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