On May 19, 2021 Veracyte, Inc. (Nasdaq: VCYT) reported pivotal clinical validation data showing that the company’s noninvasive nasal swab test can significantly improve the early assessment of lung cancer (Press release, Veracyte, MAY 19, 2021, View Source [SID1234580257]). The new findings show that the Percepta Nasal Swab, a first-of-its-kind genomic test, accurately classifies lung cancer risk in current or former smokers with lung nodules so that those with benign nodules may safely avoid unnecessary additional procedures, while those with likely cancerous nodules may receive more timely diagnosis and treatment. The findings will be presented June 4, 2021 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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"Lung nodules are often the first sign of lung cancer and cannot be ignored, yet most of them are benign," said Carla R. Lamb, M.D., interventional pulmonologist at Lahey Hospital & Medical Center in Burlington, Mass., who was an investigator on the nasal classifier study. "Today, physicians have limited objective tools to determine which patients with lung nodules found on CT scans have cancer and which don’t. Our findings showed that the nasal swab test can determine, with a high level of accuracy, which patients are at low risk of cancer and can avoid invasive procedures. Similarly, it can identify which patients are at high risk and may be confidently directed to further work-up and, potentially, to the treatment they need. An objective tool that can accurately inform these decisions could be a game-changer for early lung cancer assessment."

For the study, researchers evaluated the performance of the nasal swab test on a blinded, independent validation set of 249 patients from multiple cohorts of prospectively collected nasal samples of current or former smokers undergoing evaluation for lung nodules found on computed tomography (CT). All were followed for up to one year or until physicians made a final, adjudicated diagnosis. The cancer prevalence in the validation cohort was 54% — higher than the 25% cancer prevalence expected in the broad population of patients with suspicious nodules, on which the test is expected to be used.

Results of the validation study demonstrate that the test identifies patients as low risk for cancer with a sensitivity of 96.3% (CI: 91.6%-98.4%) and specificity of 41.7% (CI: 33.1%-50.9%). At the same time, the test identifies patients as high risk for cancer with a specificity of 90.4% (CI: 83.68%-94.57%) and sensitivity of 58.2% (CI: 49.74%-66.22%). These findings show the test classifies more than 40% of patients with confirmed benign nodules as low risk, allowing them to avoid further procedures, and it classifies nearly 60% with confirmed malignant nodules as high risk, enabling them to be directed to more timely diagnosis and potential treatment. The remaining patients were classified as intermediate risk for cancer.

When the test’s performance was applied to a population with 25% cancer prevalence, it showed that the test’s negative predictive value (NPV) is 97.1%, which means that a patient classified as low risk has only a 2.9% risk of malignancy. Similarly, the positive predictive value (PPV) is 67%, meaning that nearly 70% of patients classified as high risk will have lung cancer. The American College of Chest Physicians’ current guidelines recommend diagnostic biopsy for patients with more than 65% cancer risk.

"What is really exciting about these data is that doctors will be able to tell their patients with suspicious lung nodules that they are low risk for cancer and can likely avoid further work-up, with very high certainty that they have not missed a cancer," said Giulia C. Kennedy, Ph.D., Veracyte’s chief scientific officer and chief medical officer. "At the same time, they can be confident in guiding patients who are high risk to further diagnostic procedures, in line with current guidelines. These findings suggest that the Percepta Nasal Swab test will be able to objectively and accurately stratify approximately half of the patients with lung nodules found on CT scans to low or high risk, while those not classified will remain a candidate for current standard of care. We are excited about the opportunity to transform the early assessment of lung nodules with a simple nasal swab test."

The Percepta Nasal Swab test uses advanced genomic and established "field of injury" technology to detect smoking-related damage associated with lung cancer in current or former smokers using a sample collected from the nasal passage. Veracyte developed the final classifier using RNA whole-transcriptome sequencing and machine learning on a rich training set of nasal samples from more than 1,100 patients representing a wide range of lung and tumor biology.

Veracyte expects to begin making the Percepta Nasal Swab test available to a select number of sites in the second half of 2021. The company aims to adapt the test on the nCounter Analysis System in 2022, enabling its expansion to physicians and their patients in global markets in 2023.

The Percepta Nasal Swab test is a key part of Veracyte’s comprehensive lung cancer portfolio, which aims to transform care at every step of the patient journey. Collectively, the company’s tests are leveraging cutting-edge genomic science and technology to provide answers and insights that enable physicians and patients to make better, faster and more confident care decisions. The lung cancer portfolio includes the Percepta Genomic Sequencing Classifier, which helps improve lung cancer diagnosis when bronchoscopy results are inconclusive, and the in-development Percepta Genomic Atlas, which is intended to detect gene alterations that may inform lung cancer treatment decisions, using the same small biopsy that was collected for diagnosis.

Development and validation of the Percepta Nasal Swab test is part of Veracyte’s ongoing collaboration with the Lung Cancer Initiative at Johnson & Johnson.*

Conference Call and Webcast Details

Veracyte will host a conference call and webcast on Thursday, May 20, at 10:00 a.m. Eastern Time to discuss the Percepta Nasal Swab test data. The conference call will be webcast live from the company’s website and will be available via the following link: View Source The webcast should be accessed 10 minutes prior to the conference call start time. A replay of the webcast will be available for one year following the conclusion of the live broadcast and will be accessible on the company’s website at View Source

The conference call can be accessed as follows:

About Lung Cancer

Lung cancer kills more than 1.8 million people worldwide each year.i Early detection is key, with a five-year survival rate of nearly 60 percent when the cancer is found early, compared to 6 percent when it is found at a later stage.ii Lung nodules are typically the first sign of lung cancer, but most lung nodules are benign. Each year in the U.S., an estimated 1.6 million lung nodules are found incidentally on CT scans and, with recently expanded recommendations from the U.S. Preventive Services Task Force, an estimated 15 million Americans are eligible for annual lung cancer CT screening. Physicians currently lack objective tools to determine which lung nodules found on CT are benign and which are cancerous.

On May 19, 2021 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported updated interim clinical data, from the ongoing Phase 1/2 CIRLL (Cirmtuzumab and Ibrutinib targeting ROR1 for Leukemia and Lymphoma) clinical trial, that will be presented in poster form at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Annual Meeting (Press release, Oncternal Therapeutics, MAY 19, 2021, View Source [SID1234580274]). In the CIRLL study, cirmtuzumab, an investigational anti-ROR1 monoclonal antibody, is being evaluated in combination with ibrutinib in patients with MCL and CLL. The clinical trial is being conducted in collaboration with UC San Diego School of Medicine and is partially funded by the California Institute for Regenerative Medicine.

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The updated interim data will be presented at the Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia session on June 7, 2021 as part of the ASCO (Free ASCO Whitepaper) 2021 Annual Meeting:

Abstract Title: Phase 1/2 Study of Cirmtuzumab and Ibrutinib in Mantle Cell Lymphoma (MCL) or Chronic
Lymphocytic Leukemia (CLL)
Abstract Number: 7556
Session Title: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia
Session Date and Time: June 7, 2021 at 11:30 am (Eastern Time)
"These updated clinical data with the combination of cirmtuzumab and ibrutinib remain very encouraging in heavily pre-treated patients with relapsed/refractory MCL, including the impressive 83% best ORR and the durability of complete responses. The enrolled patients also had negative prognostic features, making the results even more compelling. Deep responses to cirmtuzumab plus ibrutinib after prior ibrutinib therapy are particularly intriguing. We look forward to the continuing development of cirmtuzumab," said Hun Ju Lee, M.D., Associate Professor of Medicine in the Department of Lymphoma & Myeloma at the University of Texas MD Anderson Cancer Center, who is an investigator on the CIRLL clinical trial and the first author on the 2021 ASCO (Free ASCO Whitepaper) poster presentation.

"We are pleased that the interim results of the CIRLL study remain strong and consistent with further follow-up, including that median PFS and OS have still not been reached for these heavily pre-treated MCL and CLL patients. Adding cirmtuzumab to ibrutinib appears well tolerated, with no apparent additional toxicities noted to date," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "We are particularly pleased with our robust enrollment to date and the number and durability of CRs for the patients with MCL. We remain in active dialogue with the US FDA concerning potential pivotal study designs and the potential pathway to seeking regulatory approval."

The results that will be presented in poster form at ASCO (Free ASCO Whitepaper) 2021 include an increased population of 26 patients with relapsed/refractory MCL enrolled in the dose-finding and dose-expansion cohorts of the CIRLL clinical trial (Part 1 + Part 2), of whom 18 were evaluable for efficacy as of the April 16, 2021 data cut-off date.

Patients had high-risk factors and were heavily pre-treated at study entry, 70% with a high Ki-67 proliferative index (≥30%), 15% with intermediate/high sMIPI prognostic score, and a median of two systemic prior therapies (range 1-5).
The ORR of 83% (15 of 18 evaluable patients), which includes recently enrolled patients with relatively short follow-up time, is comparable to the 87% ORR (13 of 15 evaluable patients) previously presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting.
Eight of 18 (44%) evaluable patients achieved a partial response (PR) and two patients (11%) had stable disease (SD), for a total clinical best benefit rate (CR, PR, SD) of 94%.
The complete response rate was 39% (7 of 18 evaluable patients). CRs have remained durable, for 8-30+ months as of the data cutoff date.
The clinical benefit rate and median duration of response were favorable in patients with high-risk features associated with difficult to treat disease:
≥30% Ki-67: Clinical benefit rate of 89%; median duration of response of 14 months (95% CI: 8.66, NE)
>1 prior systemic therapy: Clinical benefit rate of 100%; median duration of response not reached
Four patients had received prior treatment with ibrutinib and all four achieved clinical responses, with two CRs and two PRs.
Median PFS and OS have not been reached, after a median follow-up of 18.9 months, regardless of number of prior systemic therapies, including three recently enrolled evaluable patients with a shorter follow-up time. Further, median PFS has not been reached for patients achieving a CR.
Historical data published for single agent ibrutinib for 370 patients with relapsed/refractory MCL from three clinical trials showed an ORR of 66%, CR rate of 20% and median PFS of 12.8 months (Rule et al., 2017, British Journal of Haematology).
As of the April 16, 2021 data cut-off date, 34 patients with CLL have been enrolled in the dose-finding and dose-confirming cohorts of this clinical trial (Part 1 & Part 2), of which 34 were evaluable for efficacy. The Company plans to present updated data from the randomized cohort (Part 3) in the second half of 2021.

Patients had high-risk factors, and most were heavily pre-treated at study entry, with 85% having RAI staging ≥2, 65% with lymphocytosis, and a median of two systemic prior therapies (range 1-15).
The ORR is similar, 94% (32 of 34 evaluable patients), compared to a 91% ORR presented for 31 of 34 evaluable patients at ASH (Free ASH Whitepaper) 2020.
The CR rate is 15% (5 of 34 evaluable patients), 3 CRs were unconfirmed. Twenty-seven patients (79%) achieved a PR and two patients (6%) had SD, for a total clinical benefit rate (CR, PR, SD) of 100%.
Median PFS and OS have not been reached, after a median follow up of 22.1 months, in this high risk and mostly heavily pre-treated CLL population.
The combination of cirmtuzumab plus ibrutinib has been well tolerated, with treatment emergent adverse events and hematologic abnormalities consistent with, or slightly lower than those reported for ibrutinib alone. There have been no dose-limiting toxicities and no serious adverse events attributed to cirmtuzumab alone.

About the CIRLL Clinical Trial
The CIRLL clinical trial (CIRM-0001) is a Phase 1/2 trial evaluating cirmtuzumab in combination with ibrutinib in separate groups of patients with CLL or MCL. Enrollment of the dose-finding cohorts in CLL and MCL, dose-expansion cohort in CLL and randomized Phase 2 cohort in CLL has been completed. Enrollment of the dose-expansion cohort in MCL is ongoing. Additional information about the CIRM-0001 clinical trial and other clinical trials of cirmtuzumab may be accessed at ClinicalTrials.gov.

About Cirmtuzumab
Cirmtuzumab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Cirmtuzumab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of MCL or CLL, in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine: (i) a Phase 1b clinical trial of cirmtuzumab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer, and (ii) a Phase 2 clinical trial of cirmtuzumab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen – not usually expressed on adult cells, and its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically targeting ROR1 expressing tumors. This led to the development of cirmtuzumab, that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when cirmtuzumab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to cirmtuzumab for the treatment of MCL and CLL/small lymphocytic lymphoma. Cirmtuzumab is in clinical development and has not been approved by the FDA for any indication.

On May 19, 2021 Bio-Techne Corporation (NASDAQ: TECH) reported that Chuck Kummeth, President and Chief Executive Officer, will present at the Jefferies Virtual Healthcare Conference on Thursday, June 3, 2021 at 1:00 p.m. EDT (Press release, Bio-Techne, MAY 19, 2021, View Source [SID1234580290]). A live webcast of the presentation can be accessed via the IR Calendar page of Bio-Techne’s Investor Relations website at View Source

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On May 19, 2021 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that it will present new research data for its three lead DXd antibody drug conjugates (ADCs) in multiple types of cancer at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (#ASCO21) Virtual Scientific Program to be held June 4 to 8, 2021 (Press release, Daiichi Sankyo, MAY 19, 2021, https://www.businesswire.com/news/home/20210519005576/en/Daiichi-Sankyo-Advances-Science-Across-Three-Lead-DXd-ADCs-with-New-Data-in-Multiple-Cancers-at-2021-ASCO-Virtual-Meeting [SID1234580306]).

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Presentations will highlight the company’s growing leadership in developing multiple potential treatment approaches for cancer including an oral presentation featuring extended follow-up data from a phase 1 trial of patritumab deruxtecan (HER3-DXd) in patients with locally advanced or metastatic TKI-resistant, EGFR-mutated non-small cell lung cancer (NSCLC). Preliminary data from this trial informed the recently initiated pivotal HERTHENA-Lung01 phase 2 trial. Additionally, a dose analysis from the NSCLC cohort of the TROPION-PanTumor01 trial, which formed the basis of the datopotamab deruxtecan (Dato-DXd) dose being evaluated in the pivotal TROPION-Lung01 phase 3 trial, will be presented.

Final overall survival results from the pivotal DESTINY-Gastric01 phase 2 trial and final results from the DESTINY-CRC01 phase 2 trial of ENHERTU (trastuzumab deruxtecan) also will be featured. ENHERTU was recently highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the "ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers," based on data from both DESTINY-Gastric01 and DESTINY-CRC01.

"The data being presented at ASCO (Free ASCO Whitepaper) showcase Daiichi Sankyo’s sustained progress in advancing our three lead DXd ADCs across multiple cancers including lung, breast, gastric and colorectal cancers," said Ken Takeshita, MD, Global Head, Research and Development, Daiichi Sankyo. "All of these new data, biomarker research and trial-in-progress updates demonstrate our commitment to translating our innovative science and technology into potential treatment options for patients with cancer."

Additional ENHERTU data to be highlighted at ASCO (Free ASCO Whitepaper) includes updated subgroup analysis of the pivotal DESTINY-Breast01 trial in patients with metastatic HER2 positive breast cancer and brain metastases, initial results from the ENHERTU arm of the BEGONIA phase 1b/2 durvalumab combination trial in patients with triple negative breast cancer (TNBC), and pooled subgroup analysis across two phase 1 studies of patients with HER2 expressing salivary gland cancer.

Daiichi Sankyo will hold two ASCO (Free ASCO Whitepaper) conference calls for investors and analysts on Monday, June 7, 2021 from 6:30 PM-8:00 PM EDT (investors located in Japan) and on Tuesday, June 8, 2021 from 7:00 AM-8:30 AM EDT (investors located outside of Japan). Company executives will provide an overview of the ASCO (Free ASCO Whitepaper) research data, updates for the oncology portfolio and address questions from investors and analysts.

Following is an overview of the research data from the oncology portfolio of Daiichi Sankyo to be presented at ASCO (Free ASCO Whitepaper) 2021:

Presentation Title

Author

Abstract

Presentation Details

Patritumab deruxtecan (HER3-DXd)

NSCLC

Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor–resistant, EGFR-mutated non-small cell lung cancer (NSCLC)

P. Jänne

9007

Oral Presentation

Lung Cancer – Non-Small Cell Metastatic: Friday, June 4, 2021; 1:00 – 4:00 PM EDT

A randomized phase 2 study of patritumab deruxtecan (U3-1402) in patients with previously treated metastatic or locally advanced EGFR-mutated NSCLC

P. Jänne

TPS9139

Poster Presentation

Datopotamab deruxtecan (Dato-DXd)

NSCLC

TROPION-PanTumor01: dose analysis of the TROP2 directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd; DS-1062) for the treatment of advanced or metastatic non-small cell lung cancer

F. Meric-Bernstam

9058

Poster Presentation

A randomized, phase 3 study of datopotamab deruxtecan (Dato-DXd; DS-1062) vs docetaxel in previously treated advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (TROPION-Lung01)

K. Yoh

TPS9127

Poster Presentation

Breast

BEGONIA: phase 1b/2, open-label, platform study of the safety and efficacy of durvalumab (D) ± paclitaxel (P) with novel oncology therapies for first-line metastatic triple-negative breast cancer (mTNBC): addition of Arm 7, D + datopotamab deruxtecan (Dato-DXd; DS-1062)

P. Schmid

TPS1105

Poster Presentation

ENHERTU (trastuzumab deruxtecan; T-DXd)

Colorectal

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2 expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01)

T. Yoshino

3505

Oral Presentation

Gastrointestinal Cancer – Colorecal and Anal: Monday, June 7; 1:15 – 4:15 PM EDT

Trastuzumab deruxtecan in patients with HER2 overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): a randomized, multicenter, phase 2 study (DESTINY-CRC02)

K. Raghav

TPS3620

Poster Presentation

Gastric

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2 positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01)

K. Yamaguchi

4048

Poster Presentation

Quality-adjusted time without symptoms or toxicity (Q-TWiST) of trastuzumab deruxtecan (T-DXd) versus chemotherapy in patients with advanced gastric cancer from the DESTINY-Gastric01trial

D. Cella

4057

Poster Presentation

Breast

Trastuzumab deruxtecan (T-DXd) in patients with HER2+ metastatic breast cancer with brain metastases: a subgroup analysis of the DESTINY-Breast01 trial

G. Jerusalem

526

Poster Presentation

BEGONIA: phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple negative breast cancer (TNBC): Initial results from Arm 1, D+paclitaxel (P), and Arm 6, D+trastuzumab deruxtecan

P. Schmid

1023

Poster Discussion Session

Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2 positive advanced or metastatic breast cancer: a phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07)

F. Andre

TPS1096

Poster Presentation

Prevalence of HER2 low in breast cancer subtypes using the VENTANA anti-HER2/neu (4B5) assay

M. Scott

1021

Poster Discussion Session

Machine learning models to quantify HER2 for real-time tissue image analysis in prospective clinical trials

B.Glass

3061

Poster Presentation

Pan Tumor

Trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-expressing salivary duct carcinoma: Subgroup analysis of two phase 1 studies

H. Bando

6079

Poster Presentation

A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of solid tumors harboring specific HER2 activating mutations (DESTINY-PanTumor01)

B.Li

TPS3162

Poster Presentation

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of seven ADCs with six in clinical development across multiple types of cancer. The company’s three lead ADCs include ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Three additional ADCs including DS-7300 (B7-H3), DS-6157 (GPR20) and DS-6000 (CDH6) are being developed through a strategic research collaboration with Sarah Cannon Research Institute.

Each ADC is designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver chemotherapy inside cancer cells that express a specific cell surface antigen. Each ADC consists of a monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved under accelerated approval in the U.S, under conditional marketing authorization in the EU and the UK, and under the conditional early approval system in Japan for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4 mg/kg) is also approved in the U.S. and Japan for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

Patritumab deruxtecan, datopotamab deruxtecan, DS-7300, DS-6157 and DS-6000 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

U.S. Important Safety Information for ENHERTU

Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.
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 a confirmatory trial.

Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Contraindications
None.

Warnings and Precautions
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer
In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Metastatic Breast Cancer
In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4mg/kg, a decrease in neutrophil count was reported in 62% of patients. Sixteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 23 days (range: 6 to 547). Febrile neutropenia was reported in 1.7% of patients.

Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity
ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Additional Dose Modifications
Thrombocytopenia
For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less. Reduce dose by one level.

Adverse Reactions
Metastatic Breast Cancer
The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (79%), white blood cell count decreased (70%), hemoglobin decreased (70%), neutrophil count decreased (62%), fatigue (59%), vomiting (47%), alopecia (46%), aspartate aminotransferase increased (41%), alanine aminotransferase increased (38%), platelet count decreased (37%), constipation (35%), decreased appetite (32%), anemia (31%), diarrhea (29%), hypokalemia (26%), and cough (20%).

Locally Advanced or Metastatic Gastric Cancer
The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma in DESTINY‑Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (75%), white blood cell count decreased (74%), neutrophil count decreased (72%), lymphocyte count decreased (70%), platelet count decreased (68%), nausea (63%), decreased appetite (60%), anemia (58%), aspartate aminotransferase increased (58%), fatigue (55%), blood alkaline phosphatase increased (54%), alanine aminotransferase increased (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), blood bilirubin increased (24%), pyrexia (24%), and alopecia (22%).

Use in Specific Populations

Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.
Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were ≥65 years and 5% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (53%) as compared to younger patients (42%). Of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

On May 19, 2021 Transcenta Holding Limited ("Transcenta"), a global biotherapeutics company with fully-integrated capabilities in discovery, development and manufacturing of antibody-based therapeutics, reported that the updated Phase I clinical study (NCT04272944) data on the safety and efficacy of MSB2311, a pH-dependent PD-L1 antibody, in Chinese patients with advanced solid tumors and hematological malignancies have been presented as an abstract online publication at the 2021 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Abstract #e14547, 5:00 PM, U.S. East Time, Wednesday, May 19, 2021) (Press release, Transcenta, MAY 19, 2021, View Source [SID1234580322]).

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The study, presented at the 2021 ASCO (Free ASCO Whitepaper) annual meeting by abstract, was led by Professor Lin Shen from Beijing Cancer Hospital, and was a Phase I study of MSB2311 with a unique pH-dependent antigen binding property in Chinese patients with advanced solid tumors and lymphoma. Its primary objectives were to evaluate the safety and tolerability and to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). The secondary objectives included the assessment of pharmacokinetic parameter, immunogenicity, and preliminary anti-cancer activity per RECIST version 1.1.

The study included a dose escalation Phase and a dose expansion Phase. In the dose escalation Phase, MSB2311 was given at dose levels of 3, 10, and 20mg/kg intravenously every 3 weeks. At the dose expansion Phase, patients with biomarker expression, including EBV+, PD-L1+ (TPS≥50%), MSI-High or TMB-High (≥10muts/Mb), were dosed at 20mg/kg Q3W or 10mg/kg Q2W.

As of data cutoff by Aug 31, 2020, 33 Chinese patients had been treated, including 27 heavily pre-treated solid tumor patients and 6 lymphoma patients. No dose limiting toxicity was reported and MTD has not been reached. The most common AEs (>20%) included: anemia, hypothyroidism, aspartate aminotransferase elevated, proteinuria and weight loss. 13 patients (39.4%) experienced grade 3 AEs, and 6 patients (18.2%) experienced serious adverse events (SAEs). No treatment related grade 4 or 5 AEs was reported.

Of the 17 efficacy evaluable solid tumor patients with biomarker expression, 6 achieved confirmed partial response with an ORR of 35%: 2/8 (25%) at 10mg/kg Q2W and 4/9 (44%) at 20mg/kg Q3W. Additionally, one patient achieved sustained iPR per iRECIST. 4 out of 7 responding patients (including one iPR) achieved tumor shrinkage of more than 50%, 3 of them got durable response (≥24 weeks). 1 out of 6 lymphoma patients achieved PR.

"In recent years, tumor immunotherapy has gradually become a research hotspot in the field of tumor treatment. It has played a great role in the treatment of tumors, and we have been making efforts in this area," said Professor Lin Shen, the leading investigator from Beijing Cancer Hospital. "Patients with metastatic solid tumors or selected lymphoma progressed on or after standard treatments were enrolled in this Phase I study. This Phase I study showed promising preliminary efficacy and tolerability of MSB2311 in patients with advanced solid tumors and hematological malignancies."

"MSB2311 demonstrated a manageable safety profile and promising antitumor activity in patients with advanced solid tumors and lymphomas." said Dr. Michael Shi, EVP, Head of Global R&D and CMO of Transcenta. "We are excited to see how our in-house developed medicines can help to benefit the patients. We will continue to forge ahead with our commitment to differentiated and affordable biologics for patients around the world."

About MSB2311

MSB2311 is an investigational humanized PD-L1 with pH dependent binding property. PD-L1 is involved in inhibiting the immune system’s response to fight cancer. MSB2311 blocks the interaction between PD-L1 and PD-1, which reactivates the suppressed or exhausted anti-tumor effector T cell function in the tumor microenvironment. MSB2311 employs engineered IgG1 which lacks FcR binding. In addition, the binding of MSB2311 to PD-L1 results in internalization of MSB2311 and MSB2311 can dissociate from bound PD-L1 in endosome with pH level lower than 5.5. This allows MSB2311 to be recycled to plasma membrane and be reused to bind with PD-L1 on another tumor cell or immune cell. Results from preclinical studies demonstrate that MSB2311 can inhibit tumor growth of PD-L1 expressing tumor cells in syngeneic mouse-model. Two Phase 1 studies of MSB2311 have been completed in the US and China. MSB2311 is currently to be tested in Phase 2 trial in patients with solid tumors expressing selected biomarker in China.