On June 3, 2022 Parker Institute for Cancer Immunotherapy reported that Researchers have identified certain patients with pancreatic cancer who may be more likely to benefit from combination treatment regimens consisting of immunotherapy and chemotherapy (Press release, Parker Institute for Cancer Immunotherapy, JUN 3, 2022, View Source [SID1234615543]). These new data, stemming from a long-term collaboration between academia, biotech, pharma and nonprofits within the Parker Institute for Cancer Immunotherapy (PICI) network, were shared with the medical community at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago today . The comprehensive clinical and immunologic findings of the Phase II clinical trial, known as the PRINCE study, were published simultaneously in the peer-reviewed journal Nature Medicine.

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Approximately 60,000 people are diagnosed with pancreatic cancer every year in the U.S., and the prognosis is typically poor. For the subset of patients diagnosed with advanced metastatic pancreatic ductal adenocarcinoma (mPDAC), the disease studied in PRINCE, the five-year survival rate is less than 5%1.

The findings are part of a recent analysis of data from the PRINCE trial, sponsored by PICI, and designed on the basis of decades of research by lead Principal Investigator Robert Vonderheide, M.D., D.Phil., and others at the University of Pennsylvania. The trial involved seven PICI network institutions, and uncovered various predictive biomarkers associated with longer overall survival for a subset of mPDAC patients.

The PRINCE trial evaluated the combination of standard-of-care chemotherapy (gemcitabine + nab-paclitaxel) and nivolumab, a PD-1 inhibitor, and/or sotigalimab, an experimental antibody that is an agonist of the CD40 protein. As part of exploratory analyses, PICI researchers discovered distinct biosignatures associated with survival for the nivolumab-chemotherapy and sotigalimab-chemotherapy treatment arms, which reflect each immunotherapy’s distinct mechanisms of action. Few biomarkers predicted survival in patients receiving the sotigalimab-nivolumab-chemotherapy regimen.

"While the data from the trial suggest that these treatment regimens may not be appropriate for all PDAC patients, we uncovered various predictive biomarkers from the circulation and tumor that may correlate with longer survival and warrant further study," said Lacey Padron, Ph.D., Vice President, Informatics at PICI and lead study author. "We are encouraged by the data and believe chemoimmunotherapy combinations may improve outcomes for some patients with metastatic PDAC. Following up on these results, the scientific community can work to better understand who is most likely to benefit and why."

The PRINCE trial was conducted in collaboration with:

Bristol Myers Squibb, which provided nivolumab
Apexigen, which provided sotigalimab
Cancer Research Institute
In addition to the University of Pennsylvania, participating research sites from the PICI network include the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, Stanford Medicine, University of California, Los Angeles, University of California, San Francisco and The University of Texas MD Anderson Cancer Center.

"The PRINCE trial illustrates how this groundbreaking clinical research fostered collaboration between clinicians, researchers, nonprofits and industry, with the goal of bringing innovative treatments to patients faster," said Ute Dugan, M.D., Ph.D., Chief Medical Officer of PICI. "We look forward to building on these interesting results."

PDAC remains one of the most intractable challenges in oncology. Pancreatic cancer, the third-leading cause of cancer death in the U.S. in 2020, is predicted to become the No. 2 cause of cancer death in the U.S. by 20402. In the metastatic setting, while combination chemotherapy reliably offers tumor control and clinical stabilization, both standard regimens of gemcitabine plus nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil and leucovorin) are limited in response durability and incur toxicity. Thus, new treatment strategies for this disease are urgently needed.

"The identification of signals that may help predict clinical outcomes for pancreatic cancer patients receiving combination treatment with chemotherapy and immunotherapy has significant potential to save more lives, as oncologists will be better equipped to design optimal treatment plans for their patients based on the presence or absence of these signals," said Jill O’Donnell-Tormey, Ph.D., Chief Executive Officer and Director of Scientific Affairs at the Cancer Research Institute.

The PRINCE trial is a collaborative research effort designed to work towards advancing more efficacious therapies that can create durable response, and ultimately remission, in patients. The translational work highlighted at ASCO (Free ASCO Whitepaper) and in Nature Medicine has identified biological signals in the blood and tumor that may uncover which patients have longer survival after these combination treatment regimens. The goal of this research is to one day predict via a simple test ahead of time whether a patient stands to benefit from a particular chemoimmunotherapy regimen.

"While scientific and medical advances in immunotherapy are helping to turn cancer into a curable disease for many patients, pancreatic cancer presents unique challenges that deserve the attention of the greatest scientific minds," said William Hoos, cancer research and collaboration lead at 1440 Foundation, a nonprofit that funds innovative pancreatic cancer research and collaboration, including support for the REVOLUTION study of novel immunotherapy combinations in pancreatic cancer, at PICI. "The potential for a biomarker selection strategy to identify the right immunotherapy combination for each patient holds potential for progress in pancreatic cancer. These new findings suggest next steps for researchers, and hope for pancreatic cancer patients and their families. We look forward to continued progress in this promising field."

More Information about the ASCO (Free ASCO Whitepaper) Presentation

Title: Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer
Abstract No.: 4010
Session: Clinical Science Symposium: Can We Begin to Predict Responders to Targeted Therapy in Gastrointestinal Cancer?
Location: McCormick Place, Hall D1 (in person and via livestream)
Date and Time: Friday, June 3, 2022, 5:30-7 p.m. ET/4:30-6 p.m. CT/2:30-4 p.m. PT
Lead Author and Presenter: Lacey Padron, Ph.D., Vice President, Informatics at PICI

The study’s comprehensive clinical and immunologic findings, "Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: Clinical and immunologic analyses from the randomized Phase 2 PRINCE trial," were published in the peer-reviewed journal Nature Medicine. The study authors conclude the Phase Ib/II study is a first step toward characterizing which patients may derive clinical benefit from these chemoimmunotherapy regimens by having identified potential biomarkers that can now be validated prospectively to determine if this allows for minimally invasive biomarker-enrichment designs for chemoimmunotherapy treatment in metastatic PDAC.

"The presentation and publication of these results in pancreatic cancer underscore PICI’s commitment to advancing our understanding of the toughest tumor types," said John Connolly, Ph.D., Chief Scientific Officer of PICI. "This shared knowledge can help patients, clinicians and researchers, alike, combat this deadly disease."

About Pancreatic Cancer

Pancreatic cancer is one of the deadliest types of tumors, and the number of diagnosed cases continues to rise each year. The disease is often difficult to catch early, such that by the time most people are diagnosed, their cancer is advanced and may have already spread. In addition, the tumors usually contain a variety of mutations, which often means a single targeted therapy isn’t enough to stop the disease by itself. For patients diagnosed with advanced metastatic pancreatic ductal adenocarcinoma (mPDAC), the five-year survival rate is less than 5%.

On June 3, 2022 Dxcover Limited, a clinical stage diagnostics company developing spectroscopic liquid biopsy technology for early detection of multiple cancers, reported that new data from a large-scale study on multi-cancer detection at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Dxcover, JUN 3, 2022, View Source [SID1234615542]).

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Presented by Dr. Matthew Baker, co-founder and Chief Technology Officer at Dxcover, the results showcase the need for an effective test that accurately identifies patients with non-specific symptoms who have cancer in its earliest stages, while it is still treatable. Dxcover has pioneered the early detection and identification of cancer by employing infrared spectroscopy of circulating pan-omic biomarkers. Its platform combines novel hardware with artificial intelligence algorithms to analyze a patient’s blood and detect the presence or absence of disease.

The study, which recruited 2,094 patients, set out to distinguish cancer from non-cancer, as well as differentiate organ specific detection from other forms of cancer including brain, breast, colorectal, kidney, lung, ovary, pancreas, and prostate. Results from the research, which applied the Dxcover Cancer Liquid Biopsy, proved the importance and impact of early cancer detection. At a 99% specificity the model achieved 64% sensitivity for stage I cancers. For overall cancer classification, the model achieved 90% sensitivity and 61% specificity when tuned for sensitivity. Detection rates were 93% for stage I, 84% for stage II, 92% for stage III and 95% for stage IV.

"Our mission is to lead the way in liquid biopsy detection of cancers to improve survival and overall quality of life. We have successfully completed two groundbreaking studies on earlier diagnosis of brain cancer using the Dxcover platform, and today’s study demonstrates its ability to detect multiple cancers at their earliest stages, which we know is critical in providing the necessary care and treatment while it can be most impactful to patient outcomes," said Dr. Matthew Baker, co-founder and Chief Technology Officer at Dxcover.

Additionally, Dxcover released results from its proof-of-concept study investigating the use of Dxcover’s liquid biopsy as a novel approach for pancreatic cancer, the 7th most deadly cancer worldwide. The study focused on the discrimination between both cancer and control samples, and cancer and symptomatic non-malignant control samples.

Results showed that the two groups were significantly distinguished, achieving up to a sensitivity of 91.0%, specificity of 87.6% and accuracy of 89.3% with PLS-DA, underscoring that early-stage detection of pancreatic cancer would be key in improving prognosis and survival rates of patients in combination with targeted earlier surgery and treatments.

On June 3, 2022 Scorpion Therapeutics, Inc. ("Scorpion Therapeutics"), a pioneering oncology company redefining the frontier of precision medicine through its Precision Oncology 2.0 strategy, reported that Axel Hoos, M.D., Ph.D., Chief Executive Officer of Scorpion Therapeutics, will present a corporate overview at the Jefferies Healthcare Conference on Friday, June 10, 2022 at 9:30 a.m. ET in New York City (Press release, Scorpion Therapeutics, JUN 3, 2022, View Source [SID1234615541]).

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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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"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.

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