-201 (formerly HBI0101) is a BCMA-targeted investigational chimeric antigen receptor T (CAR-T) cell therapy that is being studied in a comprehensive clinical development program for the treatment of patients with relapsed or refractory multiple myeloma and AL amyloidosis. The design consists of a structurally differentiated CAR-T with our proprietary BCMA-targeting CAR which has demonstrated reduced toxicity in NEXICART-1, supporting investigating NXC-201 as an outpatient therapy.

As of the October 23, 2022 data cutoff, updated clinical data in 47 patients from the ongoing Phase 1b/2a portion of the NEXICART-1 (NCT04720313) study of the novel, autologous, BCMA-targeted chimeric antigen receptor T (CAR-T) cell therapy NXC-201 for the treatment of relapsed or refractory multiple myeloma and light chain amyloidosis (AL) showed:
Multiple Myeloma – 90% overall response rate (59% complete responses) for NXC-201 at the therapeutic dose in an ongoing 42-Patient Phase 1 expansion trial (Haematologica View Source, 5th European CAR-T cell meeting View Source/) in relapsed/refractory multiple myeloma. All patients treated with NXC-201 were triple-class refractory (to at least 1 immunomodulatory drug, 1 proteasome inhibitor and 1 anti-CD38 antibody).
Additional data in 2023 demonstrated outpatient CAR-T treatment potential: cytokine release syndrome (CRS) median onset day zero; median CRS duration 1 day; no grade 4 CRS; only 1 grade 3 CRS across 42 relapsed/refractory multiple myeloma patients
The expected primary endpoint for a pivotal study of NXC-201 in relapsed/refractory multiple myeloma is overall response rate.
AL Amyloidosis – 100% organ response rate (cardiac, renal, liver), 100% complete hematologic responses (MRD negativity 10-5), for NXC-201 in 8 relapsed/refractory AL Amyloidosis patients, of which the initial cohort was presented at the 5th European CAR-T cell meeting View Source/, and published in Clinical Cancer Research View Source,
The expected primary endpoint for a pivotal study of NXC-201 in relapsed/refractory AL Amyloidosis is overall response rate.
The expected therapeutic dose of NXC-201 (800 million CAR+T cells) has already been established as the recommended Phase 2 dose (RP2D) for both multiple myeloma and AL amyloidosis.
Additional information on NXC-201 multiple myeloma clinical data as of October 23, 2022 is available here.

About Multiple Myeloma

Multiple myeloma ("MM") is an incurable blood cancer of plasma cells that starts in the bone marrow and is characterized by an excessive proliferation of these cells. Despite initial remission, unfortunately, most patients are likely to relapse. There are 34,470 patients in the United States diagnosed with MM each year. Prognosis for patients who do not respond to or relapse after treatment with standard therapies, including protease inhibitors and immunomodulatory agents remains poor. The $13.9 billion Multiple Myeloma market in 2017 is expected to reach $28.7 billion in 2027 according to Wilcock, et al. Nature Reviews.

About AL Amyloidosis

AL amyloidosis is a rare systemic disorder caused by an abnormality of plasma cells in the bone marrow. Misfolded amyloid proteins produced by plasma cells cause buildup in and around tissues, nerves and organs, gradually affecting their function. This can cause progressive and widespread organ damage, and high mortality rates.

AL amyloidosis affects roughly 30,000 – 40,000 patients in total throughout the U.S. and Europe, and it is estimated that there are approximately 3,000 – 4,000 new cases of AL amyloidosis annually in the U.S. The annual global incidence of AL Amyloidosis is ~15,000 patients. The Amyloidosis market was $3.6 billion in 2017, expected to reach $6 billion in 2025, according to Grand View Research.

On April 4, 2023 iBio, Inc. (NYSEA:IBIO) ("iBio" or the "Company"), an AI-driven innovator of precision antibody immunotherapies, reported that a presentation given today by its VP & Head of Machine Learning & Platform Technologies, Matt Greving, Ph.D., during Carterra’s "Unlocking High-Throughput Biology and Drug Discovery" symposium in San Diego, CA, revealed the discovery of a panel of CD3 T-cell binding antibodies, representing an important first step for the Company into bispecific immuno-oncology therapies (Press release, iBioPharma, APR 4, 2023, View Source [SID1234629798]).

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T-cell-redirecting bispecific antibodies are a new class of therapeutic antibodies designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-specific antigens ("TSA") or tumor-associated antigens ("TAA"), inducing T-cell-mediated killing of tumor cells.1

Early studies of CD3-based T-cell engagers showed promising clinical efficacy, but were hampered by severe dose-limiting toxicities, due in large part to anti-CD3 binders with high potency.2 Another hurdle in the development of CD3-based T-cell engagers has been the often-observed lack of cross-reactivity with non-human primates. This has made it difficult to assess the potential of CD3 antibody therapies in humans, potentially delaying their clinical development.3

With the aim of overcoming these challenges, iBio employed its patented epitope steering technology to guide antibodies towards specific CD3 epitopes. The Company’s AI-based antibody optimizer, combined with its mammalian display technology broadened the range of CD3 affinities, identified antibodies with cross-reactivity to non-human primates and increased the humanness of the antibody sequences.

Dr. Greving explained, "Our leading epitope-steering and mammalian-display integration enabled efficient discovery of a diverse panel of CD3 antibodies. With our technology stack, we were able to overcome key challenges associated with CD3 antibody discovery, including identifying T-cell binding antibodies with non-human primate cross-reactivity."

In response to the Company’s latest AI platform success, iBio’s Interim Chief Executive Officer and Chief Scientific Officer, Martin Brenner, DVM, Ph.D., affirmed that, "By combining two of our platform technologies, we were successful in generating anti-CD3 antibodies with highly desirable characteristics. By adding CD3-based T-cell engaging antibodies as a tumor cell killing modality, we now have a valuable option to tune efficacy and safety of our future and existing pipeline programs."

References

1. L. Haber, K. Olson, M. P. Kelly, A. Crawford, D. J. DiLillo, R. Tavaré, E. Ullman, S. Mao, L. Canova, O. Sineshchekova, J. Finney, A. Pawashe, S. Patel, R. McKay, S. Rizvi, E. Damko, D. Chiu, K. Vazzana, P. Ram, K. Mohrs, A. D’Orvilliers, J. Xiao, S. Makonnen, C. Hickey, C. Arnold, J. Giurleo, Y. P. Chen, C. Thwaites, D. Dudgeon, K. Bray, A. Rafique, T. Huang, F. Delfino, A. Hermann, J. R. Kirshner, M. W. Retter, R. Babb, D. MacDonald, G. Chen, W. C. Olson, G. Thurston, S. Davis, J. C. Lin, E. Smith, Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning. Sci Rep. 11, 14397 (2021).

2. O. Vafa, N. D. Trinklein, Perspective: Designing T-Cell Engagers With Better Therapeutic Windows. Frontiers in Oncology. 10 (2020) (available at https://www.frontiersin.org/articles/10.3389/fonc.2020.00446).

3. F. R. Brennan, J. Cavagnaro, K. McKeever, P. C. Ryan, M. M. Schutten, J. Vahle, G. F. Weinbauer, E. Marrer-Berger, L. E. Black, Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment. mAbs. 10, 1–17 (2018).

On April 4, 2023 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:HCM; HKEX:13) reported that it has consulted the China National Medical Products Administration ("NMPA") and reached an agreement to initiate the registration phase of the ongoing Phase II trial of HMPL-453 for intrahepatic cholangiocarcinoma ("IHCC") patients with fibroblast growth factor receptors ("FGFR") 2 fusion (Press release, Hutchison China MediTech, APR 4, 2023, View Source [SID1234629797]). If positive, the data from the registration phase may be used to support a future New Drug Application ("NDA") filing. The first patient received their first dose in March 2023.

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In addition, it also reached an agreement to initiate the registration phase of the ongoing Phase II trial of savolitinib for gastric cancer patients with mesenchymal–epithelial transition ("MET") amplification following NMPA consultation. If positive, the data from the registration phase may be used to support a future NDA filing. The first patient also received their first dose in March 2023.

The study of HMPL-453 is a single-arm, multi-center, open-label, Phase II registration study to evaluate the efficacy, safety and pharmacokinetic of HMPL-453 in treating advanced IHCC patients with FGFR2 fusion. Primary endpoint is objective response rate ("ORR"). Secondary endpoints include progression-free survival ("PFS"), disease control rate (DCR), duration of response (DoR) and overall survival (OS). The study is expected to enroll approximately 90 additional patients. Additional details may be found at clinicaltrials.gov using identifier NCT04353375.

The study of savolitinib is a single-arm, multi-center, open-label, Phase II registration study to evaluate the efficacy, safety and tolerability of savolitinib in treating gastric cancer and esophagogastric junction adenocarcinoma patients with MET amplification. Primary endpoint is ORR evaluated by the Independent Review Committee (IRC) (RECIST 1.1). Secondary endpoints include PFS and incidence of various adverse events (AE). The study is expected to enroll approximately 60 additional patients. Further details may be found at clinicaltrials.gov using identifier NCT04923932.

About HMPL‑453
HMPL‑453 is a novel, highly selective and potent inhibitor targeting FGFR 1, 2 and 3. Aberrant FGFR signaling has been found to be a driving force in tumor growth (through tissue growth and repair), promotion of angiogenesis and resistance to anti-tumor therapies. Abnormal FGFR gene alterations are believed to be the drivers of tumor cell proliferation in several solid tumor settings.

HUTCHMED currently retain all rights to HMPL-453 worldwide.

About IHCC with FGFR2 Fusion
IHCC is one of the subtypes of primary liver cancer. In China, an estimated 61,900 newly diagnosed IHCC occurred in 2015 and the overall IHCC incidence increased by 9.2% per year between 2006 and 2015.[i] FGFR2 fusion has been reported to have a prevalence of 10-15% in IHCC patients.[ii] [iii]

About savolitinib
Savolitinib is an oral, potent and highly selective MET tyrosine kinase inhibitor that has demonstrated clinical activity in advanced solid tumors. Іt blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression.

Savolitinib is marketed in China under the brand name ORPATHYS for the treatment of patients with non-small cell lung cancer ("NSCLC") with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. Іt is currently under clinical development for multiple tumor types, including lung, kidney and gastric cancers, as a single treatment and in combination with other medicines. Starting on March 1, 2023, ORPATHYS was included in the National Reimbursement Drug List (NRDL) for the treatment of locally advanced or metastatic NSCLC adult patients with MET exon 14-skipping alterations who have progressed after or unable to tolerate platinum-based chemotherapy.

Іn 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize savolitinib. Joint development of savolitinib in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of savolitinib in China. AstraZeneca is responsible for the commercialization of savolitinib in China and worldwide. Sales of savolitinib are recognized by AstraZeneca.

About Gastric Cancer with MET Amplification
MET-driven gastric cancer has a very poor prognosis.[iv] The ongoing registration trial follows multiple Phase II studies that have been conducted in Asia to study ORPATHYS in MET-driven gastric cancer patients, including VIKTORY.3 VIKTORY is an investigator initiated Phase II umbrella study in gastric cancer in South Korea in which a total of 715 patients were successfully sequenced into molecular-driven patient groups, including those with MET amplified gastric cancer. Patients whose tumors harbor MET amplification were treated with ORPATHYS monotherapy.

It is estimated that MET amplification accounts for approximately 4-6% of gastric cancer patients.[v],[vi] The annual incidence of MET amplification gastric cancer is estimated to be approximately 24,000 in China.