Opdivo + Yervoy: First combination immunotherapy for advanced renal cell carcinoma (kidney cancer) receives TGA approval

OPDIVO now approved in Australia for ten indications across six cancer types1,2

OPDIVO combination therapy reduces relative risk of death by 37% versus a current standard of care in intermediate/poor risk patients3  

Melbourne, Australia, Wednesday 11 July 2018 - Bristol-Myers Squibb (BMS) today welcomed the TGA registration of OPDIVO® (nivolumab) 3 mg/kg in combination with another BMS immuno-oncology (I-O) agent, YERVOY® (ipilimumab), 1 mg/kg for the treatment of patients with intermediate/poor-risk, previously untreated advanced renal cell carcinoma (RCC).1,2

This registration was granted under the new TGA Priority Review process that aims to expedite evaluation timeframes of new medicines and indications for serious conditions when there is substantial evidence of a major therapeutic advance.

The TGA approval was based on results of the clinical trial CheckMate 2141,3 that showed OPDIVO in combination with ipilimumab reduced the risk of death by 37% compared with sunitinib (HR=0.63 p<0.0001), in intermediate and poor-risk patients, meeting the co-primary end-point for overall survival (OS).3

The objective response rate was 42% with OPDIVO combination versus 27% with sunitinib (p<0.001).  Progression free survival (PFS) was 11.6 months with OPDIVO plus ipilimumab and 8.4 months with sunitinib (p=0.03, not significant).3

Grade 3 or 4 treatment-related adverse events occurred in 46% of patients treated with OPDIVO plus ipilimumab and 63% of patients treated with sunitinib.3

The clinical results were recently published in the New England Journal of Medicine3 after the trial was stopped early based on a pre-planned interim analysis which determined a significant survival benefit in the OPDIVO combination arm.

Kidney cancer is the ninth most commonly diagnosed cancer in Australia accounting for 3,512 new cases in 2017.4

This is estimated to increase to 4,130 Australians by 2020, with renal cell carcinoma being the most common type of kidney cancer in adults.5

Medical oncologist, Professor Ian Davis, welcomed the announcement as a step towards bringing new treatment options to patients with advanced kidney cancer.

Professor Davis said: "When kidney cancer is found in an advanced stage, current treatment options can be effective but they rarely lead to cures. We already know that some single immunotherapy drugs can be very useful for some patients. This new combination immunotherapy will provide another option for doctors and their patients to consider as treatment for this disease."

"Immuno-oncology and the use of these treatments in combination is a rapidly evolving field. This Priority Review approval means that Australians affected by kidney cancer now have this treatment option approved months sooner than would otherwise have been possible," said Professor Davis.

Dr Jonathan Anderson, Medical Director for Bristol-Myers Squibb Australia and New Zealand said combination I-O therapy was an important new area of cancer treatment for seriously ill patients.

He said: "We believe the future of cancer care lies in the combination of our immuno-oncology agents. Our pioneering I-O science evaluates how targeting two distinct and complementary pathways may provide a new alternative to current treatments."

"The registration of this OPDIVO combination means more options for patients fighting advanced kidney cancer. We will be working closely with the Department of Health, physicians and patient organisations to make this treatment available to patients via the Pharmaceutical Benefits Scheme (PBS) as soon as possible," said Dr Anderson.

OPDIVO in combination with YERVOY for the treatment of patients with intermediate/poor-risk, previously untreated advanced RCCis not listed on the PBS. However, the combination therapy was under consideration for these patients at the Pharmaceutical Benefits Advisory Committee meeting last week.6

In Australia, this is the second indication registered for the OPDIVO and YERVOY combination therapy (the combination is already registered for unresectable or metastatic melanoma).

About CheckMate 2143

CheckMate 214 is a phase 3, randomised, open-label study evaluating the combination of OPDIVO (nivolumab) plus ipilimumab versus sunitinib in patients with previously untreated clear-cell advanced renal cell carcinoma. Patients in the combination group (n=550) received OPDIVO 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by OPDIVO monotherapy 3 mg/kg every 2 weeks. Patients in the comparator group (n=546) received sunitinib 50 mg once daily for 4 weeks of each 6-week cycle. Patients were treated until progression or unacceptable toxic effects. The primary endpoints of the trial were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in an intermediate to poor-risk patient population (approximately 75% of patients).

OPDIVO plus ipilimumabreduced the risk of death by 37% (HR 0.63; 99.8% CI: 0.44 to 0.89; p < 0.0001) compared with sunitinib in intermediate and poor-risk patients.3The co-primary end-point of objective response rate was 42% (95%CI, 37 to 47) with combination treatment versus 27% (95%CI, 22 to 31) with sunitinib (p<0.001), complete responses were 9.4%  and 1% (p<0.001), respectively.3 The co-primary end-point of progression free survival (PFS) did not meet the pre-specified threshold for significance (p=0.009) with 11.6 months median with OPDIVO plus ipilimumab and 8.4 months with sunitinib (HR=0.82, 99.1% CI, 0.64 to 1.05; p=0.03).

Treatment-related adverse events3 of any grade occurred in 509 of 547 patients (93%) treated with OPDIVO plus ipilimumab and 521 of 535 patients (97%) treated with sunitinib. Grade 3 or 4 adverse events occurred in 250 patients (46%) and 335 (63%) in the respective groups. The most frequent treatment-related adverse events (any grade) reported during Checkmate 214 with OPDIVO plus ipilimumab combination included fatigue (37%), pruritus (28%), diarrhoea (27%), rash (22%), nausea (20%), increased lipase level (16%), hypothyroidism (16%), decreased appetite (14%), asthenia (13%) and vomiting (11%).

About OPDIVO combination therapy

OPDIVO combination therapy is associated with immune-related adverse reactions (irARs) including pneumonitis, colitis, hepatitis, nephritis, renal dysfunction, severe rash or skin reactions (including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, some with fatal outcome), endocrinopathies, neurological and other adverse reactions including Vogt-Koyanagi-Harada syndrome and solid organ transplant rejection. Caution in patients with autoimmune disease, immunosuppressive therapy, symptomatic interstitial lung disease, active brain metastases, specific populations excluded from clinical trials, moderate or severe hepatic impairment or severe renal impairment.

About Immuno-Oncology (I-O)

Immuno-oncology is based on the premise that the immune system is the body's most powerful and effective tool for recognising and fighting disease.Immuno-oncology treatments are designed to harness the patient's own immune system to combat cancer by targeting the same immune pathways that tumour cells use to evade recognition and destruction. OPDIVO and YERVOY target distinct and complementary checkpoint pathways (PD-1 and CTLA-4, respectively).

Please refer to the Approved Product Information before prescribing. The Product Information is available upon request from BMS Medical Information Department: 1800 067 567 or can be accessed athttp://www.medicines.org.au/files/bqpopdiv.pdf

AUSTRALIAN MINIMUM PRODUCT INFORMATION: OPDIVO® (NIVOLUMAB) FOR ADVANCED RENAL CELL CARCINOMA. For all other indications, please refer to full PI.

NAME OF THE MEDICINE: OPDIVO® (nivolumab). INDICATIONS: OPDIVO as monotherapy is indicated for the treatment of patients with advanced clear cell renal cell carcinoma after prior anti-angiogenic therapy.OPDIVO, in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with intermediate/poor-risk, previously untreated advanced renal cell carcinoma. DOSAGE AND ADMINISTRATION: Recommended dose of OPDIVO as monotherapy is 3 mg/kg administered intravenously (IV) over 60 minutes every 2 weeks. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. OPDIVO in combination with YERVOY (ipilimumab): For intermediate/poor risk RCC: The recommended dose of OPDIVO in the combination phase is 3mg/kg administered IV over 60 minutes every 3 weeks for the first 4 doses followed by ipilimumab 1mg/kg administered IV over 30 minutes. The recommended dose of OPDIVO in the single-agent phase is 3mg/kg as monotherapy administered IV over 60 minutes every 2 weeks. Continue treatment with OPDIVO as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. Management of irARs may require withholding of a dose and initiation of corticosteroid or other immunosuppressive therapy or permanent discontinuation of OPDIVO therapy. CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients. PRECAUTIONS: OPDIVO as monotherapy and administered in combination with YERVOY  is associated with immune-related adverse reactions (irARs) including pneumonitis, colitis, hepatitis, nephritis, renal dysfunction, severe rash or skin reactions (including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, some with fatal outcome), endocrinopathies, neurological and other adverse reactions including Vogt-Koyanagi-Harada syndrome and solid organ transplant rejection. Caution in patients with autoimmune disease, immunosuppressive therapy, symptomatic interstitial lung disease, active brain metastases, specific populations excluded from clinical trials, moderate or severe hepatic impairment or severe renal impairment. OPDIVO is not approved for combination with EGFR TKI use in NSCLC. Use in children below 18 years of age is not recommended. Pregnancy Category D. Refer to the Product Information (PI) for a complete list of precautions. INTERACTIONS WITH OTHER MEDICINES: OPDIVO is not metabolised by drug metabolising enzymes, therefore it is not expected to have pharmacokinetic-based interactions. ADVERSE EFFECTS: OPDIVO monotherapy: Very common (≥10%): fatigue, rash, diarrhoea, nausea, pruritus and neutropenia. Common (≥1/100 to <1/10): upper respiratory tract infection, infusion related reaction, hypersensitivity, hypothyroidism, hyperthyroidism, decreased appetite, peripheral neuropathy, headache, dizziness, hypertension, pneumonitis, dyspnoea, cough, colitis, stomatitis, vomiting, abdominal pain, constipation, dry mouth, vitiligo, dry skin, erythema, alopecia, musculoskeletal pain, arthralgia, pyrexia, oedema (including peripheral oedema) and weight decreased. OPDIVO in combination with YERVOY (ipilimumab) in RCC: Very common (≥10%): hyperthyroidism, rash, fatigue, diarrhoea, pruritus, nausea, pyrexia, decreased appetite, hypothyroidism, vomiting, musculoskeletal pain and arthralgia. Common (≥1/100 to <1/10): pneumonia, upper respiratory tract infection, infusion related reaction, hypersensitivity, adrenal insufficiency, hypophysitis, thyroiditis, diabetes mellitus, dehydration, headache, hepatitis, peripheral neuropathy, dizziness, blurred vision, tachycardia, hypertension, pneumonitis, dyspnea, pleural effusion, cough, stomatitis, pancreatitis, constipation, colitis, abdominal pain, dry mouth, dry skin, erythema, urticaria, arthritis, renal failure (including acute kidney injury), oedema (including peripheral oedema), pain and chest pain. Post allogeneic transplant complications have been reported after previous exposure to OPDIVO. Other irARs (some with fatal outcome) such as pancreatitis, uveitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis and rhabdomyolysis have also been reported in clinical trials (<1%) with OPDIVO monotherapy and OPDIVO in combination with YERVOY (ipilimumab). Vogt-Koyanagi-Harada syndrome has been reported post marketing. 

Please refer to the PI for a full list of adverse events and further details.

Prepared from the Approved Product Information dated July 2018. 1506AU1803985

― ENDS ―

OPDIVO® (nivolumab) and YERVOY® (ipilimumab) are a registered trademark of Bristol-Myers Squibb.

Notes to Editors:

ProfessorIan Davis has served on advisory boards for which compensation was paid to ANZUP Cancer Trials Group.  Professor Davis has been involved in clinical trials sponsored by Bristol-Myers Squibb. In relation to this BMS media announcement, no compensation was provided to Professor Davis and the opinions expressed are his own. Professor Davis has been briefed by Bristol-Myers Squibb on the approved use of this product.

About OPDIVO

OPDIVO is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body's own immune system to help restore anti-tumor immune response. By harnessing the body's own immune system to fight cancer, OPDIVO has become an important treatment option across multiple cancers.

OPDIVO's leading global development program is based on Bristol-Myers Squibb's scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the OPDIVO clinical development program has enrolled more than 25,0007 patients. The OPDIVO trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from OPDIVO across the continuum of PD-L1 expression.

In July 2014, OPDIVO was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. OPDIVO is currently approved in more than 607 countries, including the United States, the European Union, Japan and Australia. In October 2015, the OPDIVO and YERVOY combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 507 countries, including the United States, the European Union and Australia.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the centre of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational medicines, including Immuno-Oncology (I-O) therapeutic approaches for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the integrated scientific understanding of both tumour cell and immune system pathways through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 24 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency.

We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how a patient's tumour biology can be used as a guide for treatment decisions throughout the journey.

We understand making the promise of transformational medicines like I-O therapies a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at bmsa.com.au.

For any further information or to arrange an interview please contact:

Ben Seal- Palin Communications

0402 386 392| 02 9412 2255| ben@palin.com.au              

Caroline Duell - Bristol-Myers Squibb

0428 429 086| 03 8523 4272|caroline.duell@bms.com.au

References

1.Therapeutic Goods Administration. Search the TGA website. Available at: https://www.ebs.tga.gov.au/[Accessed: July 2018]

2.OPDIVO Approved Product Information

  1. Motzer RJ et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277-1290.

4.Australian Institute of Health and Welfare, 2017. "Kidney Cancer in Australia". Available at:https://www.aihw.gov.au/reports/cancer/cancer-compendium-information-and-trends-by-cancer-type/report-contents/kidney-cancer-in-australia Accessed: June 2018

5.Australian Institute of Health and Welfare. "Cancer incidence projections Australia, 2011 to 2020". Available at: http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=10737421440Accessed: June 2018

6.PBAC agenda for July 2018 http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/agenda/july-2018-pbac-meeting-agendaAccessed: June 2018

  1. Data on file

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