On December 11, 2020 Odonate Therapeutics, Inc. (NASDAQ: ODT), a pharmaceutical company dedicated to the development of best‑in‑class therapeutics that improve and extend the lives of patients with cancer, reported that positive results from CONTESSA, a Phase 3 study of tesetaxel in patients with metastatic breast cancer (MBC), were presented in an oral presentation at the 2020 San Antonio Breast Cancer Symposium (SABCS) (Press release, Odonate Therapeutics, DEC 11, 2020, View Source [SID1234572689]). The results were presented by Joyce O’Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, Texas Oncology and Chair, Breast Cancer Research, US Oncology, and Co‑Principal Investigator of CONTESSA (please click here for slides).

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CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with MBC. CONTESSA is comparing tesetaxel dosed orally at 27 mg/m2 on the first day of each 21‑day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21‑day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day dosed orally for 14 days of each 21‑day cycle) in 685 patients randomized 1:1 with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Capecitabine is an oral chemotherapy agent that is considered a standard‑of‑care treatment in MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin‑dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is progression‑free survival (PFS) as assessed by the Independent Radiologic Review Committee (IRC). The secondary efficacy endpoints are overall survival (OS), objective response rate (ORR) as assessed by the IRC and disease control rate (DCR) as assessed by the IRC. CONTESSA is being conducted at 180 investigational sites in 18 countries in North America, Europe and Asia.

CONTESSA met the primary endpoint of improved PFS as assessed by the IRC. Median PFS was 9.8 months for tesetaxel plus a reduced dose of capecitabine versus 6.9 months for the approved dose of capecitabine alone, an improvement of 2.9 months. The risk of disease progression or death was reduced by 28.4% [hazard ratio=0.716 (95% confidence interval: 0.573-0.895); p=0.003] for tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone.

The ORR as assessed by the IRC was 57% for tesetaxel plus a reduced dose of capecitabine versus 41% for the approved dose of capecitabine alone (p=0.0002). The DCR as assessed by the IRC was 67% for tesetaxel plus a reduced dose of capecitabine versus 50% for the approved dose of capecitabine alone (p<0.0001). While OS data are immature, a recent interim analysis indicated the absence of an adverse effect on OS with tesetaxel plus a reduced dose of capecitabine. A protocol‑specified final analysis of OS is expected to occur in 2022.

Tesetaxel plus capecitabine was associated with a manageable side effect profile consistent with findings from previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients were: neutropenia (70.9% for tesetaxel plus capecitabine vs. 8.3% for capecitabine alone); diarrhea (13.1% for tesetaxel plus capecitabine vs. 8.9% for capecitabine alone); hand‑foot syndrome (6.8% for tesetaxel plus capecitabine vs. 12.2% for capecitabine alone); febrile neutropenia (13.1% for tesetaxel plus capecitabine vs. 1.2% for capecitabine alone); fatigue (8.6% for tesetaxel plus capecitabine vs. 4.5% for capecitabine alone); hypokalemia (8.6% for tesetaxel plus capecitabine vs. 2.7% for capecitabine alone); leukopenia (9.8% for tesetaxel plus capecitabine vs. 0.9% for capecitabine alone); and anemia (8.0% for tesetaxel plus capecitabine vs. 2.4% for capecitabine alone).

Adverse events resulting in treatment discontinuation in ≥1% of patients were: neutropenia or febrile neutropenia (4.2% for tesetaxel plus capecitabine vs. 1.5% for capecitabine alone); neuropathy (3.6% for tesetaxel plus capecitabine vs. 0.3% for capecitabine alone); sepsis or septic shock (1.8% for tesetaxel plus capecitabine vs. 0.6% for capecitabine alone); diarrhea (0.9% for tesetaxel plus capecitabine vs. 1.5% for capecitabine alone); and hand-foot syndrome (0.6% for tesetaxel plus capecitabine vs. 2.1% for capecitabine alone). Treatment discontinuation due to any adverse event occurred in 23.1% of patients treated with tesetaxel plus capecitabine versus 11.9% of patients treated with capecitabine alone.

Tesetaxel dose reductions occurred in 76% of patients treated with tesetaxel plus capecitabine, primarily due to neutropenia. Dose reductions occurred in 61% of patients treated with capecitabine alone, primarily due to hand-foot syndrome. The relative delivered dose intensity, which accounts for not only the frequency, but also the magnitude of reductions and treatment adherence, was higher in patients treated with tesetaxel plus capecitabine. Specifically, 81% of the intended dose of tesetaxel through cycle 12 was delivered in patients treated with tesetaxel plus capecitabine versus 76% of the intended dose of capecitabine through cycle 12 in patients treated with capecitabine alone.

Grade 2 alopecia (hair loss) occurred in 8.0% of patients treated with tesetaxel plus capecitabine versus 0.3% of patients treated with capecitabine alone. Grade ≥3 neuropathy occurred in 5.9% of patients treated with tesetaxel plus capecitabine versus 0.9% of patients treated with capecitabine alone. There were no treatment-related hypersensitivity reactions.

"Tesetaxel represents a potential important clinical advance for patients with metastatic breast cancer," said Joyce O’Shaughnessy, M.D. "There remains a significant unmet medical need for novel therapies that offer quality‑of‑life advantages for patients with metastatic breast cancer."

"The PFS improvement observed in CONTESSA, along with once‑every‑three‑weeks oral dosing and low rates of clinically significant hair loss and neuropathy, could make tesetaxel an important new treatment option for patients with metastatic breast cancer," said Andrew Seidman, M.D., Medical Director, Bobst International Center, Memorial Sloan Kettering Cancer Center and Professor of Medicine, Weill Cornell Medical College, and Co‑Principal Investigator of CONTESSA.

"We would like to thank all of the investigators, study team personnel, and especially the patients and their caregivers who made CONTESSA possible," said Kevin Tang, Chief Executive Officer of Odonate. "We look forward to working closely with global regulatory authorities to make tesetaxel available to patients with metastatic breast cancer. We plan to submit a New Drug Application for tesetaxel to the FDA in mid‑2021."

The Company will host a Virtual Investor and Analyst Event today at 1:00 p.m. CT / 2:00 p.m. ET.

Virtual Investor and Analyst Event Information

Date: December 11, 2020
Time: 1:00 p.m. CT / 2:00 p.m. ET
Webcast Link: Please click here
Dial-in (domestic): (866) 300-4090
Dial-in (international): (636) 812‑6660
Conference ID: 8698553

About Tesetaxel

Tesetaxel is an investigational, orally administered chemotherapy agent that belongs to a class of drugs known as taxanes, which are widely used in the treatment of cancer. Tesetaxel has several pharmacologic properties that make it unique among taxanes, including: oral administration with a low pill burden; a long (~8-day) terminal plasma half-life in humans, enabling the maintenance of adequate drug levels with relatively infrequent dosing; no history of hypersensitivity (allergic) reactions; and significant activity against chemotherapy-resistant tumors. In patients with metastatic breast cancer, tesetaxel was shown to have significant, single-agent antitumor activity in two multicenter, Phase 2 studies. Tesetaxel currently is the subject of three studies in breast cancer, including a multinational, multicenter, randomized, Phase 3 study in patients with metastatic breast cancer, known as CONTESSA. Positive results of CONTESSA were recently presented at the 2020 San Antonio Breast Cancer Symposium.

About CONTESSA

CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with metastatic breast cancer (MBC). CONTESSA is comparing tesetaxel dosed orally at 27 mg/m2 on the first day of each 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day dosed orally for 14 days of each 21-day cycle) in 685 patients randomized 1:1 with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)‑negative MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is progression-free survival (PFS) as assessed by an Independent Radiologic Review Committee (IRC). The secondary efficacy endpoints are overall survival (OS), objective response rate (ORR) as assessed by the IRC and disease control rate (DCR) as assessed by the IRC.

On December 11, 2020, Seelos Therapeutics, Inc. (the "Company") reported that it entered into a Securities Purchase Agreement (the "Securities Purchase Agreement") with Lind Global Asset Management II, LLC (the "Investor") pursuant to which, among other things, on December 11, 2020, the Company issued and sold to the Investor, in a private placement transaction (the "Private Placement"), in exchange for the payment by the Investor of $10,000,000, (1) a convertible promissory note (the "Note") in an aggregate principal amount of $12,000,000 (the "Principal Amount"), which will bear no interest and mature on December 11, 2022 (the "Maturity Date"), and (2) 975,000 shares (the "Closing Shares") of common stock of the Company, par value $0.001 per share ("Common Stock") (Filing, 8-K, Apricus Biosciences, DEC 11, 2020, View Source [SID1234572982]).

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At any time following June 11, 2021, and from time to time before the Maturity Date, the Investor shall have the option to convert any portion of the then-outstanding Principal Amount of the Note into shares of Common Stock at a price per share of $1.60, subject to adjustment for stock splits, reverse stock splits, stock dividends and similar transactions (the "Conversion Price"). Prior to June 11, 2021, the Company shall have the right to prepay up to sixty-six and two-thirds percent (662/3%) of the then-outstanding Principal Amount of the Note with no penalty. On or after July 11, 2021, the Company shall have the right to prepay up to the then-outstanding Principal Amount of the Note with no penalty; however, if the Company exercises such prepayment right, the Investor will have the option to convert up to thirty-three and one-third percent (331/3%) of the amount that the Company elects to prepay at the Conversion Price.

The Company intends to use the proceeds from the Private Placement for general corporate purposes and to advance the development of its product candidates.

Subject to certain exceptions, the Company will be required to direct proceeds from any subsequent debt financings (including subordinated debt, convertible debt or mandatorily redeemable preferred stock but other than purchase money debt or capital lease obligations or other indebtedness incurred in the ordinary course of business) to repay the Note, unless waived by the Investor in advance.

Beginning on June 9, 2021, the Note will amortize in eighteen monthly installments equal to the quotient of (i) the then-outstanding Principal Amount of the Note, divided by (ii) the number of months remaining until the Maturity Date. All amortization payments shall be payable solely in cash, plus a 2% premium.

In conjunction with the Securities Purchase Agreement and the Note, on December 11, 2020, the Company and the Investor entered into a security agreement (the "Security Agreement"), which provides the Investor with a first priority lien on the Company’s assets and properties.

Until December 11, 2021, the Investor will, subject to certain exceptions, have the right to participate for up to 10% of any Common Stock equity financing of the Company.

The Securities Purchase Agreement contains customary representations and warranties of the Company and the Investor. In addition, the Note contains restrictive covenants and event of default provisions that are customary for transactions of this type.

The foregoing summaries of the Securities Purchase Agreement, the Note and the Security Agreement do not purport to be complete and are qualified in their entirety by reference to the copies of the Securities Purchase Agreement and Form of Note filed herewith as Exhibits 10.1, 4.1 and 10.2, respectively.

The representations, warranties and covenants contained in the Securities Purchase Agreement were made only for purposes of such agreement and as of specific dates, were solely for the benefit of the parties to the Securities Purchase Agreement, and may be subject to limitations agreed upon by the contracting parties. Accordingly, the Securities Purchase Agreement is incorporated herein by reference only to provide investors with information regarding the terms of the Securities Purchase Agreement, and not to provide investors with any other factual information regarding the Company or its business, and should be read in conjunction with the disclosures in the Company’s periodic reports and other filings with the Securities and Exchange Commission (the "SEC").

On December 10, 2020 Xenetic Biosciences, Inc. (NASDAQ:XBIO) ("Xenetic" or the "Company"), a biopharmaceutical company focused on advancing XCART, a personalized CAR T platform technology engineered to target patient- and tumor-specific neoantigens, reported that it has entered into a securities purchase agreement with several institutional and accredited investors providing for the purchase and sale of 2,448,980 shares of the Company’s common stock at a purchase price of $2.45 per share, in a registered direct offering priced at-the-market under Nasdaq rules (Press release, Xenetic Biosciences, DEC 10, 2020, View Source [SID1234572584]). The offering is expected to result in gross proceeds to Xenetic of approximately $6.0 million before deducting placement agent fees and other offering expenses payable by Xenetic.

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H.C. Wainwright & Co. is acting as the exclusive placement agent for the offering.

The Company intends to use the net proceeds of this offering for general corporate purposes, working capital, and for the advancement of the XCART platform, the Company’s differentiated, proprietary approach to personalized CAR T therapy in development for the treatment of multiple tumor types of B-cell Non-Hodgkin lymphomas.

The registered direct offering is expected to close on or about December 14, 2020, subject to the satisfaction of customary closing conditions.

The shares described above are being offered by Xenetic pursuant to a "shelf" registration statement on Form S-3 (File No. 333-227572) previously filed with the U.S. Securities and Exchange Commission ("SEC") on September 27, 2018 and declared effective by the SEC on October 12, 2018. Such shares may be offered only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. A final prospectus supplement and the accompanying prospectus relating to the offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Alternatively, when available, electronic copies of the final prospectus supplement and the accompanying prospectus may be obtained from H.C. Wainwright & Co., LLC, 430 Park Avenue, New York, NY 10022, by email at [email protected] or by phone at (646) 975-6996.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On December 10, 2020 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported the first immunotherapy combination study results for ENHERTU (fam-trastuzumab deruxtecan-nxki), reporting preliminary results from two cohorts of a four cohort phase 1b trial evaluating the efficacy and safety of ENHERTU in combination with nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, in patients with previously treated HER2 positive or HER2 low metastatic breast cancer (Press release, Daiichi Sankyo, DEC 10, 2020, View Source [SID1234572617]). Results were presented in a Spotlight Poster Discussion at the virtual 2020 San Antonio Breast Cancer Symposium (#SABCS20).

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This interim analysis found that the combination of ENHERTU (5.4 mg/kg) and nivolumab (360 mg), administered every three weeks, was well tolerated in patients with HER2 positive or HER2 low metastatic breast cancer, providing the first data showing that ENHERTU may be safely combined with an immunotherapy agent, at therapeutic doses of both agents and for a meaningful treatment duration.

The overall safety and tolerability of ENHERTU and nivolumab combination therapy was similar to that seen with ENHERTU monotherapy in patients with HER2 positive metastatic breast cancer and nivolumab monotherapy across tumors. No new safety signals were observed; however, the rate of treatment-emergent adverse events leading to treatment discontinuation (18.8%) was numerically higher with the combination than previous reports from either monotherapy alone. There were no dose limiting toxicities observed in part 1 of the trial. Overall, 43.8% of patients experienced a grade 3 or higher treatment-emergent adverse event, with 18.8% identified as events related to ENHERTU and 18.8% related to nivolumab. The most common any-grade treatment-emergent adverse events were nausea (54.2%), fatigue (45.8%), and alopecia (41.7%). There were five cases (10.4%, all HER2 positive) of treatment-related interstitial lung disease (ILD) or pneumonitis, determined by an independent adjudication committee, including one death (grade 5). The remaining four cases were grade 2.

Preliminary efficacy results for 48 evaluable patients found that patients in the HER2 positive cohort (n=32) and the HER2 low cohort (n=16) showed a confirmed objective response rate of 59% and 38%, respectively. Disease control rates of 91% and 75% were observed in the HER2 positive and HER2 low cohorts, respectively. Median duration of response has not yet been reached in either cohort.

"As HER2 positive metastatic breast cancer continues to progress, and multiple lines of HER2 directed therapy have been exhausted, consideration needs to be given to evaluating a combination of medicines with different mechanisms of action," said Erika Hamilton, MD, Director, Breast Cancer and Gynecologic Cancer Research Program, Sarah Cannon Research Institute at Tennessee Oncology. "These preliminary data provide a promising signal that ENHERTU, a HER2 directed antibody drug conjugate, may be combined with nivolumab, an immune checkpoint inhibitor. Longer follow-up and more research is needed to determine whether adding immunotherapy to ENHERTU to treat HER2 positive or HER2 low metastatic breast cancer may provide further clinical benefit than receiving ENHERTU alone."

"Additional treatment strategies are needed for patients with HER2 positive metastatic breast cancer as the disease still remains incurable," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "These initial findings indicate treatment with ENHERTU and nivolumab, an immune checkpoint inhibitor, may be combined and administered for longer periods of time. These findings also support our broader research effort to better understand whether the directed delivery of potent chemotherapy with ENHERTU along with immunotherapy may benefit patients with HER2 expressing metastatic breast cancer regardless of the levels of HER2 expression."

In the phase 1b study, the majority of patients in the HER2 positive (88%) and HER2 low (75%) cohorts had received four or more prior therapies. Median duration of treatment with ENHERTU was 6.5 months (range, 1.4-14.0 months) in the HER2 positive cohort and 6.3 months (range, 0.7-10.4 months) in the HER2 low cohort. The median duration of treatment with nivolumab was 5.2 months (range, 1.3-11.3 months) and 4.9 months (range, 0.7-10.4 months) in the HER2 positive and HER2 low cohorts, respectively. Median duration of follow-up was 7.0 months for HER2 positive patients and 6.9 months for HER2 low patients. As of data cut-off on June 8, 2020, 56.3% of HER2 positive and 50.0% of HER2 low patients remained on treatment with ENHERTU. Fifty percent of HER2 positive and 43.8% of HER2 low patients remained on treatment with nivolumab.

About the Trial

The trial is a two-part, phase 1b, multicenter, open-label trial evaluating ENHERTU in combination with nivolumab in patients with HER2 expressing breast and urothelial cancer that experience disease progression during or after prior therapies, did not respond to standard therapies, or for whom no standard therapy is currently available.

The trial was performed in two parts: Part 1 evaluated different doses of ENHERTU when given along with a fixed dose of nivolumab (360 mg), administered every three weeks, to determine the recommended dose for expansion (RDE); Part 2 assessed the efficacy and safety of this dose combination at the RDE. Part 2 of the trial enrolled patients into four cohorts: cohort 1 was comprised of patients with HER2 positive breast cancer who had received prior treatment with trastuzumab emtansine (T-DM1); cohort 2 was comprised of patients with HER2 low triple negative breast cancer who had previously received standard treatment; cohorts 3 and 4 are comprised of patients with HER2 high or HER2 low expressing urothelial cancer, respectively, who had received prior platinum-based therapy with documented progression and had not received prior immunotherapy.

The primary efficacy endpoint in Part 2 of the trial is objective response rate confirmed by independent central review. Additional efficacy endpoints include duration of response, disease control rate, progression-free survival, overall survival, safety, and pharmacokinetics.

About HER2 Expressing Breast Cancer

In women, breast cancer is the most common cancer and one of the most common causes of cancer mortality worldwide; there were an estimated 2.1 million new cases of female breast cancer diagnosed in 2018.1 Breast cancer occurs mainly in women but in rare cases, it can also occur in men.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including gastric, breast and lung cancers. HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poor prognosis.3

Approximately one in five breast cancers are HER2 positive, and an additional 40% of all breast cancers may have low levels of HER2 expression.4,5,6 Despite recent improvements and approvals of new medicines, metastatic breast cancer remains incurable and additional treatment strategies are needed for patients with HER2 positive metastatic breast cancer.7,8 Currently, no anti-HER2 agents are indicated for HER2 low expressing tumors.

About ENHERTU

ENHERTU is a HER2 directed antibody drug conjugate (ADC). Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform.

ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. ENHERTU is comprised of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker.

ENHERTU (5.4 mg/kg) is approved in the U.S. under Accelerated Approval, and in Japan for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2 based regimens based on the DESTINY-Breast01 trial. ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity.

ENHERTU (6.4 mg/kg) is also approved in Japan for the treatment of patients with HER2 positive unresectable advanced or recurrent gastric cancer that has progressed after chemotherapy based on the DESTINY-Gastric01 trial.

About the ENHERTU Clinical Development Program

A comprehensive development program is underway globally, with nine pivotal trials evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, colorectal and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

In October 2020, ENHERTU was granted Priority Review from the U.S. Food and Drug Administration (FDA) for the treatment of patients with HER2 positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. In May 2020, ENHERTU received a Breakthrough Therapy Designation (BTD) and Orphan Drug Designation (ODD) for gastric cancer, including GEJ adenocarcinoma.

In May 2020, ENHERTU also received a BTD for the treatment of patients with metastatic NSCLC whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy. ENHERTU is not approved in the U.S. in either NSCLC or gastric cancer.

In July 2020, the European Medicines Agency’s Committee for Medicinal Products for Human Use granted accelerated assessment of ENHERTU for the treatment of adults with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens.

About the Collaboration Between Daiichi Sankyo and AstraZeneca

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU (a HER2 directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2 directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of ENHERTU and datopotamab deruxtecan.

U.S. FDA-Approved Indication for ENHERTU

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.

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. In clinical studies, of the 234 patients with unresectable or metastatic HER2 positive breast cancer treated with ENHERTU, 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).

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 prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Of the 234 patients with unresectable or metastatic HER2 positive breast cancer who received ENHERTU, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.

Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction. 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.

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. 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. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. 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.

Adverse Reactions

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 adverse reactions (frequency ≥20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).

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%).
Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please click for full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our DXd antibody drug conjugate technology, our powerful research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. For more information, please visit: www.DSCancerEnterprise.com.

On December 10, 2020 Menarini Silicon Biosystems, a pioneer of liquid biopsy technology, reported new data from the DETECT study program (Press release, Menarini Silicon Biosystems, DEC 10, 2020, View Source [SID1234572634]). These data focused on women with HER2 negative metastatic breast cancer (MBC) based on primary tumor biopsy, and HER2+ CTCs. The results of this large program demonstrate that screening for HER2+ CTCs, in the blood samples of these patients, is an important tool to guide therapy decisions and improve patient outcomes. Furthermore, the randomized DETECT III phase III study, discussed in a poster spotlight session during the 2020 San Antonio Breast Cancer Symposium, shows that adding reference HER2 targeted TKI (tyrosine kinase inhibitor) lapatinib to standard therapy has a positive impact on OS (overall survival) in this particular patient population. DETECT program is the largest screening analysis to-date on the added value of taking into consideration HER2+ overexpression by CTCs in women with a primary HER2 negative breast cancer tumor biopsy, to optimize patient management.

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Prof. Dr. med. Tanja N. Fehm, full Professor and Head of the Department of Gynecology & Obstetrics at the Heinrich-Heine University of Düsseldorf, Germany, said: "The results obtained in the overall DETECT program clearly indicate that CTC HER2 status is an additional important prognostic and predictive tool to CTC enumeration, because it allows us to better understand, beyond the information gathered from the primary tumor biopsy, what our most critical patients need, so that we can provide them with better care." Metastatic disease remains, indeed, the principal cause of cancer related deaths. CTCs have repeatedly been shown to represent qualified biomarkers to decipher various clinical and molecular complexities of advanced cancers. "The opportunity provided by the DETECT III study, to optimize treatment for patients with metastatic disease who are initially diagnosed with HER2 negative- breast cancer and therefore logically deprived of the HER2 therapy they may actually need, is likely to remove a significant roadblock in the search for a cure to the high burden of this distant recurrent type of breast cancer," she added.

More than 1,900 patients with HER2 negative MBC were screened for CTC enumeration and phenotype using Menarini Silicon Biosystems’ CELLSEARCH CTC System. The CTCs were labeled with an anti HER2 antibody*, stained and classified according to staining intensity. HER2 status of CTCs was assessed in 1,159 CTC-positive patients. A total of 174 (15.0%) patients had a CTC count ≥1 with strong HER2 staining. This situation was significantly associated, in a univariate analysis, with shorter OS.

Finally 105 patients with moderate-to-strong positive CTC-HER2 staining were enrolled in the DETECT III study and randomized to either the lapatinib in combination with standard therapy arm or standard therapy alone arm. Patients in the lapatinib arm had a significantly improved OS. In addition, patients with no evidence of CTC (CTC0), at the time of first follow-up within a median of 73 days, showed better OS compared to patients with CTCs (HR 0.36; 95% CI 0.17 – 0.76; p-value= 0.005). The main conclusion of the DETECT program is that HER2 over expression on CTCs, in patients with metastatic HER2 negative primary breast cancer, provides a key signal to physicians to consider a more appropriate therapeutic option.

"Breast cancer is a heterogenous disease with an increasing number of therapeutic strategies that physicians can prescribe depending on individual patient characteristics and for which they are eager to obtain appropriate noninvasive diagnostic tools to help them optimize their choices in real-time," said Cecilia Simonelli, MD and Global Medical Affairs Head at Menarini Silicon Biosystems. "We are particularly committed to leveraging our technology so that this becomes possible and so that we can contribute to the ultimate goal of allowing even the most difficult cancers to become curable."

About the DETECT study program

DETECT is the largest study program on the role of Circulating Tumor Cell (CTC) count and HER2 phenotype assessment to personalize treatment strategies for HER2 negative MBC. The aim of this program is to evaluate the impact of adapting therapeutic interventions based on CTC phenotypes in patients with a discordant HER2 negative primary tumor biopsy and HER2+ over expression of CTCs in the metastatic setting. The study results consistently show the importance of adding HER2 targeted therapy in this patient population to optimize patient outcomes.

About CELLSEARCH

CELLSEARCH is the first and only clinically validated blood test cleared by the U.S. Food & Drug Administration (FDA) for detecting and counting CTCs to aid physicians in managing patients with metastatic breast, prostate, and colorectal cancers when used in conjunction with other clinical methods of monitoring. The test is also approved by the China National Medical Products Administration (NMPA) for use in monitoring patients with Metastatic Breast Cancer. The CELLSEARCH System is the most extensively studied CTC technology, with research published in more than 650 peer-reviewed publications.

CELLSEARCH Circulating Tumor Cell Kit is not cleared or approved for use to guide treatment decisions. For more information on the full intended use and limitations of the CELLSEARCH system, please refer to the Instructions for Use at View Source

*The CELLSEARCH Tumor Phenotyping Reagent (HER-2/neu) is for Research Use Only. Not for Use in Diagnostic Procedures. The performance characteristics and safety have not been established and are not cleared or approved by the FDA.