On June 3, 2022 Daiichi Sankyo it’s New data from (TSE: 4568) patritumab deruxtecan (HER3-DXd) showed clinically meaningful and durable responses in two early-stage trials in previously treated patients with HER3 expressing metastatic breast cancer or advanced non-small cell lung cancer (NSCLC) without EGFR-activating mutations (Press release, Daiichi Sankyo, JUN 3, 2022, View Source [SID1234615540]). These data will be presented during an oral presentation (Abstract #1002) and a poster discussion session (Abstract #9017) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (#ASCO22) Annual Meeting.

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Patritumab deruxtecan is a potential first-in-class HER3 directed antibody drug conjugate (ADC) discovered and being developed by Daiichi Sankyo.

Advanced breast and lung cancer are two of the leading causes of cancer-related death in the U.S. with five-year survival rates of 30% and 7%, respectively.1,2 New therapeutic approaches are needed to improve outcomes for these cancers and HER3 is a promising target for therapeutic development. HER3 is broadly expressed in these tumors and is associated with an increased incidence of metastases, reduced survival and is one of the mechanisms of resistance to standard of care treatment.3,4

"Results of these two trials of patritumab deruxtecan in patients with certain subtypes of advanced breast or lung cancer further support the potential of Daiichi Sankyo’s DXd antibody drug conjugate technology across different types of cancer," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "These data also reinforce the potential emerging role of targeting HER3 with an antibody drug conjugate to overcome resistance to standard of care treatment in patients with HER3 expressing metastatic breast cancer as well as in patients with advanced non-small cell lung cancer without EGFR activating mutations, which we plan to continue to explore in additional trials."

HER3 Expressing Metastatic Breast Cancer Results

Pooled analysis from a three-part, first-in-human phase 1/2 trial evaluating patritumab deruxtecan (n=182) showed clinically meaningful and durable responses after a median follow-up of 31.9 months (range, 15-56) in patients with three different subtypes of HER3 expressing metastatic breast cancer, including HR positive/HER2 negative, triple negative and HER2 positive disease. Responses were seen across a broad range of HER3 expression.

A confirmed objective response rate (ORR) of 30.1% (95% CI: 21.8-39.4) was observed with patritumab deruxtecan in the cohort of 113 patients with HER3 high or HER3 low, HR positive/HER2 negative metastatic breast cancer, as assessed by blinded independent central review (BICR). Partial responses (PRs) were observed in 30.1% of patients and 50.4% of patients had a best overall response (BOR) of stable disease (SD). Median duration of response (DOR) was at 7.2 months (95% CI: 5.3-NE). Median progression-free survival (PFS) was 7.4 months (95% CI: 4.7-8.4) and median overall survival (OS) was 14.6 months (95% CI: 11.3-19.5).

In the cohort of 53 patients with HER3 high metastatic triple negative breast cancer (TNBC), an ORR of 22.6% (95% CI: 12.3-36.2) was observed with patritumab deruxtecan, as assessed by BICR. PRs were observed in 22.6% of patients and 56.6% of patients had a BOR of SD. Median DOR was 5.9 months (95% CI: 3.0-8.4). Median PFS was 5.5 months (95% CI: 3.9-6.8) and the median OS was 14.6 months (95% CI: 11.2-17.2).

An ORR of 42.9% (95% CI: 17.7-71.1) was observed with patritumab deruxtecan in the cohort of 14 patients with HER3 high, HER2 positive metastatic breast cancer, as assessed by BICR. PRs were observed in 42.9% of patients and 50.0% of patients had a BOR of SD. Median DOR was 8.3 months (95% CI: 2.8-26.4). Median PFS was 11.0 months (95% CI: 4.4-16.4) and median OS was at 19.5 months (95% CI: 12.2-NE).

"Significant unmet need still remains for the treatment of patients with metastatic breast cancer and new treatment strategies need to be continuously explored," said Ian E. Krop, MD, PhD, Chief Clinical Research Officer, Associate Cancer Center Director for Clinical Research, Yale Cancer Center. "Results from this trial show that patritumab deruxtecan produces clinically meaningful and durable antitumor activity in patients and further study is warranted to further evaluate the efficacy and safety of this HER3 directed antibody drug conjugate across patients with HR positive/HER2 negative, HER2 positive and triple negative breast cancer."

Pooled safety was analyzed for all patients (n=182) enrolled in the trial. Treatment-emergent adverse events (TEAEs) associated with treatment discontinuation was 9.9%. Treatment-related Grade ≥ 3 TEAEs occurred in 120 patients (65.9%) and included neutrophil count decrease, platelet count decrease, white blood cell count decrease, anemia, alanine aminotransferase increase, aspartate aminotransferase increase, decreased appetite, nausea, fatigue, diarrhea, malaise, stomatitis and vomiting. Overall, 12 patients (6.6%) had confirmed treatment-related interstitial lung disease (ILD) or pneumonitis as determined by an independent adjudication committee. Most ILD events were low-grade with three (1.6%) grade 1 and five (2.7%) grade 2 events; three grade 3 (1.6%) and one grade 5 (death) event occurred (0.5%).

Patients were heavily pre-treated, and those with HR positive/HER2 negative metastatic breast cancer had received a median of six (range, 2-13) prior lines of therapy in the advanced setting; patients with metastatic TNBC had received a median of two (range, 1-13) prior therapies; and patients with HER2 positive breast cancer had received a median of 5.5 (range, 2-11) prior therapies. Median treatment duration was 5.9 months (range, 0.7-30.6). As of the data cut-off on August 16, 2021, four patients remained on study treatment with patritumab deruxtecan.

Summary of Results of HER3 Expressing Breast Cancer Phase 1/2 Trial

Efficacy Measures

HR positive/

HER2 negative

HER3 high and

HER3 low

n=113

TNBC

HER3 high

n=53

HER2 positive

HER3 high

n=14

Confirmed ORR, % (95% CI)i

30.1% (21.8-39.4)

22.6% (12.3-36.2)

42.9% (17.7-71.1)

Confirmed BOR

PR, % (n)

30.1% (34)

22.6% (12)

42.9% (6)

SD, % (n)

50.4% (57)

56.6% (30)

50.0% (7)

PD, % (n)

11.5% (13)

17.0% (9)

7.1% (1)

NE, % (n)

8.0% (9)

3.8% (2)

0% (0)

DOR, median (95% CI), months

7.2 months

(5.3-Not Estimable)

5.9 months (3.0-8.4)

8.3 months (2.8-26.4)

PFS, median (95% CI), months

7.4 months (4.7-8.4)

5.5 months (3.9-6.8)

11.0 months (4.4-16.4)

6-month PFS rate, % (95% CI)

53.5% (43.4-62.6)

38.2% (24.2-52.0)

51.6% (22.1-74.8)

OS, median (95% CI), months

14.6 months (11.3-19.5)

14.6 months (11.2-17.2)

19.5 months

(12.2-Not Estimable)

BOR, best overall response; DOR, duration of response; HER, human epidermal growth factor receptor; HR, hormone receptor; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; NE, not evaluable; TNBC, triple negative breast cancer

i 95% exact binomial confidence interval using Clopper-Pearson method

NSCLC Without Common EGFR-Activating Mutations Results

First preliminary results from one cohort of an ongoing phase 1 trial reported durable responses with patritumab deruxtecan after a median follow-up of 19.7 months (range, 13.8-29.2) in patients with locally advanced or metastatic NSCLC without most frequent EGFR activating mutations (EX19del, L858R, L861Q or G719X) or without identified driver genomic alterations.

An ORR of 28.6% (95% CI: 11.3-52.2), as assessed by BICR, was observed with patritumab deruxtecan in 21 patients with advanced NSCLC with identified driver genomic alterations other than EGFR activating mutations. Six patients had PRs and 10 patients had a best overall response of stable disease. Median DOR was 9.4 months (95% CI: 4.2-NE) and a disease control rate (DCR) of 76.2% (95% CI: 52.8-91.8) was observed. Median PFS was 10.8 months (95% CI: 2.8-16.0). Responses with patritumab deruxtecan were seen in patients with a broad range of driver genomic alterations, including KRAS/NRAS mutations and ALK fusions.

In patients with NSCLC without identified driver genomic alterations, an ORR of 26.9% (95% CI: 11.6-47.8) was observed with patritumab deruxtecan in 26 patients, as assessed by BICR. One patient had a complete response (CR), six had PRs and 12 patients had stable disease as a best overall response. Median DOR was 9.6 months (95% CI: 1.6-NE) and a DCR of 73.1% (95% CI: 52.2-88.4) was observed.

"Similar to previously reported results in patients with EGFR mutated non-small cell lung cancer, patritumab deruxtecan shows promising durable responses in patients with heavily pretreated advanced non-small cell lung cancer with or without driver genomic alterations," said Conor E. Steuer, MD, Assistant Professor, Department of Hematology and Medical Oncology, Emory University School of Medicine. "Further research is warranted to further confirm whether targeting HER3 is an effective treatment strategy to overcome treatment resistance in these patients."

Safety of patritumab deruxtecan seen in this cohort was consistent with that previously observed in patients with EGFR-mutated NSCLC. Treatment-related Grade ≥ 3 TEAEs occurred in 24 patients (51.1%) and included neutropenia, fatigue, thrombocytopenia, hypokalemia, anemia, leukopenia and pneumonia. Five patients (10.6%) had confirmed treatment-related ILD as determined by an independent adjudication committee. Most of these ILD events were low-grade with one grade 1 (2.1%) and four grade 2 (8.5%) events. As of data cut-off of January 28, 2022, five patients (10.6%) remained on treatment with patritumab deruxtecan.

About the Phase 1/2 Breast Cancer Trial

The global, open-label, three-part phase 1/2 trial is evaluating the safety and efficacy of patritumab deruxtecan in patients with HER3 expressing advanced/unresectable metastatic breast cancer who are refractory or intolerant to standard treatment, or for whom no standard treatment is available.

The dose escalation part of the trial is assessing the safety and tolerability of increasing doses of patritumab deruxtecan to determine the maximum tolerated dose. The dose finding part of the trial assessed the safety and efficacy of patritumab deruxtecan at selected dosing levels to determine the recommended dose for expansion. Patients in the dose escalation and dose finding parts of the trial must have received six or fewer prior chemotherapy regimens, at least two of which were administered for treatment of advanced/unresectable metastatic disease, and at least one prior chemotherapeutic regimen must have included a taxane, administered in the neoadjuvant, adjuvant or advanced setting.

The phase 2 part of the trial is evaluating the safety and efficacy of patritumab deruxtecan at the recommended dose for expansion in four different cohorts of patients with HER3 expressing and HER2 negative locally advanced or metastatic breast cancer, including HR positive and triple negative breast cancer. For more information, visit ClinicalTrials.gov.

About the Phase 1 Non-Small Cell Lung Cancer Trial

The global, multicenter, open label, two-part phase 1 trial is evaluating patritumab deruxtecan in previously treated patients with metastatic or unresectable NSCLC.

The dose escalation part of the trial is evaluating patients with EGFR-mutated disease either with progression on osimertinib or T790M-negative after progression on erlotinib, gefitinib or afatinib. The primary objective of this part of the trial was to assess the safety and tolerability of patritumab deruxtecan and determine the recommended dose for expansion (RDE).

The dose expansion part of the trial is evaluating patritumab deruxtecan at the RDE (5.6 mg/kg every three weeks) in three cohorts. Cohort 1 includes patients with locally advanced or metastatic EGFR-mutated NSCLC who experienced disease progression after taking one or more EGFR TKIs and one or more platinum-based chemotherapy regimens. Cohort 2 includes patients with squamous or non-squamous NSCLC without EGFR-activating mutations following platinum-based chemotherapy and following an anti-PD-1 or anti-PD-L1 antibody regimen. Cohort 3 includes patients with NSCLC with EGFR-activating mutations including any histology other than combined small cell and non-small cell lung cancer; patients in Cohort 3 are randomized 1:1 to receive the 5.6 mg/kg RDE regimen (Cohort 3a) or an escalating up-titration regimen of patritumab deruxtecan (Cohort 3b).

The primary objective of the dose expansion part of the trial is to assess efficacy of patritumab deruxtecan as measured by confirmed objective response rate (ORR) assessed by blinded independent central review. Secondary trial endpoints include investigator-assessed ORR, safety and pharmacokinetics. The trial enrolled patients at multiple sites in Asia, Europe and North America. For more information, visit ClinicalTrials.gov.

About Breast Cancer and Non-Small Cell Lung Cancer

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.5 More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.5 The five-year survival rate of advanced breast cancer is 30% in the U.S.1

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths worldwide.6 More than 2.2 million cases of lung cancer were diagnosed in 2020, resulting in nearly 1.8 million deaths globally.6 NSCLC accounts for about 84% of all lung cancers.7 About half of patients with NSCLC are diagnosed at an advanced stage and they often have a poor prognosis with worsening outcomes after each line of subsequent therapy.8,9,10 The five-year survival rate of advanced lung cancer is 7% in the U.S.2

About HER3

HER3 is a member of the EGFR family of receptor tyrosine kinases, which are associated with aberrant cell proliferation and survival.3 It is estimated that about 83% of all NSCLC tumors express the HER3 protein. Overexpression is associated with metastatic progression and decreased relapse-free survival.11 Currently, no HER3 directed medicines are approved for the treatment of any cancer.

About Patritumab Deruxtecan

Patritumab deruxtecan (HER3-DXd) is one of three lead DXd ADCs in the oncology pipeline of Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, patritumab deruxtecan is comprised of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other anticancer therapies. The development program includes HERTHENA-Lung01, a pivotal phase 2 study in patients with locally advanced or metastatic EGFR-mutated NSCLC previously treated with a TKI and platinum-based chemotherapy; a phase 1/2 study in HER3 expressing metastatic breast cancer; a phase 1 study in combination with osimertinib in locally advanced/metastatic EGFR-mutated NSCLC; and, a phase 1 study in previously treated patients with metastatic or unresectable NSCLC.

In December 2021, patritumab deruxtecan was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) for the treatment of patients with metastatic or locally advanced EGFR-mutated NSCLC with disease progression on or after treatment with a third-generation TKI and platinum-based therapies.

Patritumab deruxtecan is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.

On June 3, 2022 Merck, a leading science and technology company, reported an update on the progress of the company’s innovative oncology development pipeline focused on DNA damage biology (Press release, Merck & Co, JUN 3, 2022, View Source [SID1234615539]). With clinical programs designed to further advance standards of care in core tumors and assess the potential of novel mechanisms of action, including an industry-leading portfolio of DNA Damage Response inhibitors (DDRi), the company continues to build its focused leadership in the oncology space.

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

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"Within our clinical-stage pipeline and our discovery programs, we have the opportunity to unlock and address DNA biology and apply a diversity of mechanisms to the treatment of multiple cancers," said Victoria Zazulina, M.D., Head of Development Unit Oncology for the Healthcare business of Merck. "We have advanced our DDRi portfolio in a number of settings, as well as agents like xevinapant that could enhance cancer cell death by synergizing with other treatments, such as chemotherapy or radiotherapy."

Advancing Understanding of Novel Mechanisms

The company has advanced the development of its orally administered ataxia telangiectasia and Rad3-related (ATR) inhibitor M1774. Following completion of the monotherapy dose-escalation part of the DDRiver Solid Tumors 301 study, a monotherapy dose for M1774 has been confirmed for further evaluation in Phase Ib. Findings, which show a favorable exposure-safety relationship for M1774, will be shared at an upcoming congress. The ongoing study will assess M1774 as a single agent in patients with whose tumors have specific DDR mutations (defined loss-of-function mutation in ARIDIA, ATRX and/or DAXX, and ATM), and in combination with the poly-ADP ribose polymerase (PARP) inhibitor niraparib.

The ATR pathway is one of the most promising in the DDRi field as illustrated by recent data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The development of M1774 will build on learnings from the exploration of the intravenous ATR inhibitor berzosertib, which has been studied in approximately 1,000 patients to date in multiple combinations, including with chemotherapy, radiotherapy, immunotherapy and PARP inhibitors across company- and investigator-sponsored studies.

Following an interim analysis of the ongoing global Phase II DDRiver SCLC 250 trial of berzosertib in combination with topotecan in patients with relapsed, platinum-resistant small cell lung cancer (SCLC), the decision has been made to discontinue the study due to low probability of meeting the pre-defined objective of this trial. The safety profile for berzosertib plus topotecan was consistent with that observed in other clinical trials to date. SCLC remains a difficult-to-treat disease, with minimal advances in the past 20 years. This is particularly true for patients whose disease is resistant to first-line platinum-based chemotherapy, underscoring the need for additional treatment options. The company will continue its open innovation approach, with ongoing external studies exploring berzosertib in additional combinations and clinical settings.

"While we did not see the outcomes we hoped for with this combination in this particularly challenging population of patients with platinum-resistant SCLC, we are confident in the potential of ATR inhibition, as combination with chemotherapy is only one avenue to take advantage of DNA Damage Response. We continue to progress our oral ATR inhibitor, M1774, and other investigational treatments in our DDRi portfolio as we evaluate the totality of data for berzosertib to assess our path forward," said Zazulina.

Addressing Unmet Needs in Head and Neck Cancer

In addition to inhibiting specific pathways of the DNA Damage Response, the company is exploring other mechanisms that can synergize with DNA damaging agents by modulating cancer cell death caused by these treatment modalities. With the Phase III development program for the potentially first-in-class Inhibitor of Apoptosis Proteins (IAPs) inhibitor xevinapant, the company is building on its long-standing leadership in the treatment of squamous cell carcinoma of the head and neck (SCCHN).

The first of two Phase III clinical trials, the international, randomized, double-blind, placebo-controlled TrilynX study (NCT04459715) to evaluate the efficacy and safety of xevinapant versus placebo when added to definitive chemoradiotherapy (CRT) in patients with unresected locally advanced (LA) SCCHN, is currently recruiting.
The second Phase III clinical trial, XRay Vision (NCT05386550), a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of xevinapant versus placebo in combination with adjuvant, post-operative radiotherapy in patients with resected LA SCCHN who are at high risk for relapse and are ineligible for cisplatin, is expected to open for enrollment in summer 2022.
Working to Progress Treatment Paradigms in Bladder Cancer

Based on the results of the Phase III JAVELIN Bladder 100 study and emerging real-world data, BAVENCIO (avelumab) first-line maintenance therapy has advanced the standard of care in locally advanced or metastatic urothelial carcinoma. The recently opened Phase II JAVELIN Bladder Medley study will evaluate whether optimization of first-line maintenance treatment by adding a novel therapy to avelumab could improve outcomes for patients. This randomized umbrella study will evaluate avelumab monotherapy versus the combination of avelumab with the company’s investigational anti-TIGIT antibody M6223 in the first-line maintenance setting in patients with advanced urothelial carcinoma whose disease did not progress with first-line platinum-containing chemotherapy. The biomarker analysis of the JAVELIN Bladder 100 study suggests that the combination of avelumab and M6223 is rational, given the impact of TIGIT expression and Fc-gamma mutational status on avelumab efficacy. The study will also evaluate avelumab in combination with Nektar Therapeutics’ interleukin-15 (IL-15) receptor agonist, NKTR-255, and in combination with Gilead Sciences’ Trodelvy (sacituzumab govitecan-hziy).

Merck is a science-led organization dedicated to delivering transformative medicines with the goal of making a meaningful difference in the lives of people affected by cancer. Our oncology research efforts aim to leverage our synergistic portfolio in oncogenic pathways, immuno-oncology, and DNA Damage Response (DDR) to tackle challenging tumor types in gastrointestinal, genitourinary, and thoracic cancers. Our curiosity drives our pursuit of treatments for even the most complex cancers, as we work to illuminate a path to scientific breakthroughs that transform patient outcomes. Learn more at www.merckgrouponcology.com.

*Trodelvy is a registered trademark of Gilead Sciences.

About Xevinapant

Xevinapant is a potentially first-in-class potent oral small-molecule IAP (Inhibitor of Apoptosis Proteins) inhibitor. In preclinical studies, xevinapant restored sensitivity to apoptosis in cancer cells, thereby enhancing the effects of chemotherapy and radiotherapy. As the most clinically advanced IAP inhibitor, xevinapant in combination with chemoradiotherapy (CRT) significantly improved efficacy outcomes, including three-year PFS and OS, compared with placebo plus CRT in a Phase 2 study in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Xevinapant, formerly known as Debio 1143, was licensed from Debiopharm in 2021. Xevinapant is not approved for any use anywhere in the world.

About BAVENCIO (avelumab)

BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models. In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications

The European Commission (EC) has authorized the use of BAVENCIO as monotherapy for the first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) who are progression-free following platinum-based chemotherapy. BAVENCIO in combination with axitinib is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). BAVENCIO is also authorized by the EC for use as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (MCC).

In the US, BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

BAVENCIO in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced RCC. Additionally, the US Food and Drug Administration (FDA) granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic MCC. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

BAVENCIO is currently approved for at least one indication for patients in more than 50 countries.

BAVENCIO Safety Profile from the EU Summary of Product Characteristics (SmPC)

The special warnings and precautions for use for BAVENCIO monotherapy include infusion-related reactions, as well as immune-related adverse reactions that include pneumonitis and hepatitis (including fatal cases), colitis, pancreatitis (including fatal cases), myocarditis (including fatal cases), endocrinopathies, nephritis and renal dysfunction, and other immune-related adverse reactions. The special warnings and precautions for use for BAVENCIO in combination with axitinib include hepatotoxicity.

The SmPC list of the most common adverse reactions with BAVENCIO monotherapy in patients with solid tumors includes fatigue, nausea, diarrhea, decreased appetite, constipation, infusion-related reactions, weight decreased and vomiting. The list of most common adverse reactions with BAVENCIO in combination with axitinib includes diarrhea, hypertension, fatigue, nausea, dysphonia, decreased appetite, hypothyroidism, cough, headache, dyspnea, and arthralgia.

About Berzosertib

Berzosertib is an investigational, potent and selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) protein that blocks ATR activity in several cancer cell lines. Berzosertib is the first ATR inhibitor evaluated in a randomized clinical trial in any tumor type, and it is the lead candidate in Merck’s DNA Damage Response (DDR) inhibitor portfolio. It is currently being investigated in several internal and external studies with early phase I/II data in small cell lung cancer, ovarian cancer, and various solid tumors. Berzosertib, formerly known as M6620 or VX-970, was licensed from Vertex Pharmaceuticals in 2017. Berzosertib is not approved for any use anywhere in the world.

All Merck press releases are distributed by e-mail at the same time they become available on the Merck website. Please go to www.merckgroup.com/subscribe to register online, change your selection or discontinue this service.

On June 3, 2022 EMD Serono, the healthcare business of Merck KGaA, Darmstadt, Germany, in the US and Canada, reported an update on the progress of the company’s innovative oncology development pipeline focused on DNA damage biology (Press release, EMD Serono, JUN 3, 2022, View Source [SID1234615538]). With clinical programs designed to further advance standards of care in core tumors and assess the potential of novel mechanisms of action, including an industry-leading portfolio of DNA Damage Response inhibitors (DDRi), the company continues to build its focused leadership in the oncology space.

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

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

                  Schedule Your 30 min Free Demo!

"Within our clinical-stage pipeline and our discovery programs, we have the opportunity to unlock and address DNA biology and apply a diversity of mechanisms to the treatment of multiple cancers," said Victoria Zazulina, M.D., Head of Development Unit, Oncology, for the Healthcare business of Merck KGaA, Darmstadt, Germany. "We have advanced our DDRi portfolio in a number of settings, as well as agents like xevinapant that could enhance cancer cell death by synergizing with other treatments, such as chemotherapy or radiotherapy."

Advancing Understanding of Novel Mechanisms

The company has advanced the development of its orally administered ataxia telangiectasia and Rad3-related (ATR) inhibitor M1774. Following completion of the monotherapy dose-escalation part of the DDRiver Solid Tumors 301 study, a monotherapy dose for M1774 has been confirmed for further evaluation in Phase Ib. Findings, which show a favorable exposure-safety relationship for M1774, will be shared at an upcoming congress. The ongoing study will assess M1774 as a single agent in patients with whose tumors have specific DDR mutations (defined loss-of-function mutation in ARIDIA, ATRX and/or DAXX, and ATM), and in combination with the poly-ADP ribose polymerase (PARP) inhibitor niraparib.

The ATR pathway is one of the most promising in the DDRi field as illustrated by recent data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The development of M1774 will build on learnings from the exploration of the intravenous ATR inhibitor berzosertib, which has been studied in approximately 1,000 patients to date in multiple combinations, including with chemotherapy, radiotherapy, immunotherapy and PARP inhibitors across company- and investigator-sponsored studies.

Following an interim analysis of the ongoing global Phase II DDRiver SCLC 250 trial of berzosertib in combination with topotecan in patients with relapsed, platinum-resistant small cell lung cancer (SCLC), the decision has been made to discontinue the study due to low probability of meeting the pre-defined objective of this trial. The safety profile for berzosertib plus topotecan was consistent with that observed in other clinical trials to date. SCLC remains a difficult-to-treat disease, with minimal advances in the past 20 years. This is particularly true for patients whose disease is resistant to first-line platinum-based chemotherapy, underscoring the need for additional treatment options. The company will continue its open innovation approach, with ongoing external studies exploring berzosertib in additional combinations and clinical settings.

"While we did not see the outcomes we hoped for with this combination in this particularly challenging population of patients with platinum-resistant SCLC, we are confident in the potential of ATR inhibition, as combination with chemotherapy is only one avenue to take advantage of DNA Damage Response. We continue to progress our oral ATR inhibitor, M1774, and other investigational treatments in our DDRi portfolio as we evaluate the totality of data for berzosertib to assess our path forward," said Zazulina.

Addressing Unmet Needs in Head and Neck Cancer

In addition to inhibiting specific pathways of the DNA Damage Response, the company is exploring other mechanisms that can synergize with DNA damaging agents by modulating cancer cell death caused by these treatment modalities. With the Phase III development program for the potentially first-in-class Inhibitor of Apoptosis Proteins (IAPs) inhibitor xevinapant, the company is building on its long-standing leadership in the treatment of squamous cell carcinoma of the head and neck (SCCHN).

The first of two Phase III clinical trials, the international, randomized, double-blind, placebo-controlled TrilynX study (NCT04459715) to evaluate the efficacy and safety of xevinapant versus placebo when added to definitive chemoradiotherapy (CRT) in patients with unresected locally advanced (LA) SCCHN, is currently recruiting.
The second Phase III clinical trial, XRay Vision (NCT05386550), a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of xevinapant versus placebo in combination with adjuvant, post-operative radiotherapy in patients with resected LA SCCHN who are at high risk for relapse and are ineligible for cisplatin, is expected to open for enrollment in summer 2022.
Working to Progress Treatment Paradigms in Bladder Cancer

Based on the results of the Phase III JAVELIN Bladder 100 study and emerging real-world data, BAVENCIO (avelumab) first-line maintenance therapy has advanced the standard of care in locally advanced or metastatic urothelial carcinoma. The recently opened Phase II JAVELIN Bladder Medley study will evaluate whether optimization of first-line maintenance treatment by adding a novel therapy to avelumab could improve outcomes for patients. This randomized umbrella study will evaluate avelumab monotherapy versus the combination of avelumab with the company’s investigational anti-TIGIT antibody M6223 in the first-line maintenance setting in patients with advanced urothelial carcinoma whose disease did not progress with first-line platinum-containing chemotherapy. The biomarker analysis of the JAVELIN Bladder 100 study suggests that the combination of avelumab and M6223 is rational, given the impact of TIGIT expression and Fc-gamma mutational status on avelumab efficacy. The study will also evaluate avelumab in combination with Nektar Therapeutics’ interleukin-15 (IL-15) receptor agonist, NKTR-255, and in combination with Gilead Sciences’ Trodelvy (sacituzumab govitecan-hziy).

Merck KGaA, Darmstadt, Germany is a science-led organization dedicated to delivering transformative medicines with the goal of making a meaningful difference in the lives of people affected by cancer. Our oncology research efforts aim to leverage our synergistic portfolio in oncogenic pathways, immuno-oncology, and DNA Damage Response (DDR) to tackle challenging tumor types in gastrointestinal, genitourinary, and thoracic cancers. Our curiosity drives our pursuit of treatments for even the most complex cancers, as we work to illuminate a path to scientific breakthroughs that transform patient outcomes. Learn more at www.emdseronooncology.com.

*Trodelvy is a registered trademark of Gilead Sciences.

About Xevinapant

Xevinapant is a potentially first-in-class potent oral small-molecule IAP (Inhibitor of Apoptosis Proteins) inhibitor. In preclinical studies, xevinapant restored sensitivity to apoptosis in cancer cells, thereby enhancing the effects of chemotherapy and radiotherapy. As the most clinically advanced IAP inhibitor, xevinapant in combination with chemoradiotherapy (CRT) significantly improved efficacy outcomes, including three-year PFS and OS, compared with placebo plus CRT in a Phase 2 study in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Xevinapant, formerly known as Debio 1143, was licensed from Debiopharm in 2021. Xevinapant is not approved for any use anywhere in the world.

About BAVENCIO (avelumab)

BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models. In November 2014, Merck KGaA, Darmstadt, Germany and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications

BAVENCIO (avelumab) is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

BAVENCIO in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

BAVENCIO is currently approved for at least one indication for patients in more than 50 countries.

BAVENCIO Important Safety Information from the US FDA-Approved Label

BAVENCIO can cause severe and fatal immune-mediated adverse reactions in any organ system or tissue and at any time after starting treatment with a PD-1/PD-L1 blocking antibody, including after discontinuation of treatment.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

No dose reduction for BAVENCIO is recommended. For immune-mediated adverse reactions, withhold or permanently discontinue BAVENCIO depending on severity. In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (eg, endocrinopathies and dermatologic reactions) are discussed in subsequent sections.

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for Grade 2 and permanently discontinue for Grade 3 or Grade 4 pneumonitis. Immune-mediated pneumonitis occurred in 1.2% (21/1738) of patients, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%) and Grade 2 (0.6%) adverse reactions. Systemic corticosteroids were required in all (21/21) patients with pneumonitis.

BAVENCIO can cause immune-mediated colitis. The primary component of immune-mediated colitis consisted of diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 colitis. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including Grade 3 (0.4%) and Grade 2 (0.7%) adverse reactions. Systemic corticosteroids were required in all (26/26) patients with colitis.

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis. Withhold or permanently discontinue BAVENCIO based on tumor involvement of the liver and severity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin elevation. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% (16/1738) of patients, including fatal (0.1%), Grade 3 (0.6%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in all (16/16) patients with hepatitis.

BAVENCIO in combination with INLYTA can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation compared to BAVENCIO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold or permanently discontinue both BAVENCIO and INLYTA based on severity of AST, ALT, or total bilirubin elevation, and consider administering corticosteroids as needed. Consider rechallenge with BAVENCIO or INLYTA, or sequential rechallenge with both BAVENCIO and INLYTA, after recovery. In patients treated with BAVENCIO in combination with INLYTA in the advanced RCC trials, increased ALT and increased AST were reported in 9% (Grade 3) and 7% (Grade 4) of patients. Immune-mediated hepatitis was reported in 7% of patients including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidal immunosuppressant.

BAVENCIO can cause primary or secondary immune-mediated adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated adrenal insufficiency occurred in 0.5% (8/1738) of patients, including Grade 3 (0.1%) and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in all (8/8) patients with adrenal insufficiency.

BAVENCIO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated pituitary disorders occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction.

BAVENCIO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Thyroiditis occurred in 0.2% (4/1738) of patients, including Grade 2 (0.1%) adverse reactions. Hyperthyroidism occurred in 0.4% (7/1738) of patients, including Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 29% (2/7) of patients with hyperthyroidism. Hypothyroidism occurred in 5% (90/1738) of patients, including Grade 3 (0.2%) and Grade 2 (3.7%) adverse reactions. Systemic corticosteroids were required in 7% (6/90) of patients with hypothyroidism.

BAVENCIO can cause immune-mediated type I diabetes mellitus, which can present with diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated type I diabetes mellitus occurred in 0.1% (2/1738) of patients, including Grade 3 (0.1%) adverse reactions.

BAVENCIO can cause immune-mediated nephritis with renal dysfunction. Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 increased blood creatinine. Immune-mediated nephritis with renal dysfunction occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction. Systemic corticosteroids were required in this patient.

BAVENCIO can cause immune-mediated dermatologic adverse reactions, including rash or dermatitis. Exfoliative dermatitis including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold BAVENCIO for suspected and permanently discontinue for confirmed SJS, TEN, or DRESS. Immune-mediated dermatologic adverse reactions occurred in 5% (90/1738) of patients, including Grade 3 (0.1%) and Grade 2 (2.0%) adverse reactions. Systemic corticosteroids were required in 29% (26/90) of patients with dermatologic adverse reactions.

BAVENCIO can result in other immune-mediated adverse reactions. Other clinically significant immune-mediated adverse reactions occurred at an incidence of <1% in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies. For myocarditis, permanently discontinue BAVENCIO for Grade 2, Grade 3, or Grade 4. For neurological toxicities, withhold BAVENCIO for Grade 2 and permanently discontinue for Grade 3 or Grade 4.

BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 infusion-related reactions. Permanently discontinue BAVENCIO for Grade 3 or Grade 4 infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Eleven (92%) of the 12 patients with Grade ≥3 reactions were treated with intravenous corticosteroids.

Fatal and other serious complications of allogeneic hematopoietic stem cell transplantation (HSCT) can occur in patients who receive HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

BAVENCIO in combination with INLYTA can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Permanently discontinue BAVENCIO and INLYTA for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with INLYTA compared to 3.4% treated with sunitinib in a randomized trial. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient with locally advanced or metastatic urothelial carcinoma (UC) receiving BAVENCIO + best supportive care (BSC) as first-line maintenance treatment. In patients with previously treated locally advanced or metastatic UC, fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.

The most common adverse reactions (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were fatigue (35% vs 13%), musculoskeletal pain (24% vs 15%), urinary tract infection (20% vs 11%), and rash (20% vs 2.3%). In patients with previously treated locally advanced or metastatic UC receiving BAVENCIO, the most common adverse reactions (all grades, ≥20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Selected laboratory abnormalities (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were blood triglycerides increased (34% vs 28%), alkaline phosphatase increased (30% vs 20%), blood sodium decreased (28% vs 20%), lipase increased (25% vs 16%), aspartate aminotransferase (AST) increased (24% vs 12%), blood potassium increased (24% vs 16%), alanine aminotransferase (ALT) increased (24% vs 12%), blood cholesterol increased (22% vs 16%), serum amylase increased (21% vs 12%), hemoglobin decreased (28% vs 18%), and white blood cell decreased (20% vs 10%).

Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with INLYTA. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with INLYTA (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with INLYTA (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).

Please see full US Prescribing Information and Medication Guide available at View Source

About Berzosertib

Berzosertib is an investigational, potent and selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) protein that blocks ATR activity in several cancer cell lines. Berzosertib is the first ATR inhibitor evaluated in a randomized clinical trial in any tumor type, and it is the lead candidate in Merck KGaA, Darmstadt, Germany’s DNA Damage Response (DDR) inhibitor portfolio. It is currently being investigated in several internal and external studies with early phase I/II data in small cell lung cancer, ovarian cancer, and various solid tumors. Berzosertib, formerly known as M6620 or VX-970, was licensed from Vertex Pharmaceuticals in 2017. Berzosertib is not approved for any use anywhere in the world.

On June 3, 2022 BostonGene reported that three abstracts have been accepted for poster presentations and one abstract has been accepted for online publication for the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting (ASCO) (Free ASCO Whitepaper), which will be held June 3 – 7, 2022, at McCormick Place Convention Center in Chicago, IL (Press release, BostonGene, JUN 3, 2022, View Source [SID1234615537]). BostonGene will also exhibit at booth 27087.

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

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"We are excited to share our latest research at ASCO (Free ASCO Whitepaper) that underscores the critical need for innovative analytical tools to understand the composition and activity of the tumor and the microenvironment to improve treatment outcomes for cancer patients," said Nathan Fowler MD, Chief Medical Officer at BostonGene.

Details about the abstracts selected for presentation can be found below:

Abstract Number: 4591
Title: A classification system for urothelial carcinoma (UC) defined by genomic drivers and the tumor microenvironment (TME) is predictive of immunotherapy response
Date and Time: Saturday, June 4 | 1:15 PM – 4:15 PM
Location: McCormick Place Convention Center, Hall A
Poster Number: 82
Speaker: Krystle Nomie, PhD, BostonGene

This presentation underscores the application of BostonGene’s transcriptome-based classification platform, previously reported by Bagaev et al., to identify TME subtypes for urothelial carcinoma that are predictive of response to immunotherapy.

Abstract Number: 3020
Title: A clinical AI-driven multiplex immunofluorescence imaging pipeline to characterize tumor microenvironment heterogeneity
Date and Time: Sunday, June 5 | 8:00 AM – 11:00 AM*
Location: McCormick Place Convention Center, Hall A
Poster Number: 12
Speaker: Zhongmin Xiang, PhD, BostonGene

*A follow-up poster discussion highlighting the AI-driven BostonGene MxIF analytical pipeline and its automated microenvironment characterization across cancers will take place from 4:30 PM – 6:00 PM in Hall D2

This presentation highlights the importance of innovative MxIF platforms to characterize tumor heterogeneity at single-cell resolution with high accuracy across many cancers.

Abstract Number: 3142
Title: A digital imaging analysis (DIA) platform for identifying tertiary lymphoid structures (TLS) in lung adenocarcinoma (LUAD)
Date and Time: Sunday, June 5 | 8:00 AM – 11:00 AM
Location: McCormick Place Convention Center, Hall A
Poster Number: 134
Speaker: Ekaterina Postovalova, PhD, BostonGene

This presentation demonstrates the ability of novel and cutting-edge imaging technologies in the BostonGene pipeline to detect tertiary lymphoid structures (TLS) in lung cancer.

Online publication abstract:

Abstract Number: e20624
Title: Longitudinal Molecular Analysis of Tumor Exome and Transcriptome to Evaluate Clonal Evolution and Identify Novel Therapeutic Targets in Thymoma

This abstract highlights the importance of a longitudinal comprehensive molecular analysis using genomic and transcriptomic sequencing to improve the understanding of rare thymic epithelial tumors.

Research conducted with Massachusetts General Hospital

For more information, please visit the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting website. The abstracts will be published online in the Journal of Clinical Oncology supplement for the ASCO (Free ASCO Whitepaper) Annual Meeting Proceedings.

On June 3, 2022 Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global biotechnology company developing, manufacturing and commercializing novel therapies to treat life-threatening diseases, reported that the U.S. Food and Drug Administration (FDA) has cleared its investigational new drug (IND) application to evaluate LB1908 in a Phase 1 clinical trial in the United States (Press release, Legend Biotech, JUN 3, 2022, View Source [SID1234615536]). LB1908 is an investigational, autologous chimeric antigen receptor T-cell (CAR-T) therapy selectively targeting Claudin 18.2 through a high-affinity VHH antibody for the treatment of adults with relapsed or refractory gastric, esophageal (including gastro-esophageal junction) or pancreatic cancers. Claudin18.2 is a tight junction protein commonly expressed in patients with these cancer subtypes.1

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

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The Phase 1, first-in-human, open-label, multicenter clinical study seeks to characterize the safety and tolerability of LB1908, as well as determine the recommended dose for Phase 2 and evaluate preliminary efficacy. Study will have dose escalation and dose expansion phases. Patients enrolled in the study must sufficiently express Claudin 18.2.

A Phase 1 investigator-initiated trial evaluating LB1908 for advanced gastric cancers is also ongoing in China (NCT04467853).

"Treatment options for patients with esophageal, stomach and pancreatic cancers have improved in the last ten years, but patients in the advanced stages still face poor prognoses worldwide. Thousands of people have no symptoms until their cancers have moved into late phases and at that point, surgery is no longer an option," said Lida Pacaud, M.D., Vice-President of Clinical Development. "Based on prevailing research, we are optimistic that a CAR-T therapy targeting Claudin 18.2 can be integrated in future treatment strategies for those with relapsed or refractory gastrointestinal cancers. We look forward to the start of the trial."

About Gastric, Esophageal and Pancreatic Cancers
Stomach, esophageal and pancreatic cancers affect the tissue or glands lining these organs. They are often diagnosed when the diseases have progressed to advanced stages. In the U.S., there are an estimated 123,920 people living with stomach cancer and 49,084 living with esophageal cancers.2,3 An estimated 89,248 people in the U.S. live with pancreatic cancer. While all three cancers are treatable, the five-year survival rate is just 32% for gastric cancer; 20% for esophageal cancer; and 11.5% for pancreatic cancer, with definitive treatment at all stages of progression.4,5,6