Opdivo + Yervoy is the first new systemic therapy in over 15 years to be approved by the FDA in this setting^1,2

Approval is based on CheckMate -743 in which Opdivo + Yervoy demonstrated superior overall survival vs. standard of care chemotherapy¹

Approval marks third indication for Opdivo + Yervoy-based treatments in thoracic cancers and seventh indication overall

PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #BMS—Bristol Myers Squibb (NYSE: BMY) today announced that Opdivo (nivolumab) 360 mg every three weeks plus Yervoy (ipilimumab) 1 mg/kg every six weeks (injections for intravenous use) was approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).¹ This approval is based on a pre-specified interim analysis from the Phase 3 CheckMate -743 trial in which Opdivo + Yervoy (n=303) demonstrated superior overall survival (OS) versus the platinum-based standard of care chemotherapy (n=302) (Hazard Ratio [HR]: 0.74 [95% Confidence Interval [CI]: 0.61 to 0.89]; P=0.002), with a median OS (mOS) of 18.1 months (95% CI: 16.8 to 21.5) versus 14.1 months (95% CI: 12.5 to 16.2), respectively. (Read more…)¹ These results were observed after 22.1 months of minimum follow-up.³ At two years, 41% of patients treated with Opdivo + Yervoy were alive and 27% with chemotherapy.^1,3

“Malignant pleural mesothelioma is a rare cancer with limited treatment options. When it is diagnosed in advanced stages, the five-year survival rate is approximately 10 percent,” said study investigator Anne S. Tsao, M.D., professor and Section Chief Thoracic Medical Oncology and Director of the Mesothelioma Program at The University of Texas M.D. Anderson Cancer Center.^2,4 “The survival results from the CheckMate -743 trial show that the combination of nivolumab and ipilimumab could become a new front-line standard of care option. This is exciting news, instilling hope for patients with this devastating disease and for the healthcare providers who care for them.”^1,3

Opdivo and Yervoy are associated with Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; complications of stem-cell transplant that uses donor stem cells (allogeneic); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.¹ Yervoy is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplant after Yervoy, embryo-fetal toxicity and risks associated when administered in combination with Opdivo.⁵ Please see the Important Safety Information section below.

This is the third indication for an Opdivo + Yervoy-based combination in the first-line treatment of a form of thoracic cancer.¹ Opdivo + Yervoy is approved by the FDA as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1≥1% as determined by an FDA-approved test, and without EGFR or ALK genomic tumor aberrations.¹ It is also approved in combination with limited chemotherapy for the first-line treatment of adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations regardless of PD-L1 expression.¹

“Thoracic cancers can be complex and difficult to treat, and we are focused on developing immunotherapy options that may have the potential to extend patients’ lives,” said Adam Lenkowsky, general manager and head, U.S., Oncology, Immunology, Cardiovascular, Bristol Myers Squibb.^2,6 “Just a few months ago, Opdivo + Yervoy-based combinations received two first-line indications for certain patients with non-small cell lung cancer. Now, Opdivo + Yervoy is approved for use in another type of thoracic cancer, previously untreated unresectable MPM. With today’s announcement, Opdivo + Yervoy becomes the first new systemic therapy approved in more than 15 years in this setting, and may offer these patients a chance for a longer life.” ¹

Opdivo + Yervoy is a unique combination of two immune checkpoint inhibitors that features a potentially synergistic mechanism of action, targeting two different checkpoints (PD-1 and CTLA-4) to help destroy tumor cells: Yervoy helps activate and proliferate T cells, while Opdivo helps existing T cells discover the tumor.^1,7 Some of the T cells stimulated by Yervoy can become memory T cells, which may allow for a long-term immune response.^{7,8,9,10,11,12} Targeting of normal cells can also occur and result in immune-mediated adverse reactions, which can be severe and potentially fatal.¹ Please see the Important Safety Information section below.

This approval was granted less than six weeks following the submission of a new supplemental Biologics License Application (sBLA), which was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program. The RTOR program aims to ensure that safe and effective treatments are available to patients as early as possible.¹³ The review was also conducted under the FDA’s Project Orbis initiative, enabling concurrent review by the health authorities in Australia, Brazil, Canada and Switzerland.

About CheckMate -743

CheckMate -743 is an open-label, multi-center, randomized Phase 3 trial evaluating Opdivo plus Yervoy compared to chemotherapy (pemetrexed and cisplatin or carboplatin) in patients with histologically confirmed unresectable malignant pleural mesothelioma and no prior systemic therapy or palliative radiotherapy within 14 days of initiation of therapy (n=605).¹ Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.¹ In the trial, 303 patients were randomized to receive Opdivo 3 mg/kg every two weeks and Yervoy 1 mg/kg every six weeks; 302 patients were randomized to receive cisplatin 75 mg/m² or carboplatin AUC 5 plus pemetrexed 500 mg/m² in 3-week cycles for six cycles.¹ Treatment in both arms continued until disease progression or unacceptable toxicity or, in the Opdivo + Yervoy arm, up to 24 months.¹ The primary endpoint of the trial was OS in all randomized patients.¹ Additional efficacy outcome measures included progression-free survival (PFS), objective response rate (ORR) and duration of response (DOR), as assessed by BICR utilizing modified RECIST criteria.¹

Select Safety Profile from CheckMate -743 Study

Treatment was permanently discontinued for adverse reactions in 23% of patients treated with Opdivo + Yervoy, and 52% had at least one dose withheld for an adverse reaction.¹ An additional 4.7% of patients permanently discontinued Yervoy alone due to adverse reactions. Serious adverse reactions occurred in 54% of patients receiving Opdivo + Yervoy.¹ The most frequent (≥2%) serious adverse reactions in patients receiving Opdivo + Yervoy were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism.¹ Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.¹ The most common (≥20%) adverse reactions were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%) and pruritus (21%).¹ The median number of doses was 12 for Opdivo and 4 for Yervoy.³

About Malignant Pleural Mesothelioma

Mesothelioma is a rare but aggressive form of cancer that often forms in the lining of the lungs.^2,14 There are approximately 3,000 cases diagnosed in the United States each year.¹⁴ Malignant pleural mesothelioma is the most common type of the disease.² It is most frequently caused by exposure to asbestos and diagnosis is often delayed, with the majority of patients presenting with advanced disease.^2,15 Prognosis is generally poor: in patients with advanced malignant pleural mesothelioma, median survival is approximately one year and the five-year survival rate is approximately 10%.²

INDICATIONS

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur at any time after starting or discontinuing YERVOY. Early identification and management are essential to ensure safe use of YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue YERVOY depending on severity. In general, if YERVOY requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less followed by corticosteroid taper for at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroid therapy. Institute hormone replacement therapy for endocrinopathies as warranted.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 10% (5/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) of patients. In NSCLC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. The incidence and severity of immune-mediated pneumonitis in patients with NSCLC treated with OPDIVO 360 mg every 3 weeks in combination with YERVOY 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy were comparable to treatment with OPDIVO in combination with YERVOY only. The incidence and severity of immune-mediated pneumonitis in patients with malignant pleural mesothelioma treated with OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks were similar to those occurring in NSCLC.

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 10% (5/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) of patients.

In a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated diarrhea/colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%).

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. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 20% (10/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119) of patients.

In a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%).

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Withhold for Grades 2, 3, or 4 endocrinopathies if not clinically stable. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 4% (2/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 18% (9/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (11/49) of patients. Hyperthyroidism occurred in 10% (5/49) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 trial of YERVOY 3 mg/kg, severe to life-threatening endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients.

Immune-Mediated Skin and Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 35% (17/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16% (90/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Contacts

Bristol Myers Squibb

Media Inquiries:
609-252-3345

[email protected]

Investors:
Tim Power

609-252-7509

[email protected]

Read full story here

Opdivo + Yervoy is the first new systemic therapy in over 15 years to be approved by the FDA in this setting^1,2

Approval is based on CheckMate -743 in which Opdivo + Yervoy demonstrated superior overall survival vs. standard of care chemotherapy¹

Approval marks third indication for Opdivo + Yervoy-based treatments in thoracic cancers and seventh indication overall

PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #BMS—Bristol Myers Squibb (NYSE: BMY) today announced that Opdivo (nivolumab) 360 mg every three weeks plus Yervoy (ipilimumab) 1 mg/kg every six weeks (injections for intravenous use) was approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).¹ This approval is based on a pre-specified interim analysis from the Phase 3 CheckMate -743 trial in which Opdivo + Yervoy (n=303) demonstrated superior overall survival (OS) versus the platinum-based standard of care chemotherapy (n=302) (Hazard Ratio [HR]: 0.74 [95% Confidence Interval [CI]: 0.61 to 0.89]; P=0.002), with a median OS (mOS) of 18.1 months (95% CI: 16.8 to 21.5) versus 14.1 months (95% CI: 12.5 to 16.2), respectively. (Read more…)¹ These results were observed after 22.1 months of minimum follow-up.³ At two years, 41% of patients treated with Opdivo + Yervoy were alive and 27% with chemotherapy.^1,3

“Malignant pleural mesothelioma is a rare cancer with limited treatment options. When it is diagnosed in advanced stages, the five-year survival rate is approximately 10 percent,” said study investigator Anne S. Tsao, M.D., professor and Section Chief Thoracic Medical Oncology and Director of the Mesothelioma Program at The University of Texas M.D. Anderson Cancer Center.^2,4 “The survival results from the CheckMate -743 trial show that the combination of nivolumab and ipilimumab could become a new front-line standard of care option. This is exciting news, instilling hope for patients with this devastating disease and for the healthcare providers who care for them.”^1,3

Opdivo and Yervoy are associated with Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; complications of stem-cell transplant that uses donor stem cells (allogeneic); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.¹ Yervoy is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplant after Yervoy, embryo-fetal toxicity and risks associated when administered in combination with Opdivo.⁵ Please see the Important Safety Information section below.

This is the third indication for an Opdivo + Yervoy-based combination in the first-line treatment of a form of thoracic cancer.¹ Opdivo + Yervoy is approved by the FDA as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1≥1% as determined by an FDA-approved test, and without EGFR or ALK genomic tumor aberrations.¹ It is also approved in combination with limited chemotherapy for the first-line treatment of adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations regardless of PD-L1 expression.¹

“Thoracic cancers can be complex and difficult to treat, and we are focused on developing immunotherapy options that may have the potential to extend patients’ lives,” said Adam Lenkowsky, general manager and head, U.S., Oncology, Immunology, Cardiovascular, Bristol Myers Squibb.^2,6 “Just a few months ago, Opdivo + Yervoy-based combinations received two first-line indications for certain patients with non-small cell lung cancer. Now, Opdivo + Yervoy is approved for use in another type of thoracic cancer, previously untreated unresectable MPM. With today’s announcement, Opdivo + Yervoy becomes the first new systemic therapy approved in more than 15 years in this setting, and may offer these patients a chance for a longer life.” ¹

Opdivo + Yervoy is a unique combination of two immune checkpoint inhibitors that features a potentially synergistic mechanism of action, targeting two different checkpoints (PD-1 and CTLA-4) to help destroy tumor cells: Yervoy helps activate and proliferate T cells, while Opdivo helps existing T cells discover the tumor.^1,7 Some of the T cells stimulated by Yervoy can become memory T cells, which may allow for a long-term immune response.^{7,8,9,10,11,12} Targeting of normal cells can also occur and result in immune-mediated adverse reactions, which can be severe and potentially fatal.¹ Please see the Important Safety Information section below.

This approval was granted less than six weeks following the submission of a new supplemental Biologics License Application (sBLA), which was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program. The RTOR program aims to ensure that safe and effective treatments are available to patients as early as possible.¹³ The review was also conducted under the FDA’s Project Orbis initiative, enabling concurrent review by the health authorities in Australia, Brazil, Canada and Switzerland.

About CheckMate -743

CheckMate -743 is an open-label, multi-center, randomized Phase 3 trial evaluating Opdivo plus Yervoy compared to chemotherapy (pemetrexed and cisplatin or carboplatin) in patients with histologically confirmed unresectable malignant pleural mesothelioma and no prior systemic therapy or palliative radiotherapy within 14 days of initiation of therapy (n=605).¹ Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.¹ In the trial, 303 patients were randomized to receive Opdivo 3 mg/kg every two weeks and Yervoy 1 mg/kg every six weeks; 302 patients were randomized to receive cisplatin 75 mg/m² or carboplatin AUC 5 plus pemetrexed 500 mg/m² in 3-week cycles for six cycles.¹ Treatment in both arms continued until disease progression or unacceptable toxicity or, in the Opdivo + Yervoy arm, up to 24 months.¹ The primary endpoint of the trial was OS in all randomized patients.¹ Additional efficacy outcome measures included progression-free survival (PFS), objective response rate (ORR) and duration of response (DOR), as assessed by BICR utilizing modified RECIST criteria.¹

Select Safety Profile from CheckMate -743 Study

Treatment was permanently discontinued for adverse reactions in 23% of patients treated with Opdivo + Yervoy, and 52% had at least one dose withheld for an adverse reaction.¹ An additional 4.7% of patients permanently discontinued Yervoy alone due to adverse reactions. Serious adverse reactions occurred in 54% of patients receiving Opdivo + Yervoy.¹ The most frequent (≥2%) serious adverse reactions in patients receiving Opdivo + Yervoy were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism.¹ Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.¹ The most common (≥20%) adverse reactions were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%) and pruritus (21%).¹ The median number of doses was 12 for Opdivo and 4 for Yervoy.³

About Malignant Pleural Mesothelioma

Mesothelioma is a rare but aggressive form of cancer that often forms in the lining of the lungs.^2,14 There are approximately 3,000 cases diagnosed in the United States each year.¹⁴ Malignant pleural mesothelioma is the most common type of the disease.² It is most frequently caused by exposure to asbestos and diagnosis is often delayed, with the majority of patients presenting with advanced disease.^2,15 Prognosis is generally poor: in patients with advanced malignant pleural mesothelioma, median survival is approximately one year and the five-year survival rate is approximately 10%.²

INDICATIONS

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO^® (nivolumab), in combination with YERVOY^® (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur at any time after starting or discontinuing YERVOY. Early identification and management are essential to ensure safe use of YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue YERVOY depending on severity. In general, if YERVOY requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less followed by corticosteroid taper for at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroid therapy. Institute hormone replacement therapy for endocrinopathies as warranted.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 10% (5/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) of patients. In NSCLC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. The incidence and severity of immune-mediated pneumonitis in patients with NSCLC treated with OPDIVO 360 mg every 3 weeks in combination with YERVOY 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy were comparable to treatment with OPDIVO in combination with YERVOY only. The incidence and severity of immune-mediated pneumonitis in patients with malignant pleural mesothelioma treated with OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks were similar to those occurring in NSCLC.

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 10% (5/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) of patients.

In a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated diarrhea/colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%).

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. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 20% (10/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119) of patients.

In a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%).

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Withhold for Grades 2, 3, or 4 endocrinopathies if not clinically stable. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 4% (2/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 18% (9/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (11/49) of patients. Hyperthyroidism occurred in 10% (5/49) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 trial of YERVOY 3 mg/kg, severe to life-threatening endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients.

Immune-Mediated Skin and Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 35% (17/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16% (90/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Contacts

Bristol Myers Squibb

Media Inquiries:
609-252-3345

[email protected]

Investors:
Tim Power

609-252-7509

[email protected]

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