On September 22, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Commission (EC) has granted a marketing authorisation for TECENTRIQ (atezolizumab) as a monotherapy for the treatment of people with locally advanced or metastatic non-small cell lung cancer (NSCLC) after they have been previously treated with chemotherapy regardless of PD-L1 status (Press release, Hoffmann-La Roche, SEP 22, 2017, View Source [SID1234520608]). People with EGFR-activating mutations or ALK-positive tumour mutations should also have received targeted therapy before receiving TECENTRIQ. This approval is based on results from the large randomised Phase III OAK study and the randomised Phase II POPLAR study.1,2 The Phase III OAKstudy showed that TECENTRIQ helped people in the overall study population live a median of 13.8 months–4.2 months longer than those treated with docetaxel chemotherapy (median OS: 13.8 vs 9.6 months; hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.62, 0.87).1

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The EC has also granted marketing authorisation for TECENTRIQ as a monotherapy for the treatment of people with locally advanced or metastatic urothelial carcinoma (mUC) who have been previously treated with a platinum-containing chemotherapy or who are considered ineligible for cisplatin chemotherapy, regardless of PD-L1 status. This approval is based on results from the randomised Phase III IMvigor211 study and cohorts 1 and 2 from the single-arm Phase II IMvigor210 study. The Phase III IMvigor211 study did not meet its primary endpoint of OS, compared with chemotherapy. However, the study showed that the median duration of response (mDOR), a secondary endpoint, for those receiving TECENTRIQ was 21.7 months (95% CI: 13.0, 21.7) in the overall study population, compared with 7.4 months (95% CI: 6.1, 10.3) for those receiving chemotherapy.3

At the time of data cutoff, the majority (63%) of people who responded to treatment with TECENTRIQ continued to respond, compared with 21% of people treated with chemotherapy.3 Results from cohort 1 of the Phase II IMvigor210 study showed that TECENTRIQ achieved a median OS of 15.9 months (10.4, NE) in the overall study population.4

"We are delighted that the European Commission has approved TECENTRIQ, the first anti-PD-L1 cancer immunotherapy approved in the EU, as a monotherapy in both advanced bladder and advanced lung cancer", said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "The totality of the data for TECENTRIQ across all indications including long-term responses in advanced bladder cancer and the overall survival advantage observed in our phase III advanced lung cancer study means that we are able to extend the benefits of TECENTRIQ to people living with these types of cancer regardless of their levels of PD-L1 expression."
TECENTRIQ is already approved in the USA and in several other countries for people with metastatic NSCLC – and for people with locally advanced or mUC who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

About the OAK study
OAK is a global, multicentre, open-label, randomised, controlled Phase III study that evaluated the efficacy and safety of TECENTRIQ compared with docetaxel. It enrolled 1,225 patients with both squamous and non-squamous disease, regardless of the programmed death-ligand 1 (PD-L1) status of their tumours, and randomised them (1:1) to receive either TECENTRIQ administered intravenously at 1,200 mg every 3 weeks until loss of clinical benefit, or docetaxel administered intravenously at 75 mg/m2 every 3 weeks.

The co-primary endpoints were overall survival (OS) in the first 850 randomised patients (intention-to-treat population) and in a PD-L1-selected subgroup of this primary analysis population.

About the POPLAR study
The Phase II, multicentre, international, randomised, open-label, controlled study, POPLAR, was conducted in patients with locally advanced or metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. The primary efficacy outcome was OS. A total of 287 patients were randomised 1:1 to receive either TECENTRIQ (1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit) or docetaxel (75 mg/m2 by intravenous infusion on Day 1 of each 3-week cycle until disease progression). Randomisation was stratified by PD-L1 expression status on tumour-infiltrating immune cells (IC), by the number of prior chemotherapy regimens and by histology.

An updated analysis with a total of 200 deaths observed and a median survival follow-up of 22 months showed a median OS of 12.6 months in patients treated with TECENTRIQ vs 9.7 months in patients treated with docetaxel (HR 0.69, 95% CI: 0.52, 0.92). Objective response rate (ORR) was 15.3% vs 14.7% and median duration of response (DOR) was 18.6 months vs 7.2 months for TECENTRIQ vs docetaxel, respectively.

About non-small cell lung cancer
Lung cancer is the leading cause of cancer death globally.5 Each year 1.59 million people die as a result of the disease; this translates into more than 4,350 deaths worldwide every day.5 Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.6

About the IMvigor211 study
IMvigor211 is a Phase III study of TECENTRIQ in comparison with chemotherapy in people with advanced bladder cancer who were previously treated with a platinum-based chemotherapy. The study evaluated the efficacy and safety of TECENTRIQ compared with physician’s choice of chemotherapy (vinflunine, paclitaxel or docetaxel) administered every 3 weeks in 931 people with previously treated mUC,who had progressed during or following a platinum-based regimen. The primary efficacy endpoint was OS and key secondary endpoints include ORR, progression-free survival, DOR and safety. The IMvigor211 study did not meet its primary endpoint of OS, compared with chemotherapy. These data were presented in full at EACR-AACR-SIC.

The primary efficacy endpoint, OS, was to be tested in a successive fashion (hierarchical testing) in study populations defined by PD-L1 expression. Statistical significance needed to be achieved for the study populations in the following order: IC2/3 (≥5%), IC1/2/3 (≥1%), and ITT group. However, because such significance was not achieved for OS in the IC2/3 population, results could not be evaluated for statistical significance in the IC1/2/3 and ITT populations, and these analyses are considered descriptive in nature.

The first population tested comprised people with the highest levels of PD-L1 expression (IC2/3), followed by those with any observable level of PD-L1 expression (IC1/2/3), and followed by the overall study population (intention-to-treat: ITT). Per the pre-specified hierarchical testing order, the IC2/3 (≥5%) population was tested first, with an OS HR of 0.87 (95% CI: 0.63, 1.21; median OS (mOS) of 11.1 vs 10.6 months for TECENTRIQ and chemotherapy respectively). In the overall study population (ITT), people treated with TECENTRIQ achieved a mOS of 8.6 months (CI: 95%; 7.8, 9.6), compared with 8.0 months (CI: 95%; 7.2, 8.6) with chemotherapy (HR 0.85, 95% CI 0.73–0.99).

Overall response rates were similar to those previously reported in the Phase II IMvigor210 study and similar between the two study arms. The median duration of response (mDOR), a secondary endpoint, for those receiving TECENTRIQ was 21.7 months (95% CI: 13.0, 21.7) in the overall study population, compared with 7.4 months (95% CI: 6.1, 10.3) for those receiving chemotherapy. At the time of data cutoff, the majority (63%) of people who responded to treatment with TECENTRIQ continued to respond, compared with 21% of people treated with chemotherapy.

About the IMvigor210 study (Cohort 2)
In Cohort 2, the co-primary efficacy endpoints were confirmed ORR, as assessed by an IRF using RECIST (Response Evaluation Criteria in Solid Tumours) v1.1 and investigator-assessed ORR according to Modified RECIST (mRECIST) criteria. There were 310 patients treated with TECENTRIQ 1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit. The study met its co-primary endpoints in Cohort 2, ORRs per IRF-assessed RECIST v1.1 and investigator-assessed mRECIST, compared with a prespecified historical control response rate of 10%.
The confirmed ORR for all comers per IRF-RECIST v1.1 were 15.8% (95% CI: 11.9, 20.4). The confirmed ORR for all comers per investigator-assessed imRECIST were 19.7% (95% CI: 15.4, 24.6). The rate of complete response per IRF-RECIST v1.1 in the all-comer population was 6.1% (95% CI: 3.7, 9.4). For Cohort 2, median DOR per IRF-RECIST v1.1 was not reached in any PD-L1-expression subgroup or in all comers, but was reached in patients with PD-L1 expression <1% (13.3 months; 95% CI 4.2, NE). An analysis was also performed with a median duration of survival follow-up of 21.1 months for Cohort 2, the OS rate at 12 months was 37% in all comers.

About the IMvigor210 study (Cohort 1)
The approval for patients who are ineligible for cisplatin-based chemotherapy is based on results from Cohort 1, which consisted of 119 people with locally advanced or mUC who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant (before surgery) or adjuvant (after surgery) chemotherapy. Clinically relevant IRF-assessed ORRs per RECIST v1.1 were shown; however, when compared to a pre-specified historical control response rate of 10%, statistical significance was not reached for the primary endpoint. The median OS results for all comers were 15.9 (10.4, NE).

Pooled safety profile
The safety of TECENTRIQ is based on pooled data in 2,160 patients with mUC and NSCLC. The most common adverse all-grade reactions were fatigue (35.4%), decreased appetite (25.5%), nausea (22.9%), dyspnoea (21.8%), diarrhoea (18.6%), pyrexia (18.3%), rash (18.6%), vomiting (15.0%), arthralgia (14.2%), asthenia (13.8%) and pruritus (11.3%).

About urothelial carcinoma
Metastatic urothelial carcinoma (mUC) is associated with a poor prognosis and limited treatment options. Until recently this disease had not seen any major advances for more than 30 years.7 UC is the ninth most common cancer worldwide, with 430,000 new cases diagnosed in 2012, and it results in approximately –165,000 deaths globally each year.5 Men are three times more likely to suffer from UC than women8, and the disease is three times more common in developed countries than in less developed countries.9

About TECENTRIQ (atezolizumab)
TECENTRIQ is a monoclonal antibody designed to bind with a protein called PD-L1. TECENTRIQ is designed to bind to PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, TECENTRIQ may enable the activation of T cells. TECENTRIQ has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers

On September 22, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) injection for intravenous use for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (Press release, Bristol-Myers Squibb, SEP 22, 2017, View Source [SID1234520606]). Approval for this indication has been granted under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.1 In the CheckMate -040 trial, 14.3%* (95% CI: 9.2-20.8; 22/154) of patients responded to treatment with Opdivo. The percentage of patients with a complete response was 1.9% (3/154) and the percentage of patients with a partial response was 12.3% (19/154).1 Among responders (n=22), responses ranged from 3.2 to 38.2+ months; 91% of those patients had responses of six months or longer and 55% had responses of 12 months or longer.1

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Opdivo is associated with the following Warnings and Precautions including: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity.1 Please see the Important Safety Information section below.

"We are proud to bring the potential for clinically meaningful responses with Immuno-Oncology therapy to these advanced-stage HCC patients, who have had limited treatment options for years," said Chris Boerner, president, U.S. Commercial, Bristol-Myers Squibb. "Today’s approval marks an important step toward our mission of delivering transformational medicines to treat conditions with a high unmet need."

The burden of liver cancer in the U.S. is significant and is expected to increase in the decades to come.5,6 A recently-released American Cancer Society (ACS) report published in CA: A Cancer Journal for Clinicians notes that death rates for liver cancer are increasing at a faster pace than any other cancer, doubling since the mid-1980s.5

"Unfortunately, the majority of HCC patients are diagnosed with advanced-stage disease and are not candidates for potentially curative surgical interventions," said Adrian M. Di Bisceglie, M.D., co-director, Saint Louis University Liver Center, Chief of Hepatology. "More options are needed for advanced-stage HCC patients who have failed prior systemic therapy."

Hepatocellular carcinoma is often diagnosed in the advanced-stage where treatment options are limited and there is a high unmet need for patients who are intolerant to or who have progressed on sorafenib therapy.5,7,8

"In recent years, there has been growing interest in leveraging immuno-oncology knowledge and discoveries to add to the treatment options available for patients with advanced-stage liver cancer," said Anthony B. El-Khoueiry, M.D., lead investigator and associate professor of clinical medicine and phase I program director at the Keck School of Medicine of University of Southern California (USC) and the USC Norris Comprehensive Cancer Center. "The approval of Opdivo provides us with an encouraging approach and a new treatment option for appropriate patients with HCC following prior systemic therapy."

Approval Based on Notable Overall Response Rate and Duration of Response

CheckMate -040 included a Phase 1/2, open-label, multicenter study evaluating Opdivo in patients with HCC who progressed on or were intolerant to sorafenib.1,9 In this study, 154 patients received Opdivo 3 mg/kg administered intravenously every two weeks. The recommended dose is 240 milligrams administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.1 Efficacy outcome measures included confirmed overall response rate (as assessed by blinded independent central review using RECIST v1.1 and modified RECIST for HCC) and duration of response.1 The median age of patients participating in the study was 63 (range: 19-81), all patients had received prior sorafenib therapy and 19% of patients had received two or more prior systemic therapies.1 Patients were enrolled regardless of PD-L1 expression level and whether or not they were infected with active Hepatitis B virus (HBV) or active Hepatitis C virus (HCV).1,2 Data from CheckMate -040 were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting in June.

In the CheckMate -040 trial, 14.3%* (95% CI: 9.2-20.8; 22/154) of patients responded to treatment with Opdivo. The percentage of patients with a complete response was 1.9% (3/154) and the percentage of patients with a partial response was 12.3% (19/154). Among responders (n=22), responses ranged from 3.2 to 38.2+ months; 91% of those patients had responses of six months or longer and 55% had responses of 12 months or longer.1 The median time to response was 2.8 months (range: 1.2-7.0).2 The overall response rate based on modified RECIST was 18.2% (95% CI: 12.4-25.2; 28/154). Complete response rate was 3.2% (5/154); partial response rate was 14.9% (23/154).1 Responses were observed across PD-L1 expression levels.2

"I advocate for others because I know firsthand the terrible toll cancers of the liver take on a patient and their loved ones. In my opinion, HCC is an example of a cancer where awareness is out of sync with the impact of the disease," said Suzanne Lindley, Co-Founder, Yes! Beat Liver Tumors. "Today’s approval shines a light of awareness and hope on a disease with a high unmet medical need."

Select Safety Profile

The safety of Opdivo was evaluated in a 154-patient subgroup of patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib in the CheckMate -040 study. Patients were required to have an aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of no more than five times the upper limit of normal and total bilirubin of less than 3 mg/dL. The median duration of exposure to Opdivo was six months. Treatment with Opdivo resulted in treatment-emergent Grade 3 or 4 AST in 18% (27/154) of patients, Grade 3 or 4 ALT in 11% (16/154) of patients, and Grade 3 or 4 bilirubin in 7% (11/154) of patients. Immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients.1 Serious adverse reactions occurred in 49% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. The most common adverse reactions (≥20%) in patients receiving Opdivo (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). Opdivo was discontinued due to adverse reactions in 11% of patients and 32% of patients had a dose delay for an adverse reaction.2

About Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the fastest-growing cause of cancer death in the U.S.3,5,10 The incidence of liver cancer in the U.S. has more than tripled since 1980.3 It is estimated that there will be approximately 41,000 new cases of liver and intrahepatic bile duct cancer and 29,000 deaths from these diseases in the U.S. this year.4 The majority of these cases are caused by Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infections, making chronic infection with HBV or HCV the most common risk factor for liver cancer.10,11 However, the increasing prevalence of metabolic syndrome and nonalcoholic steatohepatitis (NASH) is expected to contribute to increased rates of HCC in the U.S. in the foreseeable future.12,13

INDICATION

OPDIVO (nivolumab) 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 tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

IMPORTANT SAFETY INFORMATION

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.

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. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients.

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 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 Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

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. 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 patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) 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 patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients.

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.

Immune-Mediated Skin 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.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients.

Embryo-Fetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia.

Common Adverse Reactions

In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%).

Please see U.S. Full Prescribing Information for OPDIVO.

About the Opdivo Clinical Development Program

On September 22, 2017 AbbVie (NYSE: ABBV) and Bristol-Myers Squibb Company (NYSE: BMY) reported a clinical trial collaboration to evaluate the combination of AbbVie’s investigational antibody drug conjugate ABBV-399 and Bristol-Myers Squibb’s immunotherapy Opdivo (nivolumab) in c-Met overexpressing non-small cell lung cancer (NSCLC) (Press release, AbbVie, SEP 22, 2017, View Source [SID1234520605]).

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A Phase 1b clinical study is underway that includes evaluating the potential of combining Opdivo, which is designed to alleviate immune suppression, with ABBV-399 to explore the tolerability and potential efficacy of the combination in subjects with advanced c-Met overexpressing NSCLC who failed one prior line of chemotherapy.

"Cancer remains one of the most challenging medical conditions for patients and physicians," said Tom Hudson, M.D., vice president, oncology early discovery and development, AbbVie. "Therapeutic advances continue to be achieved every day and we are committed to exploring the potential of our investigational compounds with other approved treatments with the goal to deliver a significant impact to patients."

"We continue to explore the potential of novel combinations of medicines with Opdivo, and AbbVie’s investigational treatments will help evaluate the role of new targets in combination with immunotherapy," said Fouad Namouni, M.D., Head of Development, Oncology, Bristol-Myers Squibb. "We look forward to continuing to partner our PD1 with AbbVie’s early- and late-stage assets as a possible treatment option for patients with lung cancer."

AbbVie is the sponsor conducting the trial. Specific terms of the agreement were not disclosed.

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 25,000 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 60 countries, including the United States, the European Union, and Japan. In October 2015, the company’s 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 50 countries, including the United States and the European Union.

About ABBV-399
ABBV-399 (telisotuzumab vedotin) is a first-in-class anti-c-Met antibody drug conjugate that targets both MET-amplified and c-Met-overexpressing tumors. It is currently being investigated to treat advanced solid tumors. c-Met expression is significantly higher in many solid tumors compared to normal tissue and is a marker of poor prognosis. ABBV-399 is an investigational compound and its safety and efficacy have not been evaluated by the FDA or any other health authority.

OPDIVO AND YERVOY INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non‑small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor 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) is indicated for the treatment of adult and pediatric (12 years and older) patients 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.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

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 patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

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 patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

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. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

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. 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 patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) 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 patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 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 patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

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 patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO . The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).. The most common adverse reactions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVO

On September 22, 2017 Novartis reported a new collaboration with The Max Foundation to support continued access to treatment at no cost for nearly 34,000 current patients with chronic myeloid leukemia (CML), gastrointestinal tumors (GIST) and other rare cancers (Press release, Novartis, SEP 22, 2017, View Source [SID1234520597]). The two organizations have been long-time collaborators in providing access to care for patients in lower-income countries through the Glivec International Patient Assistance Program (GIPAP), one of the most innovative patient assistance programs ever implemented on a global scale.

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The new collaboration, called CMLPath to Care(TM), is an evolution from GIPAP, a partnership that provided Glivec (imatinib)* at no cost to diagnosed patients in lower-income countries where there may not be access to reimbursement or funding mechanisms, and to those unable to pay for the medication. Under the new initiative, The Max Foundation, a global, patient-focused, non-governmental organization (NGO), will assume from Novartis the responsibility for delivering the treatment to these patients, including supply chain management. Novartis will provide funding and drug donation support. The collaborative agreement runs through Q1 2021 with an option to extend. During this timeframe, Novartis expects to donate more than $29 million to the collaboration, along with approximately 315,000,000 doses of medicine.

Novartis introduced GIPAP in 2002 after recognizing the impact of its breakthrough cancer therapy, Glivec. The program has served the CML treatment needs of approximately 75,000 people since its inception.

"Fifteen years ago, Novartis recognized the critical importance of ensuring patients in lower-income countries had access to breakthrough cancer therapy, and we partnered with The Max Foundation to develop a revolutionary global program to address this need," said Bruno Strigini, CEO of Novartis Oncology. "CMLPath to Care renews and extends our unique collaboration with The Max Foundation and builds on the strengths of both organizations to better serve these patients."

CMLPath to Care: A Patient-Centered Model of Access and Support
The goal of CMLPath to Care is to help people living with CML by connecting them and their carers with effective treatments, professional medical capabilities, trained physicians and hands-on support. Under the previous GIPAP model, Novartis managed the entire supply chain for the medicine and interacted directly with local stakeholders (e.g., physicians, treatment centers, NGOs, private companies and governments) in more than 75 countries where it operated. The Max Foundation provided CML patients with psychosocial support and education, services that did not previously exist in certain countries. Over time, changes in local infrastructures and capabilities, new and innovative treatments, and the growth and impact of patient groups prompted Novartis and The Max Foundation to recognize that a new, more flexible approach to access was needed.

With CMLPath to Care, Novartis will provide access to Glivec in nearly 70 countries, and in a subset of countries second-line Tasigna (nilotinib) therapy will be available for approved indications. The Max Foundation will manage the entire medicine supply chain and interactions with local stakeholders under the umbrella of Max Access Solutions, while continuing to provide hands-on, local patient support.

"Since our founding 20 years ago, The Max Foundation has grown extensively in its efforts and ability to help people face cancer with dignity and hope," said Pat Garcia-Gonzalez, CEO of The Max Foundation. "We are proud of the thousands of patients’ lives touched by our long-standing collaboration with Novartis and are pleased with our shared continued innovation, commitment and support for underserved patients with CML and other rare cancers in low resource countries."

Novartis and The Max Foundation Innovate with a Global Direct-to Patient Humanitarian Program: Reimagining What’s Possible for CML Care
CMLPath to Care is one of the broadest cancer treatment access initiatives led by a patient-centered NGO. During the last 15 years, the Novartis-Max Foundation partnership created and maintained a standard of care in many lower-income countries that may not have otherwise been possible for people with CML. In this new model – as in GIPAP – the medicine is provided at no cost for individual patients. This contrasts with more traditional humanitarian programs that provide bulk donations of a medicine. The Max Foundation is unique among NGOs in its ability to manage the complex administration of individual patient care. The transition to CMLPath to Care includes The Max Foundation’s assumption of program administration, supply chain management and oversight of the nearly 34,000 patients, 1,400 physicians, and 450 treatment centers in nearly 70 countries on four continents.

The enduring partnership with The Max Foundation has been a key component of Novartis’ long-term focus on bringing CML care to those who need the most support. The company is dedicated to transforming the lives of people with CML and holds an unwavering commitment to reimagining what is possible for CML treatment through scientific innovation and creative solutions that provide access to care regardless of geography or financial situation.

To ensure a seamless transition for patients, the program will move from Novartis to The Max Foundation through the first half of 2018 on a country-by-country basis. Both organizations are represented on an operational committee that will meet four times each year to ensure the collaboration is meeting its goals and operating efficiently.

On September 22, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Commission has approved Gazyvaro (obinutuzumab) in combination with chemotherapy, followed by Gazyvaro maintenance in people achieving a response, as a new treatment for previously untreated advanced follicular lymphoma (Press release, Hoffmann-La Roche, SEP 22, 2017, View Source [SID1234520594]).
The approval is based on results from the GALLIUM study, the first phase III study in previously untreated follicular lymphoma to show superior progression-free survival (PFS) over MabThera (rituximab)-based treatment, the current standard of care.

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"Every year an estimated 19,000 people in Europe are diagnosed with follicular lymphoma, which is considered to be incurable. We are pleased that with today’s approval of Gazyvaro, these patients now have an improved initial treatment option available to them," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "By challenging our own MabThera medicine head-to-head, we have been able to set a new standard of care for people with follicular lymphoma."

Results from the phase III GALLIUM study showed that Gazyvaro-based treatment reduced the risk of disease progression or death (progression-free survival; PFS), as evaluated by investigator assessment, by 34 percent (HR=0.66; 95% CI 0.51-0.85, p=0.001). As supported by an independent review committee (IRC), the risk of disease progression or death was reduced by 29 percent (HR=0.71; 95% CI 0.54-0.93, p=0.014) compared to MabThera-based treatment. Median PFS has not yet been reached in either treatment arm.
Investigator assessment showed that at three years, 80 percent of patients who received Gazyvaro-based treatment were progression-free compared to 73 percent of patients who received MabThera-based treatment.

This is also supported by the IRC analysis, which found that 81.9 percent of patients who received Gazyvaro-based treatment were progression-free compared to 77.9 percent of patients who received MabThera-based treatment. Adverse events observed with either Gazyvaro or MabThera were consistent with those seen in previous clinical trials when each was combined with various chemotherapies.

This is the third approval for Gazyvaro in the EU. It was approved in 2014, in combination with chlorambucil, for people with previously untreated chronic lymphocytic leukaemia with comorbidities that make them unsuitable for full-dose fludarabine-based therapy. In June 2016 Gazyvaro was also approved in combination with bendamustine, followed by Gazyvaro maintenance, in people with follicular lymphoma who did not respond or who progressed during or up to six months after treatment with MabThera or a MabThera-containing regimen.

About the GALLIUM study

GALLIUM (NCT01332968) is a global phase III open-label, multi-centre, randomised two-arm study examining the efficacy and safety of Gazyvaro plus chemotherapy followed by Gazyvaro alone for up to two years, as compared head-to-head against MabThera plus chemotherapy followed by MabThera alone for two years or until disease progression (whichever occurs first). Chemotherapies (CHOP, CVP or bendamustine) were selected by each participating study site prior to beginning enrolment. GALLIUM included 1401 patients with previously untreated indolent non-Hodgkin lymphoma (iNHL), of which 1202 patients had follicular lymphoma. The primary endpoint of the study was investigator-assessed PFS in patients with follicular lymphoma, with secondary endpoints including PFS assessed by IRC, PFS in the overall study population (iNHL), response rate (overall response, ORR; and complete response, CR), overall survival (OS), and safety. The GALLIUM study is being conducted in cooperation with the NCRI (United Kingdom), GLSG (Germany), the East German Study Group Hematology and Oncology (OSHO; Germany).