On December 11, 2023 Coherus BioSciences, Inc. (Coherus, Nasdaq: CHRS) reported that the National Comprehensive Cancer Network (NCCN) has updated the clinical practice guidelines for nasopharyngeal carcinoma (NPC) to include LOQTORZI (toripalimab-tpzi) as a preferred, category 1 first-line treatment option for adults with metastatic or recurrent locally advanced NPC when used in combination with cisplatin and gemcitabine (Press release, Coherus Biosciences, DEC 11, 2023, View Source [SID1234638413]). The guidelines also recommend LOQTORZI monotherapy as the only preferred treatment in subsequent lines of therapy if disease progression on or after a platinum-containing therapy.

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"Inclusion in the NCCN guidelines as a preferred category 1 treatment is an important step forward in treating patients with R/M NPC. We now have a new standard of care for this rare form of head and neck cancer," said Tarek Mekhail, M.D., Medical Director at AdventHealth Cancer Institute in Orlando, Florida. "Preferred category 1 placement reinforces that LOQTORZI has strong clinical data, including PFS and OS, representing a significant advancement in treating a disease where there have been no FDA-approved options until now."

"NPC is an aggressive and life-threatening form of cancer for which historically there have been limited treatment options. As the first and only FDA-approved treatment for NPC, LOQTORZI has demonstrated the potential to significantly extend survival while slowing disease progression," said Rosh Dias, M.D., Chief Medical Officer at Coherus. "The inclusion of LOQTORZI in the updated NCCN guidelines as the only immunotherapy for use in combination with chemotherapy that is listed as a preferred regimen with a category 1 listing, and as the only preferred regimen for use in subsequent lines of treatment for this disease, further reinforces the clinical benefit of LOQTORZI across all lines of therapy in NPC and should help quickly establish LOQTORZI as the standard of care for the treatment of this disease."

The NCCN recommendations are based on results of the JUPITER-02 Phase 3 study and the POLARIS-02 Phase 2 study. In the JUPITER-02 Phase 3 study, LOQTORZI combined with chemotherapy significantly improved progression-free survival (PFS), reducing the risk of disease progression or death by 48% compared to chemotherapy alone. LOQTORZI also demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), with treatment resulting in a 37% reduction in the risk of death versus chemotherapy alone. In the POLARIS-02 clinical study, LOQTORZI demonstrated durable anti-tumor activity in patients with recurrent or metastatic NPC who failed previous chemotherapy, with an objective response rate (ORR) of 20.5%, a disease control rate (DCR) of 40.0%, and a median OS of 17.4 months with an acceptable safety profile.

LOQTORZI is a next-generation programmed death receptor-1 (PD-1) monoclonal antibody that blocks PD-1 ligands PD-L1 and PD-L2 with high potency at a unique site on the PD-1 receptor, enabling the immune system to activate and kill the tumor. In October, Coherus and Junshi announced the U.S. Food and Drug Administration (FDA) approval of LOQTORZI in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and as monotherapy for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy.

About NPC
NPC is a type of aggressive cancer that starts in the nasopharynx, the upper part of the throat behind the nose and near the base of the skull. NPC is rare in the United States, with an annual incidence of fewer than one per 100,000. The five-year survival rate for all patients diagnosed with NPC is approximately 60%, however, those who are diagnosed with advanced disease have a five-year survival rate of approximately 49%.

Due to the location of the primary tumor, surgery is rarely an option, and patients with localized disease are treated primarily with radiation and chemotherapy. Patients treated with chemotherapy alone experience poor prognosis: only 20% experience one-year PFS; up to 50% developed distant metastasis during their disease course; and low median OS of 29 months.

LOQTORZI is the first FDA-approved therapy for NPC and will represent a new standard of care for treating the disease when used in combination with cisplatin and gemcitabine in the first line setting or as monotherapy in the second line or greater setting.

About LOQTORZI (toripalimab-tpzi)
LOQTORZI is a next generation anti-PD-1 monoclonal antibody that blocks PD-L1 binding to the PD⁠-⁠1 receptor at a unique site with high affinity and activates anti-tumor immunity demonstrating improvement in the overall survival of cancer patients in several tumor types.

INDICATIONS AND IMPORTANT SAFETY INFORMATION

INDICATIONS

LOQTORZI (toripalimab-tpzi) is indicated:

In combination with cisplatin and gemcitabine, for the first-line treatment of adults with metastatic or with recurrent, locally advanced nasopharyngeal carcinoma (NPC).
As a single agent, for the treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after a platinum-containing chemotherapy.
IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which can be severe or fatal, occur in any organ system or tissue, affect more than one body system simultaneously, and occur at any time after starting PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment, they can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Monitor for early identification and management. 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 LOQTORZI based on severity and type of reaction (see Dosage and Administration in Prescribing Information). In general, If LOQTORZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
LOQTORZI can cause immune-mediated pneumonitis.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, immune-mediated pneumonitis occurred in 2.1% (3/146) of patients, including Grade 2 (1.4%) adverse reactions. Pneumonitis resolved in 67% (2/3) of these patients.
In patients receiving LOQTORZI monotherapy, immune-mediated pneumonitis occurred in 2.6% (22/851) of patients, including fatal (0.2%), Grade 3 (0.7%), and Grade 2 (1.1%) adverse reactions. Systemic corticosteroids were required in 82% (18/22) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of LOQTORZI in 1.2% (10/851) of patients. Pneumonitis resolved in 23% (5/22) of these patients.
Immune-Mediated Colitis
LOQTORZI can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving LOQTORZI monotherapy, immune-mediated colitis occurred in 0.4% (3/851) of patients, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. Colitis resolved in all 3 patients.

Hepatotoxicity and Immune-Mediated Hepatitis
LOQTORZI can cause immune-mediated hepatitis.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, immune-mediated hepatitis occurred in 0.7% (1/146) of patients, which was a Grade 3 (0.7%) adverse reaction. The patient with immune-mediated hepatitis required systemic corticosteroids.
In patients receiving LOQTORZI monotherapy, immune-mediated hepatitis occurred in 3.3% (28/851) of patients, including Grade 4 (0.8%), Grade 3 (2.1%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of LOQTORZI in 1.1% of patients and withholding of LOQTORZI in 0.8% of patients. Hepatitis resolved in 54% (15/28) of these patients.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
LOQTORZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue LOQTORZI depending on severity. In patients receiving LOQTORZI monotherapy, adrenal insufficiency occurred in 0.5% (4/851) of patients, including Grade 2 (0.4%) and Grade 1 (0.1%) adverse reactions. Systemic corticosteroids were required in 75% (3/4) of the patients with adrenal insufficiency. Adrenal insufficiency led to withholding of LOQTORZI in 0.1% (1/851) of patients. In the one patient in whom LOQTORZI was withheld, LOQTORZI was reinitiated after symptom improvement.

Hypophysitis
LOQTORZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effects such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue LOQTORZI depending on severity. In patients receiving LOQTORZI monotherapy, hypophysitis occurred in 0.4% (3/851) of patients receiving LOQTORZI, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. All three patients received systemic corticosteroids. Hypophysitis led to permanent discontinuation of LOQTORZI in 0.1% (1/851) of patients and withholding of LOQTORZI in 0.1% (1/851) of patients. The one patient in whom LOQTORZI was withheld reinitiated LOQTORZI.

Thyroid Disorders
LOQTORZI 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 LOQTORZI depending on severity.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, thyroiditis occurred in 2.1% (3/146) of patients receiving LOQTORZI, including Grade 2 (1.4%). Three patients required thyroid hormone replacement therapy. Thyroiditis resolved in one of the 3 patients. Hyperthyroidism occurred in 1.4% (2/146) of patients receiving LOQTORZI in combination with cisplatin and gemcitabine. Hyperthyroidism resolved in these 2 patients. Hypothyroidism occurred in 30% (44/146) of patients receiving LOQTORZI in combination with cisplatin and gemcitabine, including Grade 2 (24%) and Grade 1 (6%). Eighty percent of the 44 patients required thyroid hormone replacement therapy. LOQTORZI was withheld in 2.1% (3/146) of the patients. Of the 3 patients in whom LOQTORZI was withheld, 2 patients reinitiated LOQTORZI.
In patients receiving LOQTORZI monotherapy, thyroiditis occurred in 0.6% (5/851) patients receiving LOQTORZI, including Grade 2 (0.1%). Two of these 5 patients received systemic corticosteroids and 2 required thyroid hormone replacement therapy. Thyroiditis resolved in 2 of the 5 patients. Hyperthyroidism occurred in 7% (55/851) of patients receiving LOQTORZI, including Grade 2 (1.9%). Hyperthyroidism resolved in 85% (47/55) of the patients. Hypothyroidism occurred in 15% (128/851) of patients receiving LOQTORZI, including Grade 2 (8%). Sixty three percent of the 128 patients required thyroid hormone replacement therapy. LOQTORZI was withheld in 0.5% of patients. Of the 4 patients in whom LOQTORZI was withheld, 3 patients reinitiated LOQTORZI.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue LOQTORZI depending on severity. In patients receiving LOQTORZI monotherapy, diabetes mellitus occurred in 0.9% (8/851) of patients receiving LOQTORZI, including Grade 4 (0.1%), Grade 3 (0.7%), and Grade 2 (0.1%). Diabetes mellitus led to permanent discontinuation in 0.4% of patients. Six of the 8 (75%) patients with diabetes mellitus required long-term insulin therapy.

Immune-Mediated Nephritis with Renal Dysfunction
LOQTORZI can cause immune-mediated nephritis.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, immune-mediated nephritis occurred in 0.7% (1/146) of patients receiving LOQTORZI. The one patient with immune-mediated nephritis (Grade 4) required systemic corticosteroids and nephritis led to discontinuation of LOQTORZI. Nephritis resolved in this patient.
In patients receiving LOQTORZI monotherapy, immune-mediated nephritis occurred in 0.5% (4/851) of patients, including Grade 3 (0.5%) adverse reactions. Nephritis resolved in 75% (3/4) of these patients.
Immune-Mediated Dermatologic Adverse Reactions
LOQTORZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue LOQTORZI depending on severity.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, immune-mediated dermatologic adverse reactions occurred in 8% (12/146) of patients, including Grade 3 (3.4%) and Grade 2 (1.4%) adverse reactions. Systemic corticosteroids were required in 25% (3/12) of the patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of LOQTORZI in 2.1% (3) of patients. Immune-mediated dermatologic adverse reactions resolved in 92% (11/12) of these patients.
In patients receiving LOQTORZI monotherapy, immune-mediated dermatologic adverse reactions occurred in 4% (34/851) of patients, including Grade 3 (0.4%) and Grade 2 (1.4%) adverse reactions. Immune-mediated dermatologic adverse reactions led to withholding of LOQTORZI in 0.4% (3) of the patients. Systemic corticosteroids were required in 12% (4/34) of the patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 71% (24/34) of these patients.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received LOQTORZI or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis, pericardial effusion
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, to include increases in serum amylase and lipase levels, gastritis, duodenitis
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis, polymyalgia rheumatica, dermatomyositis
Endocrine: Hypoparathyroidism
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
Infusion-Related Reactions
LOQTORZI can cause severe or life-threatening infusion-related reactions including hypersensitivity and anaphylaxis.

In patients receiving LOQTORZI in combination with cisplatin and gemcitabine, infusion-related reactions have been reported in 4.1% of patients, including Grade 2 (0.7%) reactions.
In patients receiving LOQTORZI monotherapy, infusion-related reactions occurred in 2% of 851 patients, including Grade 3 (0.1%) and Grade 2 (0.6%). LOQTORZI was withheld for one Grade 3 infusion related reaction. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue LOQTORZI.
Complications of Allogeneic Hematopoietic Stem Cell Transplant (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 (VOD) 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
LOQTORZI 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 women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LOQTORZI and for 4 months after the last dose.

Lactation
There are no data on the presence of toripalimab-tpzi in human milk; its effects on the breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to toripalimab-tpzi are unknown. Because of the potential for serious adverse reactions in breastfed children, advise lactating women not to breastfeed during treatment with LOQTORZI and for 4 months after the last dose.

Serious Adverse Reactions

In JUPITER-02, when LOQTORZI was administered in combination with cisplatin and gemcitabine for the first-line treatment of recurrent, locally advanced or metastatic nasopharyngeal carcinoma, serious adverse reactions occurred in 43% of patients. Serious adverse drug reactions in ≥2% were thrombocytopenia (14%), neutrophil count decreased (10%), pneumonia (10%), anemia (9%), abnormal hepatic function (2.7%), and rash (2.1%). There were three fatal adverse reactions (2.1%): one due to epistaxis; one due to intracranial hemorrhage associated with immune-related thrombocytopenia and coagulopathy; and one due to pneumonia. Permanent discontinuation of LOQTORZI, due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of LOQTORZI in ≥1% were pneumonia (2.1%), pulmonary tuberculosis (1.4%), rash (1.4%), and vomiting (1.4%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased neutrophils (58%), decreased lymphocytes (57%), decreased hemoglobin (50%) decreased platelets (33%), decreased potassium (10%), decreased sodium (9%), increased alanine aminotransferase (6%), increased or decreased magnesium (4.2% each), decreased calcium (3.5%), increased aspartate aminotransferase (2.7%), increased bilirubin (2.1%).
In POLARIS-02, when LOQTORZI was administered as a single agent to patients with previously treated, unresectable or metastatic nasopharyngeal carcinoma, serious adverse reactions occurred in 24% of patients. Serious adverse drug reactions in ≥2% were pneumonia (4.7%), abnormal hepatic function (2.6%), and hyperbilirubinemia (2.1%). Fatal adverse reactions occurred in 3.7% of patients who received LOQTORZI, including death not otherwise specified (1.6%), tumor hemorrhage (0.5%), hepatic failure and thrombocytopenia (0.5%), hyponatremia (0.5%), and sudden death (0.5%). Permanent discontinuation of LOQTORZI due to an adverse reaction occurred in 9% of patients. Adverse reaction resulting in permanent discontinuation of LOQTORZI in ≥1% included pneumonia (1.1%), abnormal hepatic function (1.1%), and hyperbilirubinemia (1.1%). The most common Grade 3 or 4 laboratory abnormalities (≥2%), were decreased sodium (11%), decreased lymphocytes (9%), decreased hemoglobin (6%), increased aspartate aminotransferase (3.8%), decreased phosphate (3.2%), and increased alkaline phosphatase (2.2%).
Common Adverse Reactions

In JUPITER-02, the most common adverse reactions (≥20%) were nausea (71%), vomiting (68%), decreased appetite (55%), constipation (39%), hypothyroidism (38%), rash (36%), pyrexia (32%), diarrhea (31%), peripheral neuropathy (30%), cough (26%), musculoskeletal pain (25%), upper respiratory infection (23%), insomnia (23%), dizziness (21%), and malaise (21%).
In POLARIS-02, in patients with previously treated, unresectable or metastatic nasopharyngeal carcinoma, the most common (≥20%) adverse reactions were hypothyroidism (27%), fatigue (22%), and cough (20%).
Please see Prescribing Information for LOQTORZI and Medication Guide

On December 11, 2023 SystImmune, a clinical-stage biopharmaceutical company, and Bristol Myers Squibb (NYSE: BMY) reported an exclusive license and collaboration agreement for SystImmune’s BL-B01D1, a potentially first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC) (Press release, Bristol-Myers Squibb, DEC 11, 2023, View Source [SID1234638412]). Under the terms of the agreement, the companies will jointly develop and commercialize BL-B01D1 in the United States. Through its affiliates, SystImmune will be solely responsible for development, commercialization, and manufacturing in Mainland China and will be responsible for manufacturing certain drug supplies for use outside of Mainland China. Bristol Myers Squibb will assume sole responsibility for development and commercialization in the rest of the world.

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BL-B01D1, a bispecific topoisomerase inhibitor-based ADC which targets both epidermal growth factor receptor and human epidermal growth factor receptor 3 (EGFRxHER3), is currently being evaluated in a global multi-center Phase 1 study (BL-B01D1-LUNG101) for safety and efficacy in individuals with metastatic or unresectable non-small cell lung cancer (NSCLC). Data from earlier clinical studies of BL-B01D1 were presented in 2023 at ASCO (Free ASCO Whitepaper), ESMO (Free ESMO Whitepaper) and the San Antonio Breast Cancer Symposium; these data demonstrate promising anti-tumor activity in patients with a range of solid tumors that had progressed after standard of care treatments, including NSCLC and breast cancer.

"Recent BL-B01D1 trials have shown broad potential across different solid tumors as well as a manageable safety profile," said Dr. Yi Zhu, Chief Executive Officer at SystImmune. "We have long admired Bristol Myers Squibb’s global clinical development and commercialization capabilities in oncology, and this strategic collaboration is an exciting step forward in delivering potential antitumor medicines to patients worldwide. We look forward to a productive partnership."

"Our collaboration with SystImmune allows us to strengthen our leadership in oncology and is consistent with our strategy to diversify beyond immuno-oncology to transform patient care," said Samit Hirawat, MD, Executive Vice President, Chief Medical Officer, Drug Development at Bristol Myers Squibb. "SystImmune’s BL-B01D1 adds yet another ADC to our diverse pipeline and helps strengthen our approach of matching the most appropriate therapeutic modality to areas of unmet medical need across solid tumor oncology. We look forward to working with SystImmune to advance BL-B01D1 in hopes of offering a differentiated treatment option for patients in need."

Financial Highlights

Bristol Myers Squibb will pay SystImmune $800 million in an upfront payment and up to $500 million in contingent near-term payments. SystImmune is eligible to receive additional payments of up to $7.1 billion contingent upon the achievement of certain development, regulatory and sales performance milestones for a total potential consideration of up to $8.4 billion. The companies will share certain global development expenses and profits and losses in the United States. Through its affiliates, SystImmune will retain exclusive development and commercialization rights in Mainland China, where Bristol Myers Squibb will receive a royalty on net sales. Outside the United States and Mainland China, SystImmune will receive a tiered royalty on net sales. The agreement is subject to customary clearance by antitrust regulators.

About SystImmune’s BL-B01D1

BL-B01D1 is a potentially first-in-class bispecific ADC developed by SystImmune, targeting both EGFR and HER3, which are highly expressed in most epithelial tumors. BL-B01D1 is comprised of SystImmune’s proprietary bispecific antibody and linker-payload which contains a stable, cleavable linker and a topoisomerase inhibitor.

On December 11, 2023 Biomea Fusion, Inc. (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported positive clinical data for BMF-219, an investigational covalent menin inhibitor, in relapsed / refractory AML patients with menin-dependent mutations at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Biomea Fusion, DEC 11, 2023, View Source [SID1234638410]). The poster can be viewed at Biomea’s website at View Source

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"We are very excited to present the clinical update at ASH (Free ASH Whitepaper) on our targeted, covalently binding menin inhibitor, BMF-219, achieving durable and sustained CRs in patients with menin inhibitor-sensitive acute leukemia, even at suboptimal dosing levels. The gene expression data we presented here validates the proposed mechanism of action of BMF-219 and is in-line with our preclinical models," said Steve Morris, M.D., Chief Development Officer at Biomea.

As of the October 31, 2023, out of 29 patients dosed in the Phase I of COVALENT-101, nearly half (45%) of the participants received prior Hematopoietic Stem Cell Transplant (HSCT) and the median prior lines of therapy was 3. A total of 7 patients were selected as evaluable for efficacy. The efficacy evaluable population includes AML patients who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A – non-CYP inhibitor Arm]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least two cycles of therapy. Within this patient population 2 Complete Responses (CRs) (CR rate 2/7 = 29%) were observed with a mean time to response of 1.8 months (1 CR patient had a NUP-98 mutation and 1 CRi patient had a NPM1 mutation).

In the CYP inhibitor arm, BMF-219 showed increasing plasma pharmacokinetic (PK) exposure with escalating dose levels, and the ability to achieve systemic exposures predicted to be efficacious based on preclinical acute leukemia models. Further dose escalation is still needed to achieve target AUC.

Pharmacodynamic data from a case study of an AML patient containing NUP98-NSD1 mutation showed suppression of key leukemogenic genes (e.g. HOXA9, MEIS1) as well as downregulation of MEN1, without noticeable increases in differentiation markers (e.g. CD14, ANPEP, ITGAM) in contrast to non-covalent menin inhibitors.

Across all patients enrolled in the trial as of the data cutoff date (n=29), BMF-219 was generally well-tolerated with no dose-limiting toxicities observed and without treatment discontinuations due to toxicity. Four participants experienced Differentiation Syndrome (DS) ≤ Grade 3, with onset 1-3 weeks after initiation of therapy and an average duration of 10 days, managed by cytoreductive therapy (hydroxyurea and steroids). Two participants recovered without dose modification or interruption, and none of the participants discontinued due to DS.

Initially, patients were enrolled agnostic to mutational status; subsequently, the study protocol was amended to enrich for patients with AML harboring menin-dependent mutations. Dose Level 4 is the first dose level which focused primarily on enrolling patients with known menin-dependent mutations. Biomea is planning to amend the dosing protocol to explore higher dosing levels in Arm B. Dose escalation is to be followed by a dose optimization/expansion to determine the recommended phase 2 dose.

About BMF-219

BMF-219 is a covalently binding inhibitor of menin, a protein known to play an essential role in oncogenic signaling in genetically defined leukemias as well as in diabetes. Preclinically, BMF-219 has demonstrated in well-established acute leukemia cell lines robust downregulation of key leukemogenic genes in addition to menin itself. Additionally, BMF-219 has shown anticancer activity in multiple in vitro, in vivo, and ex vivo models of acute leukemia, multiple myeloma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia. BMF-219 is currently being evaluated in first-in-human clinical trials enrolling patients with specific menin-dependent mutations in liquid and solid tumors as well as patients with diabetes.

About COVALENT-101

COVALENT-101 is a Phase I, open-label, multi-center, dose-escalation and dose-expansion study designed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics of oral dosing of BMF-219 in patients with relapsed/refractory (R/R) acute leukemias — including subpopulations where menin inhibition is expected to provide therapeutic benefit (e.g., patients with MLL1/KMT2A gene rearrangements or NPM1 mutations). The study is designed to enroll subsets of acute leukemia patients who are receiving a CYP3A4 inhibitor and also those not receiving a CYP3A4 inhibitor. COVALENT-101 is also investigating the dosing of BMF-219 in other patient populations where preclinical studies have shown high menin dependence, such as multiple myeloma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Additional information about this Phase I clinical trial of BMF-219 can be found at ClinicalTrials.gov using the identifier NCT05153330.

About Acute Myeloid Leukemia (AML)

AML is the most common form of acute leukemia in adults and represents the largest number of annual leukemia deaths in the U.S. and Europe. AML originates within the white blood cells in the bone marrow and can rapidly move to the blood and other parts of the body, including the spleen, central nervous system, and other organs. Approximately 30,000 people in the U.S. and Europe are diagnosed with AML each year, and the five-year overall survival rate in adults is roughly 29%. Among patients with relapsed/refractory disease, the need is greatest, as the overall survival is only approximately 3 to 9 months. It is estimated that upwards of 45% of AML patients have menin-dependent genetic drivers (MLL1-r, NPM1 mutant, and certain additional less common but recurrent gene mutations).

On December 11, 2023 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, reported preclinical data on ATA3431, a next-generation allogeneic CD20/CD19-dual targeted chimeric antigen receptor (CAR) EBV T-cell therapy candidate (Press release, Atara Biotherapeutics, DEC 11, 2023, View Source [SID1234638409]). Findings support ATA3431 advancement into clinical testing, initially focused on the treatment of B-cell malignancies. The data will be presented in a poster presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place December 9-12, 2023, in San Diego.

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"We’re very excited that ATA3431 is progressing towards an IND submission in 2025 with such a compelling and competitive profile," said Cokey Nguyen, Ph.D., Executive Vice President, Chief Scientific & Technical Officer at Atara. "Our EBV T-cell technology is well validated with over 500 patients treated across our portfolio, and allogeneic EBV T-cell based CD19 targeting is further supported by long-term academic outcomes data with an earlier-generation allogeneic EBV CD19 T-cell construct.1 Building on this robust experience, these preclinical findings provide strong proof-of-concept reinforcing the potential of ATA3431 as a best-in-class approach which we look forward to further evaluating in the clinic."

ATA3431 is an allogeneic, bispecific CAR directed against CD20 and CD19, built on Atara’s EBV T-cell platform that does not require T-cell receptor (TCR) or human leukocyte antigen (HLA) gene editing. The design consists of a tandem CD20-CD19 design, with binders oriented to optimize potency. ATA3431 also incorporates the clinically validated 1XX costimulatory domain that enhances stemness and modulates exhaustion to extend functional persistence.

Compared to an autologous CD20/CD19 CAR-T benchmark, the ATA3431 preclinical data demonstrate potent antitumor activity, long-term persistence, and superior tumor growth inhibition. Data highlights include:

In functional evaluation, ATA3431 showed stable CAR expression with a predominantly CD8+ T-cell distribution. The 1XX signaling domain and optimized manufacturing process that enriches for a less differentiated phenotype yielded a high central memory population compared with autologous CD20/CD19 bispecific CAR-T cells, achieving consistent killing of CD20+ and/or CD19+ tumor cells following repeated in vitro challenges.
ATA3431 demonstrated minimal alloreactivity against HLA mismatched targets due to the inherent ability of EBV T cells to recognize defined viral antigens. The cells also showed HLA-independent activity against CD20+/CD19+ targets in vitro.
ATA3431 mediated highly potent tumor growth inhibition in a lymphoma animal model that correlates with long-term persistence without additional exogenous cytokine support.
ATA3431 showed superior in vivo anti-tumor efficacy, survival, and functional persistence, in both CD19 high- and low-expressing lymphoma models, compared to autologous benchmark CAR-T cells with no observed treatment-related toxicities. This demonstrates ATA3431’s potential to overcome antigen escape, which is hypothesized to be a major cause of treatment resistance or disease relapse with current CD19-targeted CAR-T treatment.
Separately, an academic study presented long-term follow-up data on heavily pre-treated patients infused with an earlier generation off-the-shelf CD19 targeted EBV CAR T-cell construct in B-cell lymphoma and acute lymphoblastic leukemia. Encouraging overall survival of up to three years was observed in 12 patients with relapsed/refractory B-cell malignancies after hematopoietic cell transplant (HCT) treated with 3rd party donor derived allogeneic EBV CD19 CAR T.1

ATA3431 Poster Presentation Details:

Title: ATA3431: Allogeneic CD19/CD20 Bispecific CAR EBV T-cells for the Treatment of B-Cell Malignancies

Presenting Author: Seung Sarah Cha, PhD, Atara Biotherapeutics, Thousand Oaks, CA
Date & Time: Monday, December 11, 2023, 6-8 p.m. PST
Abstract Number: 4800
Poster Session: 703. Cellular Immunotherapies: Basic and Translational: Poster III
Location: San Diego Convention Center, Halls G-H
Next-Generation Allogeneic CAR-T Approach

Atara is focused on applying Epstein-Barr virus (EBV) T-cell biology, featuring experience in over 500 patients treated, and novel chimeric antigen receptor (CAR) technologies to meet the current limitations of autologous and allogeneic CAR therapies head-on by advancing a potential best-in-class CAR-T pipeline in oncology and autoimmune disease. Unlike gene-edited approaches aimed at inactivating T-cell receptor (TCR) function to reduce the risk for graft-vs-host disease, EBV T cells maintain expression of native TCRs that promote in vivo functional persistence while also demonstrating inherently low alloreactivity due to their recognition of defined viral antigens and partial human leukocyte antigen (HLA) matching. A molecular toolkit of clinically-validated technologies—including the 1XX costimulatory domain designed for better cell fitness and less exhaustion while maintaining stemness— offers a differentiated approach to addressing significant unmet need with the next generation CAR T.

On December 11, 2023 Affimed N.V. (Nasdaq: AFMD) ("Affimed or the "Company"), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported interim safety and efficacy data on its innate cell engager (ICE) AFM24 from the ongoing AFM24-102 combination study with atezolizumab, an anti-PD-L1 checkpoint inhibitor, in patients with advanced EGFR-expressing solid tumors (Press release, Affimed, DEC 11, 2023, View Source [SID1234638408]). The data update as of December 6th, 2023, includes 15 patients from the EGFR-wildtype NSCLC cohort with a median of 2 prior lines of therapy. Importantly, all patients were pretreated with and ultimately progressed while on PD-[L]1 targeting therapy.

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The combination of AFM24 with atezolizumab showed encouraging signals of clinical activity, including 1 unconfirmed CR, 3 PRs (1 confirmed, 2 unconfirmed) and 7 patients exhibiting SD. All eleven patients with a confirmed response, unconfirmed response or stable disease (73%) are continuing treatment, with 4 patients exceeding 3 months of therapy; 2 patients improved from SD at the first scan to PR at the second scan based on RECIST criteria.

"Most patients with advanced NSCLC will need additional treatment after first-line therapy, and currently available options for patients in the 2L+ setting provide only modest response rates and short progression-free survival," said Dr. Andreas Harstrick, Chief Medical Officer at Affimed. "Given the severity of this cancer and the urgent need for new treatments, we are very encouraged by the early safety and efficacy results demonstrated by the combination of AFM24 and atezolizumab in this cohort. We look forward to seeing the data in this cohort mature as well as to sharing data from the EGFR-mutant NSCLC cohort, anticipated in the first half of 2024."

Affimed’s ICE AFM24, in combination with atezolizumab, has the potential to reactivate the innate and consequently the adaptive immune system to recognize and destroy EGFR-positive NSCLC tumors. Considering the low ORR reported on atezolizumab monotherapy in checkpoint inhibitor—relapsing and refractory patients, Affimed believes the clinical activity observed in AFM24-102 is likely due to the synergy of AFM24 with atezolizumab.

AFM24 has demonstrated a positive safety and tolerability profile as both a monotherapy and in combination therapy. The combination with atezolizumab has not led to unexpected toxicity, and the toxicity observed to date is in line with the toxicity profile of the individual agents alone. The majority of patients experienced only mild to moderate treatment-related adverse events.

Affimed also announced that it has discontinued enrollment in AFM24-102 into the gastric cancer cohort and the basket cohort evaluating pancreatic cancer, biliary tract cancer and hepatocellular carcinoma. While clinical activity was observed in both cohorts, neither cohort is likely to achieve response rates that would meet the Company’s efficacy hurdle and the Company’s strategic focus is to advance the NSCLC program as fast as possible.

The conference call will be available via phone and webcast. The live audio webcast of the call will be available in the "Webcasts" section on the "Investors" page of the Affimed website at View Source To access the call by phone, please use link https://register.vevent.com/register/BIb2258d6c5f5a474cad74869a7b7b1bb5, and you will be provided with dial-in details and a pin number.

Note: To avoid delays, we encourage participants to dial into the conference call 15 minutes ahead of the scheduled start time. A replay of the webcast will be accessible at the same link for 30 days following the call.

About the AFM24-102 Phase 1/2a Study

AFM24-102 is a Phase 1/2a open-label, non-randomized, multicenter, dose escalation, and expansion study evaluating AFM24 in combination with atezolizumab in patients with selected EGRF-expressing advanced solid malignancies whose disease has progressed after treatment with previous anticancer therapies (NCT05109442).

The Company also announced data from the phase 1/2 data study of acimtamig in combination with allogeneic NK in relapsed/refractory Hodgkin Lymphoma patients conducted at the University of Texas MD Anderson Cancer Center. The Company will host a call today at 1:30 p.m. PST / 4:30 p.m. EST / 22:30 CET to discuss both the acimtamig and AFM24 clinical data updates and to provide an update on the status of the acimtamig LuminICE-203 study, AFM13-104.

About AFM24

AFM24 is a tetravalent, bispecific innate cell engager (ICE) that activates the innate immune system by binding to CD16A on innate immune cells and EGFR, a protein widely expressed on solid tumors, to kill cancer cells. Generated by Affimed’s fit-for-purpose ROCK platform, AFM24 represents a distinctive mechanism of action that uses EGFR as a docking site to engage innate immune cells for tumor cell killing through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

In addition to studying AMF24 in combination with the checkpoint inhibitor atezolizumab, Affimed is also evaluating options for a combination of AFM24 with an allogeneic off-the-shelf NK cell product that the Company expects to be well suited for heavily pretreated patient populations.