On March 4, 2025 Genprex, Inc. ("Genprex" or the "Company") (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, reported that members from its executive leadership team will be attending and participating at BIO Europe Spring taking place March 17-19, 2025 in Milan, Italy (Press release, Genprex, MAR 4, 2025, View Source [SID1234650879]).

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In attendance will be Ryan Confer, President and Chief Executive Officer and Thomas Gallagher, Senior Vice President of Intellectual Property and Licensing. Throughout the duration of the conference, Genprex executives will be available to conduct one-on-one meetings with industry groups to provide an overview of the Company’s gene therapies for cancer and diabetes.

For those interested in meeting with Genprex management during the conference, please request a meeting through the conference meeting portal or by contacting Investor Relations at [email protected]. The event is expected to bring together more than 3,700 executives from biotech, pharma and finance companies to engage in more than 20,000 one-on-one meetings.

On March 4, 2025 Evaxion Biotech A/S (NASDAQ: EVAX) ("Evaxion"), a clinical-stage TechBio company specializing in developing AI-Immunology powered vaccines, reported that it will be presenting at several investor and scientific conferences in March and throughout the second quarter of 2025 (Press release, Evaxion Biotech, MAR 4, 2025, View Source [SID1234650878]).

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Evaxion will be providing company and scientific updates as well as engaging with different stakeholders at conferences in both the US and Europe. As such, conference participation is an important part of our strategy to identify potential partners and opportunities for both business partnerships and scientific collaborations.

Evaxion conference participation March-June 2025:

Immunotherapy and Immuno-Oncology Congress, March 12-14 – London

HC Wainwright AI Based Drug Discovery & Development Conference, April 2 – Virtual

Jones Healthcare and Technology Innovation Conference, April 8-9 – Las Vegas

World Vaccine Congress, April 21-25 – Washington

AACR Annual Meeting, April 25-30 – Chicago

Sidoti Micro-Cap Conference, May 20-21 – Virtual

Dark Genome Target Discovery & Development Summit, June 16-18 – Boston

BIO International Convention, June 16-19 – Boston

World Conference on Infectious Diseases, June 18-20 – Stockholm

International Neoantigen Summit, June 24-26 – Amsterdam

In addition to the list above, Evaxion will be participating, but not presenting, at additional conferences to further boost our stakeholder engagement. Please visit our website for more information.

On March 4, 2025, Plus Therapeutics, Inc. (the "Company") entered into a securities purchase agreement (the "Securities Purchase Agreement") with accredited investors, including certain existing stockholders of the Company, identified on the signature page thereto (collectively, the "Purchasers") for a private placement of securities (the "Private Placement") for gross proceeds expected at closing of approximately $15.0 million (Filing, 8-K, Plus Therapeutics, MAR 4, 2025, View Source [SID1234650877]). The Securities Purchase Agreement, provides for the sale and issuance by the Company of an aggregate of 28,042,140 shares (the "Private Placement Shares") of the Company’s common stock, par value $0.001 per share ("Common Stock"), or, at the election of each Purchaser, prefunded warrants to purchase Common Stock (the "Prefunded Warrants"), exercisable immediately at an exercise price of $0.001 per share (the "Prefunded Warrant Shares"), with each Private Placement Share or Prefunded Warrant accompanied by (i) a Series A common warrant (the "Series A Warrants") to purchase one share of Common Stock (the "Series A Warrant Shares"), and (ii) one Series B common warrant (the "Series B Warrants") to purchase one share of Common Stock (the "Series B Warrant Shares," and together with the Series A Warrant Shares, the "Common Warrant Shares"). The Private Placement Shares, Prefunded Warrants, Prefunded Warrant Shares, Series A Warrants, Series B Warrants, and the Common Warrant Shares are collectively referred to herein as the "Securities."

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The combined purchase price of $0.66 for each Private Placement Share or $0.659 for each Prefunded Warrant in the Private Placement, together with one accompanying Series A Warrant and one accompanying Series B Warrant, represents the applicable "Minimum Price" in accordance with Listing Rule 5635(d) of The Nasdaq Stock Market LLC ("Nasdaq").

The initial exercise price of each Series A Warrant issued in the Private Placement is $1.32 per share of Common Stock. The Series A Warrants are exercisable only following stockholder approval and expire five (5) years thereafter. The number of securities issuable under the Series A Warrant is subject to adjustment as described in more detail in the Series A Warrant. The Series A Warrant exercise price and the related number of shares of Common Stock issuable upon exercise are subject to a "reset" provision upon certain events and are subject to anti-dilution protection upon any subsequent transaction at a fixed price lower than the warrant exercise price then in effect, as more fully described in the Series A Warrant.

The initial exercise price of each Series B Warrant issued in the Private Placement is $1.98 per share of Common Stock or pursuant to an alternative cashless exercise option. The Series B Warrants are exercisable only following stockholder approval and expire two and one-half (2.5) years thereafter. The Series B Warrant exercise price and the related number of shares of Common Stock issuable upon exercise are subject to a "reset" provision upon certain events, as more fully described in the Series A Warrant, and the Series B Warrant alternative cashless exercise provision provides that the Series B Warrant can be exercised without further payment to the Company and for three times the number of shares of Common Stock then subject to the Series B Warrant.

The Prefunded Warrants will be exercisable from the date of issuance until exercised in full and may not be exercised to the extent that immediately following such exercise, the holder would beneficially own greater than 4.99% (or, at the election of the holder, greater than 9.99%) of the Company’s outstanding Common Stock.

Of the securities issued in the Private Placement, 22,727,270 of the shares of Common Stock, or Prefunded Warrants in lieu thereof, and the accompanying 22,727,270 Series A Warrants and 22,727,270 Series B Warrants, are being issued in consideration of new capital subscriptions, and 5,314,870 of the shares of Common Stock, or Prefunded Warrants in lieu thereof, and the accompanying 5,314,870 Series A Warrants and 5,314,870 Series B Warrants, are being issued in exchange (the "Exchange") for the cancelation of approximately $3.2 million in aggregate principal amount of outstanding senior convertible promissory notes (the "Exchange Notes") issued pursuant to that certain Securities Purchase and Exchange Agreement, dated February 13, 2025 (the "SPEA"), by and among the Company and the signatories named therein (the "Investors").

The closing under the Securities Purchase Agreement is expected to occur on March 4, 2025 (the "Closing Date"), subject to the satisfaction of customary closing conditions. The aggregate gross proceeds at the Closing Date are expected to total approximately $15.0 million, before deducting certain expenses payable by the Company. Pending the closing, the funds received by the Company will be deposited into an escrow account, subject to release only
upon confirmation from Nasdaq that the Company has demonstrated compliance for continued listing on the Nasdaq Capital Market at the current time. The Company previously disclosed in its Current Report on Form 8-K filed on November 1, 2024, that the Company was not in compliance with the requirement under Nasdaq Listing Rule 5550(b)(1) to maintain a minimum of $2.5 million in stockholders’ equity (the "Minimum Stockholders’ Equity Requirement"). If the Company does not receive confirmation from Nasdaq by March 31, 2025, that the Company has demonstrated compliance for continued listing on the Nasdaq Capital Market at the current time and will not be delisted, the Private Placement will be terminated, the funds returned to the Purchasers and the Exchange and the Repurchase (as defined below) will be considered void ab initio.

In addition to the stockholder approval of the Series A Warrants and Series B Warrants, the Company has also covenanted to seek if necessary stockholder approval to, among other things, amend the Company’s Certificate of Incorporation, as amended, to increase the authorized share capital of the Company to an amount sufficient to cover the shares of Common Stock issuable upon the exercise of the Series A Warrants and Series B Warrants.

First Amendment to the SPEA

In connection with entering into the Securities Purchase Agreement, the Company entered into that certain First Amendment to the SPEA, dated February 13, 2025, by and among the Company and the Investors (the "First Amendment"). The SPEA included certain limitations and restrictions on the Company’s ability to issue securities and provided the Investors participation rights in future equity and equity-linked offerings of securities, subject to certain limited exceptions (the "Financing Restrictions"). Pursuant to the First Amendment, subject to consummation of the Private Placement, the Company agreed to repurchase from the Investors $3,362,251 in principal amount of the Company’s outstanding senior convertible promissory notes (the "Funding Notes") and 3,002,009 warrants (the "SPEA Warrants") issued pursuant to the SPEA for an aggregate purchase price of $4.25 million (the "Repurchase"). In exchange for the repurchase by the Company of the Funding Notes and SPEA Warrants, the Purchasers agreed to consent to the Private Placement and eliminate the Financing Restrictions.

Registration Rights

In connection with the Securities Purchase Agreement, as amended, the Company entered into a registration rights agreement (the "Registration Rights Agreement"), dated as the Closing Date, with the Purchasers, pursuant to which the Company agreed to prepare and file a registration statement with the U.S. Securities and Exchange Commission (the "SEC") covering the resale of the Private Placement Shares, Prefunded Warrant Shares and Common Warrant Shares (the "Registration Statement") no later April 4, 2025 (the "Filing Due Date"), and to have the registration statement declared effective as promptly as practical thereafter, and in any event no later than May 5, 2025 (the "Effectiveness Due Date"). In addition, pursuant to the Registration Rights Agreement, the Company is required to use its reasonable best efforts to keep the Registration Statement continuously effective from the date on which the SEC declares the Registration Statement to be effective until such date that all Registrable Securities (as such term is defined in the Registration Rights Agreement) covered by the Registration Statement have been sold pursuant to a registration statement under the Securities Act of 1933, as amended (the "Securities Act"), under Rule 144 as promulgated by the SEC under the Securities Act ("Rule 144"), or otherwise shall have ceased to be Registrable Securities.

In the event that (i) the Company fails to file the Registration Statement by the Filing Due Date, (ii) the Company fails to file with the SEC a request for acceleration of the Registration Statement within 5 Trading Days (as such term is defined in the Registration Rights Agreement) of the date that the Company is notified by the SEC that such Registration Statement will not be "reviewed" or will not be subject to further review, (iii) the Registration Statement is not declared effective on or prior to the Effectiveness Due Date, (iv) after being declared effective, (A) the Registration Statement ceases to remain continuously effective as to all Registrable Securities for which it is required to be effective, or (B) the holders are not permitted to utilize the prospectus in the Registration Statement to sell Registrable Securities, other than certain allowed delays, or (v) an allowed delay exceeds beyond the length permitted for an allowed delay, then the Company has agreed (unless the Registrable Securities are freely tradable pursuant to Rule 144) to make payments to each Purchaser as liquidated damages in an amount equal to 1% of the aggregate amount invested by each such holder in the Registrable Securities, subject to a 6% cap in the aggregate as set forth in the Registration Rights Agreement.

The Company has granted the Purchasers customary indemnification rights in connection with the Registration Rights Agreement. The Purchasers have also granted the Company customary indemnification rights in connection with the Registration Rights Agreement.

The foregoing descriptions of the Securities Purchase Agreement, Series A Warrant, Series B Warrant, Prefunded Warrant, First Amendment, and Registration Rights Agreement are qualified in their entirety by reference to the full text of such documents, copies of which are attached hereto as exhibits, and each of which is incorporated herein in its entirety by reference. The representations, warranties and covenants contained in such agreements were made only for purposes of such agreements and as of specific dates, were solely for the benefit of the parties to such agreements and may be subject to limitations agreed upon by the contracting parties.

Compliance with Nasdaq Equity Listing Requirement

As a result of the Private Placement, the Company believes that it has regained compliance with Nasdaq Listing Rule 5550(b)(1).

On March 4, 2025 Compugen Ltd. (Nasdaq: CGEN) (TASE: CGEN) a clinical-stage cancer immunotherapy company and a pioneer in computational target discovery, reported financial results for the fourth quarter and full year 2024 and provided a corporate update (Press release, Compugen, MAR 4, 2025, View Source [SID1234650875]).

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"I believe Compugen is well-positioned for growth, building on significant progress made in 2024 together with a diverse and innovative pipeline and with a strong focus on execution in 2025," said Anat Cohen-Dayag, Ph.D., President and CEO of Compugen. "The clinical data we presented at SITC (Free SITC Whitepaper) 2024, consistent with previous data, support advancing our potential first-in-class anti-PVRIG, COM701, to be evaluated as a maintenance treatment option for patients with platinum sensitive ovarian cancer. We are on track to initiate an adaptive platform trial, which is scheduled to start with a randomized placebo controlled sub-trial evaluating single agent COM701 therapy in Q2 2025. This development path is supported by a strong clinical and biological rationale and has the potential to open the door to advance COM701 as a single agent and as a backbone to future drug combinations."

Dr. Cohen-Dayag continued, "We are also encouraged by the promising rilvegostomig data presented by our partner, AstraZeneca, in 2024. Rilvegostomig is a PD-1/TIGIT bispecific antibody, the TIGIT component of which is derived from COM902. AstraZeneca is running seven Phase 3 trials with rilvegostomig across lung and gastrointestinal cancers and plans to share early data for rilvegostomig in combination with their ADCs in 2025. AstraZeneca’s broad development strategy for rilvegostomig to replace existing PD-1/PD-L1 inhibitors represents a significant potential revenue source for Compugen as we may be eligible for both future milestone payments and mid-single digit tiered royalties on future sales.

Dr. Cohen-Dayag added, "Our solid financial position with a cash runway expected to fund our operations into 2027 allows us to advance our innovative clinical and early-stage pipeline. This includes advancing the Phase 1 trial of GS-0321, a potential first-in-class anti-IL18BP licensed to Gilead, for which we received a $30 million milestone payment for achieving IND clearance in 2024. Additionally, it enables us to continue to leverage our AI/ML powered predictive computational discovery platform, UnigenTM, to accelerate our research efforts supporting our early pipeline. Our Unigen platform is validated by our multiple potential first-in-class and potential best-in-class clinical programs, as well as our partnerships with AstraZeneca and Gilead."

Next Planned Milestones

•
Q2 2025 – initiation of a randomized adaptive platform trial comparing COM701 maintenance therapy to placebo in total of 60 patients with relapsed platinum sensitive ovarian cancer
•
2025 – Compugen’s partner, AstraZeneca, plans to share early data for rilvegostomig in combination with their ADCs
•
H2 2026 – data from projected interim analysis of single agent COM701 sub-trial 1 as maintenance therapy in relapsed platinum sensitive ovarian cancer

Fourth Quarter and Full Year 2024 Financial Highlights

Cash: As of December 31, 2024, Compugen had approximately $103.3 million in cash, cash equivalents, short-term bank deposits and investment in marketable securities. The cash balance at the end of 2024 includes the receipt of the upfront payment of $60 million from Gilead for the licensing of GS-0321, the $30 million milestone payment from Gilead for IND clearance (both subject to a 15% withholding tax) and the $15 million milestone payments from AstraZeneca on dosing of the first patient in the first and second major indications for rilvegostomig Phase 3 trials.

In January and February 2025, subsequent to the financial results for the year ended December 31, 2024, a total of approximately 3.96 million shares were sold through the Company’s ATM facility contributing net proceeds of approximately $8.87 million (net of $274 thousand commission issuance expenses).

Compugen expects that its current cash will be sufficient to fund its operating plans into 2027. The Company has no debt.

Revenues: Compugen reported approximately $1.5 million in revenues for the fourth quarter of 2024 and $27.9 million in revenues for the year ended December 31, 2024, compared to approximately $33.5 million in revenues for each of the comparable periods in 2023. The revenues for 2024 include the portion of the upfront payment and the IND milestone payment from the license agreement with Gilead and the $5 million clinical milestone payment from AstraZeneca, while the revenues for 2023 reflect the portion of the upfront payment from the license agreement with Gilead allocated to the license and the previous clinical milestone from the license agreement with AstraZeneca in the amount of $10 million.

Cost of Revenues for the fourth quarter and year ended December 31, 2024, were approximately $0.7 million and $7.9 million, respectively, compared with approximately $2.0 million for both comparable periods in 2023. Cost of revenues for 2024 represents the cost of IND and Phase 1 activities and royalty payments in connection with Compugen’s revenues, offset by royalty reversal in 2024 due to exemption received from the Israeli Innovation Authority from the requirement to pay royalties on income derived from sales associated with products related to IL-18BP, while cost of revenues for 2023 represents milestone and royalty payments in connection with our revenues.

R&D expenses for the fourth quarter and year ended December 31, 2024, decreased to approximately $5.9 million, and $24.8 million, respectively, compared with approximately $10.9 million and $34.5 million for the comparable periods in 2023, respectively. The decrease in 2024 was mainly due to the classification of expenses related to GS-0321 to cost of revenues and to lower CMC and IND enabling activities related to GS-0321, partially offset by an increase in clinical expenses.

G&A expenses for the fourth quarter and year ended December 31, 2024, were approximately $2.2 million and $9.4 million, respectively, compared with approximately $2.5 million and $9.7 million for the comparable periods in 2023, respectively.

Net Income / Loss: During the fourth quarter of 2024, Compugen reported a net loss of approximately $6.1 million, or approximately 7 cents per basic and diluted share, compared to a net income of approximately $9.7 million, or approximately 11 cents per basic and diluted share in the comparable period of 2023. Net loss for the year ended December 31, 2024, was approximately $14.2 million, or approximately 16 cents per basic and diluted share, compared with a net loss of approximately $18.8 million, or approximately 21 cents per basic and diluted share in the comparable period in 2023.

Full financial tables are included below.

Conference Call and Webcast Information
The Company will hold a conference call today, March 4, 2025, at 8:30 AM ET to review its fourth quarter and full year 2024 results. To access the conference call by telephone, please dial 1-866-744-5399 from the United States, or +972-3-918-0644 internationally. The call will also be available via live webcast through Compugen’s website, located at the following link. Following the live audio webcast, a replay will be available on the Company’s website.

On March 4, 2025 BeiGene, Ltd. (NASDAQ: ONC; HKEX: 06160; SSE: 688235), a global oncology company that intends to change its name to BeOne Medicines Ltd., reported the U.S. Food and Drug Administration (FDA) has approved TEVIMBRA (tislelizumab-jsgr), in combination with platinum-containing chemotherapy, for the first-line treatment of adults with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1) (Press release, BeiGene, MAR 4, 2025, View Source [SID1234650874]).

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"The approval of TEVIMBRA in combination with chemotherapy for adult patients with ESCC expands first-line treatment options for patients with this disease," said Dr. Nataliya Uboha, Associate Professor, University of Wisconsin, Carbone Cancer Center. "There is a critical need for effective treatments of ESCC, and TEVIMBRA has been shown to improve outcomes in this patient population."

The additional indication is based on results from BeiGene’s RATIONALE-306 (NCT03783442), a randomized, placebo-controlled, double-blind, global Phase 3 study to evaluate the efficacy and safety of TEVIMBRA in combination with platinum-containing chemotherapy as a first-line treatment in adult patients (n=649) with unresectable, locally advanced recurrent or metastatic ESCC. The study met its primary endpoint and demonstrated a statistically significant improvement in overall survival (OS) for adult patients randomized to TEVIMBRA in combination with chemotherapy compared to placebo in combination with chemotherapy. Exploratory analyses indicated that the improvement in the intent-to-treat (ITT) population was primarily attributed to the results observed in the subgroup of patients with PD-L1 ≥1. Analysis of OS in the PD-L1 positive (≥1) population (n=481) showed a median OS of 16.8 months for patients treated with TEVIMBRA plus chemotherapy compared to 9.6 months for patients treated with placebo plus chemotherapy (HR: 0.66, [95% CI: 0.53, 0.82]), resulting in a 34% reduction in the risk of death. These results represent an unprecedented improvement in OS in first-line ESCC patients.

"Today’s approval, our third from the FDA in less than a year, reflects our dedication to advancing innovative therapies and addressing critical needs in cancer care," said Mark Lanasa, M.D., Ph.D., Chief Medical Officer, Solid Tumors at BeiGene. "FDA approval of TEVIMBRA for the first-line treatment of advanced esophageal squamous cell carcinoma marks a significant step forward in tackling the unmet needs in this challenging disease area. We are grateful to the patients, clinicians, and researchers whose commitment and courage have made this progress possible."

The safety of TEVIMBRA in combination with chemotherapy was evaluated in the same global clinical trial, RATIONALE-306. The most frequent serious adverse reactions (≥2%) were pneumonia, dysphagia, diarrhea, fatigue, and esophageal stenosis. The most common (≥20%) adverse reactions were anemia, fatigue, decreased appetite, nausea, constipation, decreased weight, diarrhea, peripheral sensory neuropathy, vomiting, and stomatitis.

TEVIMBRA is also approved in the U.S. as monotherapy for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor and in combination with chemotherapy for the first-line treatment of adults with gastric and gastroesophageal junction (G/GEJ) cancers.

The Company recently announced its intent to change its name to BeOne Medicines Ltd., reaffirming its commitment to develop innovative medicines to eliminate cancer by partnering with the global community to serve as many patients as possible.

About Esophageal Squamous Cell Carcinoma (ESCC)

Globally, esophageal cancer is the sixth most common cause of cancer-related deaths, and ESCC is the most common histologic subtype, accounting for nearly 90% of esophageal cancers. An estimated 957,000 new esophageal cancer cases are projected in 2040, an increase of nearly 60% from 2020, underscoring the need for additional effective treatments.1 Esophageal cancer is a rapidly fatal disease, and more than two-thirds of patients have advanced or metastatic disease at the time of diagnosis, with an expected five-year survival rate of less than 6% for those with distant metastases.2

About TEVIMBRA (tislelizumab-jsgr)

TEVIMBRA is a uniquely designed humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping the body’s immune cells detect and fight tumors.

TEVIMBRA is the foundational asset of BeiGene’s solid tumor portfolio and has shown potential across multiple tumor types and disease settings. The global TEVIMBRA clinical development program includes almost 14,000 patients enrolled to date in 34 countries and regions across 66 trials, including 20 registration-enabling studies. TEVIMBRA is approved in more than 42 countries, and more than 1.3 million patients have been treated globally.

U.S. Indication and Important Safety Information for TEVIMBRA (tislelizumab-jsgr) injection

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Severe and Fatal Immune-Mediated Adverse Reactions

TEVIMBRA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated reactions.

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

Withhold or permanently discontinue TEVIMBRA depending on severity. In general, if TEVIMBRA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids.

Immune-Mediated Pneumonitis

TEVIMBRA can cause immune-mediated pneumonitis, which can be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Immune-mediated pneumonitis occurred in 4.9% (96/1972) of patients receiving TEVIMBRA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (1.6%) and Grade 2 (1.9%) adverse reactions. Pneumonitis led to permanent discontinuation of TEVIMBRA in 38 (1.9%) patients and withholding of TEVIMBRA in 32 (1.6%) patients.

Seventy-four (77.1%) of the 96 patients received systemic corticosteroids. Sixty-five (67.7%) of the 96 patients received high-dose systemic corticosteroids. Immune-mediated pneumonitis resolved in 50% of the 96 patients. Of the 32 patients in whom TEVIMBRA was withheld for pneumonitis, 20 (62.5%) reinitiated TEVIMBRA after symptom improvement; of these, 2 (10%) patients had recurrence of pneumonitis.

Immune-Mediated Colitis

TEVIMBRA can cause immune-mediated colitis, which can be fatal. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1 blocking antibodies. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 0.8% (16/1972) of patients receiving TEVIMBRA, including Grade 3 (0.3%) and Grade 2 (0.4%) adverse reactions. Colitis led to permanent discontinuation of TEVIMBRA in 4 (0.2%) patients and withholding of TEVIMBRA in 5 (0.3%) patients. Twelve (75%) of the 16 patients received systemic corticosteroids. Eight (50%) of the 16 patients received high-dose systemic corticosteroids. Two (12.5%) of the 16 patients received immunosuppressive treatment. Immune-mediated colitis resolved in 93.8% of the 16 patients. All 5 patients in whom TEVIMBRA was withheld for colitis reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of colitis.

Immune-Mediated Hepatitis

TEVIMBRA can cause immune-mediated hepatitis, which can be fatal.

Immune-mediated hepatitis occurred in 1.2% (24/1972) of patients receiving TEVIMBRA, including fatal (0.1%), Grade 4 (0.2%), Grade 3 (0.5%) and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation in 3 (0.2%) patients and withholding of TEVIMBRA in 13 (0.7%) patients. Eighteen (75%) of the 24 patients received systemic corticosteroids. Thirteen (54.2%) of the 24 patients received high-dose systemic corticosteroids. Two patients (8.3%) of the 24 patients received immunosuppressive treatment. Immune-mediated hepatitis resolved in 70.8% of the 24 patients. Of the 13 patients in whom TEVIMBRA was withheld for hepatitis, 7 (53.8%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of hepatitis.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

TEVIMBRA can cause immune-mediated adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold TEVIMBRA depending on severity.

Immune-mediated adrenal insufficiency occurred in 0.4% (8/1972) of patients receiving TEVIMBRA, including Grade 4 (0.1%), Grade 3 (0.1%) and Grade 2 (0.3%) adverse reactions. Adrenal insufficiency did not lead to permanent discontinuation of TEVIMBRA. TEVIMBRA was withheld in 7 (0.4%) patients. All 8 patients received systemic corticosteroids. Three (37.5%) of the 8 patients received high-dose systemic corticosteroids. Adrenal insufficiency resolved in 25% of the 8 patients. Of the 7 patients in whom TEVIMBRA was withheld for adrenal insufficiency, 5 (71.4%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of adrenal insufficiency.

Hypophysitis

TEVIMBRA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue TEVIMBRA depending on severity.

Hypophysitis/hypopituitarism occurred in 0.2% (4/1972) of patients receiving TEVIMBRA, including a Grade 2 (0.2%) adverse reaction. No TEVIMBRA treatment discontinuation was required, while treatment was withheld in 1 (0.1%) patient. Three (75%) of the 4 patients received systemic corticosteroids. One (25%) of the 4 patients received high-dose systemic corticosteroids. Hypophysitis/hypopituitarism did not resolve in the 4 patients. For the 1 patient where TEVIMBRA was withheld for hypophysitis/hypopituitarism, there was no recurrence of hypophysitis/hypopituitarism.

Thyroid Disorders

TEVIMBRA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue TEVIMBRA depending on severity.

Thyroiditis: Immune-mediated thyroiditis occurred in 1.2% (24/1972) of patients receiving TEVIMBRA, including Grade 2 (0.5%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of TEVIMBRA. TEVIMBRA was withheld in 3 (0.2%) patients. Two (8.3%) of the 24 patients received systemic corticosteroids. Thyroiditis resolved in 41.7% of the 24 patients. All three patients in whom TEVIMBRA was withheld for thyroiditis reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of thyroiditis.

Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 4.8% (95/1972) of patients receiving TEVIMBRA, including Grade 3 (0.1%) and Grade 2 (0.9%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of TEVIMBRA in 1 (0.1%) patient and withholding of TEVIMBRA in 4 (0.2%) patients. One (1.1%) of the 95 patients received systemic corticosteroids. Hyperthyroidism resolved in 75.8% of the 95 patients. Of the 4 patients in whom TEVIMBRA was withheld for hyperthyroidism, 3 (75%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of hyperthyroidism.

Hypothyroidism: Immune-mediated hypothyroidism occurred in 12.7% (250/1972) of patients receiving TEVIMBRA, including Grade 4 (0.1%) and Grade 2 (6.8%) adverse reactions. TEVIMBRA was not permanently discontinued in any patient, while treatment was withheld in 7 (0.4%) patients. Two (0.8%) of the 250 patients received systemic corticosteroids and 158 patients (63.2%) received hormone replacement therapy. Hypothyroidism resolved in 31.6% of the 250 patients. The majority (51.6%) of patients with hypothyroidism required long-term thyroid hormone replacement. Of the 7 patients in whom TEVIMBRA was withheld for hypothyroidism, 6 (85.7%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of hypothyroidism.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis

Diabetes mellitus has been reported with PD-1/PD-L1 blocking antibodies. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue TEVIMBRA depending on severity.

Diabetes mellitus occurred in 0.9% (18/1972) of patients receiving TEVIMBRA, including Grade 4 (0.1%), Grade 3 (0.4%) and Grade 2 (0.4%) adverse reactions. TEVIMBRA was permanently discontinued in 3 (0.2%) patients and TEVIMBRA treatment was withheld in 3 (0.2%) patients. Twelve (66.7%) patients received insulin therapy for diabetes mellitus. Diabetes mellitus resolved in 27.8% of the 18 patients. Of the 3 patients in whom TEVIMBRA was withheld for diabetes mellitus, none of the patients reinitiated TEVIMBRA after symptom improvement.

Immune-Mediated Nephritis with Renal Dysfunction

TEVIMBRA can cause immune-mediated nephritis, which can be fatal.

Immune-mediated nephritis with renal dysfunction occurred in 0.3% (5/1972) of patients receiving TEVIMBRA, including Grade 3 (0.1%) and Grade 2 (0.2%) adverse reactions. TEVIMBRA was permanently discontinued in 1 (0.1%) patient and treatment was withheld in 3 (0.2%) patients. Three (60%) of the 5 patients received systemic corticosteroids. All 3 (60%) of the 5 patients received high-dose systemic corticosteroids. Nephritis with renal dysfunction resolved in 40.0% of the 5 patients. Of the 3 patients in whom TEVIMBRA was withheld for nephritis, 2 (66.7%) reinitiated TEVIMBRA after symptom improvement and one (50%) patient had recurrence of nephritis.

Immune-Mediated Dermatologic Adverse Reactions

TEVIMBRA can cause immune-mediated rash or dermatitis. Cases of severe cutaneous adverse reactions (SCARs), including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported, some with fatal outcome. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue TEVIMBRA depending on severity.

Immune-mediated dermatologic adverse reactions occurred in 15.3% (301/1972) of patients receiving TEVIMBRA, including Grade 4 (0.1%), Grade 3 (0.9%) and Grade 2 (3.5%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of TEVIMBRA in 2 (0.1%) patients and withholding of TEVIMBRA in 18 (0.9%) patients. Thirty (10.0%) of the 301 patients received systemic corticosteroids. Thirteen (4.3%) of the 301 patients received high-dose systemic corticosteroids. Immune-mediated skin reactions resolved in 190 (63.1%) of the 301 patients. Of the 18 patients in whom TEVIMBRA was withheld for dermatologic adverse reactions, 15 (83.3%) reinitiated TEVIMBRA after symptom improvement; of these, 1 (6.7%) patient had recurrence of immune-mediated dermatologic adverse reactions.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than 1% each in 1972 patients who received TEVIMBRA: myositis, myocarditis, arthritis, polymyalgia rheumatica, and pericarditis.

The following additional clinically significant immune-mediated adverse reactions have been reported with other PD-1/PD-L1 blocking antibodies, including severe or fatal cases.

Cardiac/Vascular: Vasculitis.

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.­­

Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and Connective Tissue: Polymyositis, rhabdomyolysis and associated sequelae including renal failure.

Endocrine: Hypoparathyroidism.

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Infusion-Related Reactions

TEVIMBRA can cause severe or life-threatening infusion-related reactions. Infusion-related reactions occurred in 5% (99/1972) patients receiving TEVIMBRA, including Grade 3 or higher (0.2%) reactions. Monitor patients for signs and symptoms of infusion-related reactions.

Slow the rate of infusion for mild (Grade 1) and interrupt the infusion for moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue TEVIMBRA.

Complications of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action, TEVIMBRA can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TEVIMBRA and for 4 months after the last dose.

ADVERSE REACTIONS

First-line Treatment of Unresectable Advanced or Metastatic Esophageal Carcinoma (ESCC)

Permanent discontinuation of TEVIMBRA due to adverse reactions occurred in 13% of patients. The adverse reaction which resulted in discontinuation in ≥2% of patients was pneumonitis (2.2%).

Dosage interruptions of TEVIMBRA due to adverse reactions occurred in 52% of patients. Adverse reactions which required dosage interruption in ≥2% of patients were neutrophil count decreased (7%), fatigue (6%), pneumonia (6%), anemia (4.3%), neutropenia (4.3%), white blood cell count decreased (4.3%), rash (3.7%), dysphagia (2.8%), platelet count decreased (2.8%), pyrexia (2.8%), and diarrhea (2.2%).

The most common (≥20%) adverse reactions, including laboratory abnormalities were decreased neutrophil count, decreased sodium, increased glucose, anemia, fatigue, decreased appetite, increased AST, decreased potassium, increased serum creatinine, decreased calcium, increased ALT, diarrhea, stomatitis, and vomiting.

Previously Treated Unresectable Advanced or Metastatic ESCC

Permanent discontinuation of TEVIMBRA due to an adverse reaction occurred in 19% of patients. Adverse reactions which resulted in permanent discontinuation in ≥1% of patients were hemorrhage, pneumonitis (including pneumonitis and immune-mediated pneumonitis), and pneumonia.

Dosage interruptions of TEVIMBRA due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruptions in ≥2% of patients were pneumonia, pneumonitis, and fatigue.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were increased glucose, decreased hemoglobin, decreased lymphocytes, decreased sodium, decreased albumin, increased alkaline phosphatase, anemia, fatigue, increased AST, musculoskeletal pain, decreased weight, increased ALT, and cough.

Treatment of Previously Untreated Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (G/GEJ)

Permanent discontinuation of TEVIMBRA due to an adverse drug reaction occurred in 16% of patients. Adverse drug reactions which resulted in permanent discontinuation in ≥1% of patients were death, fatigue, and pneumonitis.

Dosage interruption of TEVIMBRA in the TEVIMBRA plus chemotherapy arm due to an adverse drug reaction occurred in 49% of patients. Adverse drug reactions which required dosage modifications in ≥2% of patients were, platelet count decreased (12%), neutrophil count decreased (10%), neutropenia (6%), white blood cell count decreased (6%), increased AST (4.8%), increased ALT (3.8%), increased blood bilirubin (3%), COVID-19 (3%), thrombocytopenia (2.8%), leukopenia (2.6%), pneumonitis (2.2%), and pneumonia (2%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, for TEVIMBRA in combination with chemotherapy were nausea, fatigue, decreased appetite, anemia, peripheral sensory neuropathy, vomiting, decreased platelet count, decreased neutrophil count, increased aspartate aminotransferase, diarrhea, abdominal pain, increased alanine aminotransferase, decreased white blood cell count, decreased weight, and pyrexia.

INDICATIONS

TEVIMBRA is a programmed death receptor-1 (PD-1)-blocking antibody indicated for:

Esophageal Cancer

in combination with platinum-containing chemotherapy for the first-line treatment of adults with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1).
as a single-agent, for the treatment of adults with unresectable or metastatic ESCC after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor.
Gastric Cancer

in combination with platinum and fluoropyrimidine-based chemotherapy for the first-line treatment of adults with unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (≥1).
Please see full U.S. Prescribing Information including the U.S. Medication Guide.