dm+d

704192000

Refrigerated Storage

OpdivoBristol-Myers Squibb Pharmaceuticals Ltd

Bristol-Myers Squibb Pharmaceuticals Ltd
Opdivo
10mg/mL concentrate for solution for infusion

In the event of an inadvertent temperature excursion the following data may be used:
The unopened vial can be stored at controlled room temperature up to 25°C for up to 48 hours.

Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk
Contact Bristol-Myers Squibb Pharmaceuticals Ltd in cases where additional stability data is required

No, if exposed to the conditions above
Yes, if exposed to the conditions above
24 September 2021
London MI Service

New Medicines

OpdivoNon-small cell lung cancer (NSCLC) in PD1 all-comers - first-line in combination with ipilimumab and chemotherapy

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Launched
Launched
Launched
November 2020
Nov 20Approved in EU [9].
Sep 20Recommended for EU approval by CHMP - the additional indication is "in combination with ipilimumab and 2 cycles of platinum-based chemotherapy ... for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no sensitising EGFR mutation or ALK translocation" [8].
May 20Approved in USA. Approval was based on data from a specified interim analysis from the PIII CheckMate -9LA trial. [7]
Apr 20EMA and US FDA accept regulatory submissions for nivolumab plus ipilimumab in the first-line treatment of metastatic or recurrent NSCLC. The submissions seek approval for use of the combination, administered concomitantly with a limited course of chemotherapy, in the treatment of patients with no EGFR or ALK genomic tumour aberrations. They are based on data from the Phase III CheckMate-9LA trial. FDA has granted Priority Review designation with a PDUFA date of 6/8/20 [6].
Dec 17Will be filed in the EU via the centralised procedure [1].

Category

Fully human Ig4 monoclonal antibody; programmed cell death-1 receptor (PDCD 1) inhibitor
The incidence rate of lung cancer in 2006 was 72.2 per 100,000 in men and 50.8 per 100,000 in women. Lung cancer belongs to the three most common cancers in men (14.8 % of all cancers) and women (10.9% of all cancers).
Non-small cell lung cancer (NSCLC) in PD1 all-comers - first-line in combination with ipilimumab and chemotherapy
Intravenous infusion

Further information

Yes

Trial or other data

Jan 21PIII CheckMate 9LA study is published (n=719). At the pre-planned interim analysis (median follow-up 9·7 months, overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14.1 months [95% CI 13.2–16.2] vs 10.7 months [9.5–12.4]; hazard ratio 0.69 [96.71% CI 0.55–0.87]; p=0·00065) [10].
Oct 19Manufacturers report positive results for PIII CheckMate -9LA trial. Treatment combination, given concomitantly with two cycles of chemotherapy met the primary endpoint (at interim analysis) of superior overall survival vs chemotherapy alone for up to 4 cycles [5].
Nov 18PIII CheckMate 9LA study (NCT03215706) is recruiting [3].
Dec 17PIII trial to assess efficacy of nivolumab and ipilimumab in combination with chemotherapy as a first line therapy vs. chemotherapy alone in patients with late stage NSCLC starts (CheckMate 9LA; NCT03215706). Overall survival is the defined primary endpoint of the trial. 420 patients will be enrolled in the US, Spain, Argentina, Belgium, Chile, Germany, Ireland, Romania, Russia and United Kingdom. Collection of OS data should complete Aug 19 [2].

Evidence based evaluations

OpdivoOesophageal cancer, refractory or intolerant to platinum-based combination therapy - second-line in adults

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Launched
Launched
Launched
Nov 20Approved in EU as second-line treatment for unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma [11].
Oct 20Recommended for EU approval by CHMP - the additional indication is "for the treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based combination chemotherapy" [10].
Jun 20Approved in US for for treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy [9].
Jun 20Granted EAMS status in UK [8].
Dec 16EU filing will be via the centralised route [3].

Category

A fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor (PD-1).
In 2013, there were 8,784 new cases of oesophageal cancer in the UK: 5,852 (67%) in males and 2,932 (33%) in females, giving a male:female ratio of around 20:10. The crude incidence rate shows there are 19 new oesophageal cancer cases for every 100,000 males in the UK, and 9 for every 100,000 females [2].
Oesophageal cancer, refractory or intolerant to platinum-based combination therapy - second-line in adults
Intravenous infusion

Further information

Yes

Trial or other data

Oct 19PIII NCT02569242 RCT (n=419) is published; it reports after a median follow-up of 10.5months for nivolumab arm and 8months for chemotherapy arm, primary endpoint of overall survival was significantly improved for nivolumab vs chemotherapy (median 10.9 vs 8.4 months, HR 0.77, 95% CI 0.62–0.96; p=0.019) [7].
Dec 18No update posted for PIII study (NCT02569242) [6].
Jan 18Study NCT02569242 is active but not recruiting. Timescales unchanged [5].
Dec 16PIII (NCT02569242) study is still recruiting; timescales unchanged [4].

Evidence based evaluations

OpdivoMetastatic renal cell carcinoma - first-line in combination with cabozantinib

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Launched
Launched
Launched
May 2021
May 21Licence change approved by the MHRA for use in combination with cabozantinib, for the first-line treatment of advanced renal cell carcinoma in adults [12].
Apr 21Approved in EU [11]
Feb 21Recommended for EU approval by CHMP - the additional indication is "in combination with cabozantinib ... for the first-line treatment of adult patients with advanced renal cell carcinoma (see section 5.1)" [9].
Jan 21Approved in US for in combination with nivolumab for first line treatment of advanced renal cell carcinoma [7].
Oct 20Has been filed in the EU using the centralised procedure [6].
Aug 20Filed in US [5].
Apr 20Company announce plans to work toward regulatory filings in the near future [4].
Nov 17Will be filed in the EU via the centralised procedure [1].

Category

Fully human Ig4 monoclonal antibody; programmed cell death-1 receptor (PDCD 1) inhibitor.
UK incidence of RCC is 12 per 100,000 people. Patients with stage 1 (39%) and 2 (16%) RCC, and some with stage 3 (26%), are candidates for surgery. Five-year survival ranges from 40-90% in stage 1-3 disease, and 10% in stage 4.
Metastatic renal cell carcinoma - first-line in combination with cabozantinib
Intravenous

Further information

Yes

Trial or other data

Mar 21PIII CheckMate 9ER (n=651) is published; nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival in patients with previously untreated advanced renal-cell carcinoma (median 16.6 vs. 8.3 months, respectively, HR, 0.51; 95% CI, 0.41 to 0.64; p<0.001) [10].
Feb 21New analysis from PIII CheckMate-9ER trial shows that the combination of Opdivo (nivolumab) and Cabometyx (cabozantinib) vs. sunitinib in 1st-line treatment of advanced RCC showed sustained benefits in PFS after a median follow-up of 23.5 months. Median PFS was 17 months with the study combination vs. 8.3 months with sunitinib (HR 0.52; 95% CI: 0.43 to 0.64). The company said that this combination maintained improvements in OS, demonstrating a 34% reduction in the risk of death vs. sunitinib (HR: 0.66; 95% CI: 0.50 to 0.87). Of those on this combination, 6.6% discontinued both agents due to side effects and 9.7% discontinued OPDIVO only and 7.2% discontinued CABOMETYX only.[8]
Apr 20Topline results from open-label, randomised, global PIII CheckMate 9ER trial (NCT03141177) which enrolled 701 pts with previously untreated advanced or metastatic RCC show that the primary endpoint of significantly improving PFS for the combination of cabozantinib plus nivolumab vs. sunitinib was met. Preliminary assessment shows the combination demonstrated a favourable safety profile [3,4].
Jul 19PIII CheckMate 9ER trial has finished recruiting and due to complete collection of primary outcome data in Jan 20 [3].
Dec 18PIII CheckMate 9ER trial is recruiting & now expects to collect primary outcome data by Sep 19 [2].
May 17PIII CheckMate 9ER trial to evaluate nivolumab in combination with cabozantinib tablets or in combination with ipilimumab and cabozantinib versus sunitinib in patients with previously untreated, advanced or metastatic RCC starts (CA209-9ER; NCT03141177). The open-label trial will enrol approximately 1,014 patients in the US, Western Europe and Australia. Primary outcome is progression-free survival; collection of these data is expected to complete Feb 21 [1,2].

Evidence based evaluations

OpdivoDeficient Mismatch Repair (dMMR)/Microsatellite Instability High (MSI-H) metastatic colorectal cancer - in combination with ipilimumab

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Launched
Launched
Launched
July 2021
Jul 21Approved in UK [7]
Jun 21Approved in EU [8].
May 21Recommended for EU approval by CHMP – the new indication is ‘Opdivo in combination with ipilimumab is indicated for the treatment of adult patients with mismatch repair deficient or microsatellite instability high metastatic colorectal cancer after prior fluoropyrimidine based combination chemotherapy’ [6].
Jan 21Opdivo is already licensed in the US for use in combination with ipilimumab (or as monotherapy) for treatment of adult and pediatric (12 years and older) patients with MSI-H or dMMR metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This was based on data from PII CheckMate-142 [5].
Nov 20Has been filed in the EU [3].

Category

Fully human Ig4 monoclonal antibody; programmed cell death-1 receptor (PDCD 1) inhibitor
Colorectal cancer is the second most common cause of cancer death in the UK. The age-standardised incidence rates for newly diagnosed cancers in England were 670.8 per 100,000 males and 546.1 per 100,000 females in 2014 [1].
Deficient Mismatch Repair (dMMR)/Microsatellite Instability High (MSI-H) metastatic colorectal cancer - in combination with ipilimumab
Intravenous infusion

Further information

Yes

Trial or other data

Nov 20PIII CheckMate 8HW is still recruiting and collection of primary outcome data is now due to complete Aug 25 [4].
Jul 19PIII CheckMate 8HW to compare the clinical benefit, as measured by Progression-Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS), achieved by nivolumab in combination with ipilimumab or by nivolumab monotherapy in patients with Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) metastatic colorectal cancer starts (NCT04008030). 494 adults will be recruited from sites around the world including US, EU & UK. Collection of primary outcome data (PFS) is expected to complete Oct 24 [2].

Evidence based evaluations

OpdivoUnresectable pleural mesothelioma - first-line in combination with ipilimumab

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Launched
Launched
Launched
July 2021
Jul 21Approved in UK [12].
Jun 21Licence extension approved in the EU [11].
Apr 21Recommended for EU approval by CHMP - the additional indication is "nivolumab in combination with ipilimumab is indicated for the first line treatment of adult patients with unresectable malignant pleural mesothelioma.” [10].
Feb 21Granted Early Access to Medicines status (EAMS) for use in combination with ipilimumab in the treatment of malignant pleural mesothelioma in adults [9].
Oct 20Nivolumab 360 mg every three weeks plus ipilimumab 1 mg/kg every six weeks was approved by the U.S. FDA for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma [7].
Sep 20Filed in EU via centralised procedure [6].
Mar 18EU filing will be using centralised procedure [3].

Category

Fully human Ig4 monoclonal antibody; programmed cell death-1 receptor (PDCD 1) inhibitor.
The incidence of malignant pleural mesothelioma in males in the UK is 3.4 per 100,000. There are around 2,700 new cases in the UK each year. The incidence has increased slightly in the last decade. Exposure to asbestos is a well-established cause, with occupational exposure being documented in 70-80% of those affected [1].
Unresectable pleural mesothelioma - first-line in combination with ipilimumab
Intravenous

Further information

Yes

Trial or other data

Jan 21CheckMate 743 RCT (n=605) is published; it found nivolumab plus ipilimumab significantly extended overall survival vs chemotherapy (median overall survival 18·1 months vs 14·1 months, HR 0·74, p=0·0020). 2-year overall survival rates were 41% in the nivolumab plus ipilimumab group and 27% for chemotherapy [8].
Apr 20Positive topline results announced from PIII CheckMate -743 trial which met its primary endpoint of overall survival vs. chemotherapy.[5]
Dec 19PIII CheckMate 743 trial no longer recruiting; collection of primary outcome data expected to complete Apr 21 [4].
Mar 18PIII CheckMate 743 trial still recruiting [2].
Oct 16PIII CheckMate 743 trial to assess the efficacy and tolerability of the combination of nivolumab and ipilimumab, compared to pemetrexed and cisplatin or carboplatin, as a first-line therapy, in patients with unresectable pleural mesothelioma starts (NCT02899299). The primary endpoint is overall survival, assessed at 3.5 years. The randomised, open-label trial is designed to enrol approximately 600 patients in the UK, Eastern & Western Europe, North & South America and Africa. Collection of primary outcome data is due to complete Oct 20 [2,3].

Evidence based evaluations

OpdivoOesophageal cancer or gastroesophageal junction cancer - adjuvant therapy

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Launched
Launched
Launched
September 2021
Sep 21MHRA approves a licence extension for adjuvant treatment of adult patients with completely resected oesophageal or gastro-oesophageal junction cancer who have residual pathologic disease following prior neoadjuvant chemoradiotherapy [13].
Jul 21Approved in EU [12].
Jun 21Extension to existing indication recommended for EU approval by CHMP – the new indication is “Opdivo as monotherapy is indicated for the adjuvant treatment of adult patients with oesophageal or gastro-oesophageal junction cancer who have residual pathologic disease following prior neoadjuvant chemoradiotherapy [11].
May 21Approved in US for patients with completely resected oesophageal or gastro-oesophageal junction cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy [10].
Jan 21the FDA has accepted a supplemental Biologics License Application for the treatment of patients with resected esophageal or gastroesophageal junction (GEJ) cancer in the adjuvant setting, after neoadjuvant chemoradiation therapy [8].
Dec 20Has been filed in the EU using the centralised procedure [7].

Category

A fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor (PD-1).
In 2013, there were 8,784 new cases of oesophageal cancer in the UK: 5,852 (67%) in males and 2,932 (33%) in females, giving a male:female ratio of around 20:10. The crude incidence rate shows there are 19 new oesophageal cancer cases for every 100,000 males in the UK, and 9 for every 100,000 females [2].
Oesophageal cancer or gastroesophageal junction cancer - adjuvant therapy
Intravenous infusion

Further information

Yes

Trial or other data

Apr 21Results of PIII CheckMate 577 RCT reported in NEJM [9].
Aug 20PIII CheckMate -577 trial met met its primary endpoint of disease-free survival (DFS) at a pre-specified interim analysis. Treatment with Opdivo after neoadjuvant chemoradiation therapy (CRT) and complete surgical resection demonstrated a statistically significant improvement in the primary endpoint of DFS vs. placebo. The safety profile of Opdivo was consistent with previously reported studies [6].
Dec 19PIII CheckMate 577 trial is no longer recruiting; collection of primary outcome data should now finish May 21 [5].
Nov 18PIII CheckMate 577 trial is still recruiting [4].
May 16PIII CheckMate 577 trial to assess the efficacy of adjuvant nivolumab in patients with resected oesophageal or gastro-oesophageal junction cancer starts (NCT02743494). The randomised, double-blind trial intends to enrol approximately 760 patients in countries including the US & EU (& UK). Co-primary outcome is disease-free survival and overall survival; collection of these data should complete Sep 20 [1,3].

Evidence based evaluations

OpdivoAdvanced gastric cancer - first-line in combination with chemotherapy

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Phase III Clinical Trials
Recommended for approval (Positive opinion)
Launched
Sep 21Recommended for EU approval by CHMP – the additional indication is “Opdivo in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first‑line treatment of adult patients with HER2‑negative advanced or metastatic gastric, gastro‑oesophageal junction or oesophageal adenocarcinoma whose tumours express PD-L1 with a combined positive score (CPS) ≥ 5” [11].
Apr 21Approved in the US [9].
Jan 21USA FDA accepts for priority review application for nivolumab combined with chemotherapy as first-line treatment in metastatic gastric cancer, gastroesophageal junction cancer and oesophageal adenocarcinoma [8].
Nov 20Has been filed in the EU using the centralised procedure [7].

Category

A fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor (PD-1), given over 30 minutes followed by chemotherapy every 2 or 3 weeks until disease progression or unacceptable toxicity.
Gastric cancer is the second most common cause of cancer-related death in the world. It is a difficult disease to cure, mainly because most patients present with advanced disease. 50% involve the pylorus, 25% the lesser curve and 10% the cardia. 2-8% of gastric cancers are lymphomas. 95% of gastric cancers occur in those aged over 55 years. 4,923 new diagnoses of gastric cancer were made in the UK in 2008 [1].
Advanced gastric cancer - first-line in combination with chemotherapy
Intravenous infusion

Further information

Yes

Trial or other data

Sep 20Result of PIII CheckMate -649 trial show longer median OS (HR 0.71[0.59 to 0.86]; p<0.0001) for nivolumab plus chemotherapy (14.4 months [13.1 to 16.2] vs. 11.1 months [10.0 to 12.1] for chemotherapy alone. Median PFS (0.68[0.56 to 0.81]; p<0.0001) was 7.7 months [7.0 to 9.2] in those treated with nivolumab plus chemotherapy and 6.0 months [5.6 to 6.9] among those treated with chemotherapy alone [7].
Aug 20The CheckMate-649 study met its two primary endpoints, overall survival (OS) and progression-free survival (PFS), both in pts whose tumors express PD-L1 with a combined positive score >5. The company will complete a full evaluation of the data before sharing the results at an upcoming medical conference. [6]
Dec 19PIII CheckMate649 study has finished recruiting [5].
Dec 18PIII CheckMate649 study is still recruiting patients & expects to complete collection of primary outcome data in Mar 21 [4].
Dec 17PIII CheckMate649 study is still recruiting patients [3].
Oct 16PIII CheckMate649 study to compare the efficacy of the combination of nivolumab plus ipilimumab with nivolumab plus chemotherapy standard of care (oxaliplatin plus fluoropyrimidine) in the survival rate of patients with gastric or gastroesophageal junction cancer starts (NCT02872116; CA209-64). The study will evaluate the overall survival of nivolumab plus ipilimumab versus oxaliplatin plus fluoropyrimidine in patients with previously untreated advanced or metastatic gastric or gastroesophageal junction cancer with tumours expressing programmed cell death ligand 1 (PD-L1). The open label trial is recruiting approximately 870 patients in Canada, Greece, Spain, Hungary, US, other European countries, Asia, Australia and South America. Collection of overall survival data is expected to complete Jul 19 [3].

Evidence based evaluations

OpdivoUrothelial cancer - adjuvant therapy

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
Aug 21Approved in US [9].
Apr 21US FDA accepts sBLA for adjuvant treatment of patients with surgically resected, high-risk muscle-invasive urothelial carcinoma, for Priority Review, and have assigned a PDUFA goal date of 3/9/21 [7].

Category

A fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor (PD-1)
In 2012 there were 9,124 cases of bladder cancer diagnosed in England. In the same year there were 4,379 deaths due to bladder cancer registered in England.
Urothelial cancer - adjuvant therapy
Intravenous infusion

Further information

Yes

Trial or other data

Jun 21PIII CheckMate 274 RCT (n=353) found longer disease-free survival with adjuvant nivolumab than placebo in intention-to-treat population (20.8 vs.10.8 months; 74.9 vs. 60.3% alive & disease-free at 6 months;HR 0.70; 98.22% CI, 0.55 to 0.90; p<0.001) and among patients with PD-L1 expression of ≥1% [8].
Sep 20CheckMate 274 study meets primary outcomes [5].
Feb 20Results from PIII CheckMate-274 trial announced. median disease-free survival of 21.0 months compared to 10.9 months with placebo, a risk reduction of 30% (Hazard Ratio [HR] 0.70, 98.31% Confidence Interval [CI]: 0.54 to 0.89). The safety profile of nivolumab was consistent with its use in studies in pts with solid tumors.[6]
Dec 19PIII CheckMate 274 study is no longer recruiting; collection of primary outcome data expected to complete Nov 20 [4].
Dec 18PIII CheckMate 274 study is recruiting [3].
Feb 16PIII CheckMate 274 study to evaluate the safety and efficacy of nivolumab compared to placebo, in participants who have undergone radical surgery for invasive urothelial cancer starts (NCT02632409). The trial will enrol approximately 640 patients in the UK, Eastern Europe, Western Europe, North America, South America, Asia and Australia. Primary outcome is disease-free survival; collection of these data is due to complete Apr 20 [1,2].

Evidence based evaluations

Opdivo Oesophageal cancer - first-line in combination with chemotherapy

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Pre-registration (Filed)
Sep 21FDA has accepted the supplemental Biologics License Application for nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatments for adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma. The FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of May 28, 2022. [10]
Aug 21Granted Early Access to Medicines (EAMS) status by the MHRA for use in combination with chemotherapy for the treatment of cancer of the stomach or oesophagus that has spread beyond the stomach or oesophagus [9].
Aug 21Filed in EU for use in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma (ESCC) [7].

Category

A fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor (PD-1).
In 2013, there were 8,784 new cases of oesophageal cancer in the UK: 5,852 (67%) in males and 2,932 (33%) in females, giving a male:female ratio of around 20:10. The crude incidence rate shows there are 19 new oesophageal cancer cases for every 100,000 males in the UK, and 9 for every 100,000 females [2].
Oesophageal cancer - first-line in combination with chemotherapy
Intravenous infusion

Further information

Yes

Trial or other data

Jun 21Results of CheckMate 648 reported at the American Society of Clinical Oncology (ASCO) meeting. Compared with chemotherapy alone, the combination of nivolumab plus chemotherapy reduced the risk of death by 26%, while the nivolumab plus ipilimumab combination reduced the risk by 22%. Both numbers are statistically significant and, as the study’s lead investigator, pointed out in a statement, are also clinically meaningful. These data were calculated at a median follow-up of 13 months. However, at 6 months, the results looked different with survival rates higher for the chemotherapy alone group vs nivolumab plus ipilimumab. The investigators are looking into possible reasons and patient characteristics to identify patients who may be more likely to die earlier with dual immuno-oncology therapy. Median survival time for patients on nivolumab plus chemotherapy was 15.4 months, vs 13.7 months for nivolumab plus ipilimumab and 9.1 months for chemotherapy alone. Improvements were more pronounced in patients whose tumours tested positive for the PD-L1 biomarker. In patients with PD-L1 expression of at least 1%, the death risk reduction rose to 46% for the nivolumab-chemo combination and to 36% for the nivolumab-ipilimumab combination [8].
Aug 20CheckMate 648 study now due to complete collection of primary outcome data in Aug 21 [6].
Dec 19CheckMate 648 study is no longer recruiting [4].
Dec 18CheckMate 648 study is recruiting [4].
Jun 17CheckMate 648 study to to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin starts (NCT03143153). 939 adults with histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of esophagus will be recruited from sites in South America, Australia, the EU (incl UK) and Russia. Collection of primary outcome data (progression-free and overall survival) is expected to complete May 20 [1,3].

Evidence based evaluations

Opdivo Oesophageal cancer - first-line in combination with ipilimumab

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Pre-registration (Filed)
Sep 21FDA has accepted the supplemental Biologics License Application for nivolumab in combination with ipilimumab as first-line treatments for adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma. The FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of May 28, 2022. [10]
Aug 21Filed in EU for use in combination with ipilimumab as first-line treatment for adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma (ESCC) [9].

Category

A fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor (PD-1)
In 2013, there were 8,784 new cases of oesophageal cancer in the UK: 5,852 (67%) in males and 2,932 (33%) in females, giving a male:female ratio of around 20:10. The crude incidence rate shows there are 19 new oesophageal cancer cases for every 100,000 males in the UK, and 9 for every 100,000 females [2].
Oesophageal cancer - first-line in combination with ipilimumab
Intravenous infusion

Further information

Yes

Trial or other data

Jun 21 Results of CheckMate 648 reported at the American Society of Clinical Oncology (ASCO) meeting. Compared with chemotherapy alone, the combination of nivolumab plus chemotherapy reduced the risk of death by 26%, while the nivolumab plus ipilimumab combination reduced the risk by 22%. Both numbers are statistically significant and, as the study’s lead investigator, pointed out in a statement, are also clinically meaningful. These data were calculated at a median follow-up of 13 months. However, at 6 months, the results looked different with survival rates higher for the chemotherapy alone group vs nivolumab plus ipilimumab. The investigators are looking into possible reasons and patient characteristics to identify patients who may be more likely to die earlier with dual immuno-oncology therapy. Median survival time for patients on nivolumab plus chemotherapy was 15.4 months, vs 13.7 months for nivolumab plus ipilimumab and 9.1 months for chemotherapy alone. Improvements were more pronounced in patients whose tumours tested positive for the PD-L1 biomarker. In patients with PD-L1 expression of at least 1%, the death risk reduction rose to 46% for the nivolumab-chemo combination and to 36% for the nivolumab-ipilimumab combination [8].
Apr 21BMS announce results of CheckMate 648 study show statistically significant benefit for primary endpoint of OS in patients whose tumours express PD-L1 and in the all-randomised patient population at the pre-specified interim analysis. Results to be shared at upcoming conference [7].
Aug 20CheckMate 648 study now due to complete collection of primary outcome data in Aug 21 [6].
Dec 19CheckMate 648 study is no longer recruiting [5].
Dec 18CheckMate 648 study is recruiting [4].
Jun 17CheckMate 648 study to to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin starts (NCT03143153). 939 adults with histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of esophagus will be recruited from sites in South America, Australia, the EU (incl UK) and Russia. Collection of primary outcome data (progression-free and overall survival) is expected to complete May 20 [1,3].

Evidence based evaluations

OpdivoHead and neck (or upper airways tract) cancers - first-line in combination with ipilimumab (in platinum eligible patients)

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Fully human Ig4 monoclonal antibody; programmed cell death-1 receptor (PDCD 1) inhibitor
UK incidence of head and neck cancers is 12.6 per 100,000 people, but there are marked regional variations. Squamous cell carcinoma is the most common type affecting 90% of people. 30-50% will have recurrent disease within 5 years of initial treatment.
Head and neck (or upper airways tract) cancers - first-line in combination with ipilimumab (in platinum eligible patients)
Intravenous infusion

Further information

Yes

Evidence based evaluations

Opdivo PD-L1-positive urothelial cancer - first-line in combination with ipilimumab

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials
2024

Category

A fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor (PD-1).
In 2012 there were 9,124 cases of bladder cancer diagnosed in England. In the same year there were 4,379 deaths due to bladder cancer registered in England.
PD-L1-positive urothelial cancer - first-line in combination with ipilimumab
Intravenous infusion

Further information

Yes

Opdivo Urothelial cancer - first-line in combination with ipilimumab in cisplatin-ineligible patients

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

A fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor (PD-1).
In 2012 there were 9,124 cases of bladder cancer diagnosed in England. In the same year there were 4,379 deaths due to bladder cancer registered in England.
Urothelial cancer - first-line in combination with ipilimumab in cisplatin-ineligible patients
Intravenous infusion

Evidence based evaluations

OpdivoPD-L1-positive non-small cell lung cancer (NSCLC) - first-line with ipilimumab

Information

Opdivo
Licence extension / variation
Bristol-Myers Squibb
Bristol-Myers Squibb

Development and Regulatory status

Filing withdrawn
Filing withdrawn
Launched
May 20Approved in US as first-line treatment for patients with metastatic NSCLC whose tumours express PD-L1≥1% [7].
Feb 20EU filing withdrawn after first round of questions to the company from the EMA: at this point, CHMP had concerns about some issues and its provisional opinion at that stage was that authorisation could not have been recommended. At the time of withdrawal, it was not considered possible to come to reliable conclusions on effectiveness due to the changes in the trial set-up during the study and inconsistencies in the results for different patient groups [6].
Jan 20US FDA accepts sBLA for priority review for nivolumab in combination with ipilimumab for first-line treatment of metastatic or recurrent NSCLC with no EGFR or ALK genomic tumour aberrations [5].
Dec 19Currently pre-registration in EU; CHMP decision expected Feb 20 [3].
May 17EU filing will be via the centralised procedure, and will be based on data from part 1b of Checkmate-227 [1].

Category

Fully human Ig4 monoclonal antibody; programmed cell death-1 receptor (PDCD 1) inhibitor
The incidence rate of lung cancer in 2006 was 72.2 per 100,000 in men and 50.8 per 100,000 in women. Lung cancer belongs to the three most common cancers in men (14.8 % of all cancers) and women (10.9% of all cancers).
PD-L1-positive non-small cell lung cancer (NSCLC) - first-line with ipilimumab
Intravenous infusion

Further information

Yes

Trial or other data

Sep 20PIII CheckMate-227 study is still recruiting with primary outcome data collection still due to complete Nov 20 [9].
May 20Three-year data from PIII CheckMate-227 trial presented at American Society of Clinical Oncology 2020 annual meeting. With a median follow-up of >3 years (43.1 months), nivolumab plus ipilimumab continued to show a survival benefit vs chemotherapy [Hazard Ratio (HR): 0.79; 95% CI: 0.67 to 0.93] among patients whose tumours expressed PD-L1 ≥1%. Three-year OS rates were 33% for nivolumab+ipilimumab, vs 22% for chemotherapy alone. Three-year PFS rate was 18% with nivolumab+ipilimumab vs 4% with chemotherapy alone. 38% of patients with PD-L1 ≥1% who responded to nivolumab+ipilimumab remained in response 3 years after the onset of the response vs 4% for chemotherapy alone. These ongoing responses were observed in the absence of treatment with nivolumab+ipilimumab, which were given for a maximum of two years per the trial protocol. In an exploratory analysis of OS by response status, 70% of patients whose tumours expressed PD-L1 ≥1% and who had a complete or partial response by six months to the nivolumab+ipilimumab combination were alive three years later, vs 39% of patients treated with chemotherapy. In an exploratory analysis of patients whose tumours expressed PD-L1 <1%, nivolumab+ipilimumab demonstrated 3-year OS rates of 34%, vs 15% for chemotherapy alone (HR: 0.64; 95% CI: 0.51 to 0.81). Additionally, 13% vs 2% of patients remained alive and progression-free from time of randomisation; and 34% vs 0% of patients with confirmed responses to treatment remained in response 3 years after the onset of the response, respectively. The safety profile of nivolumab+ipilimumab was consistent with previously reported studies in NSCLC [8]
Aug 19PIII CheckMate-227 study is still recruiting with primary outcome data collection due to complete Nov 20 [4].
Nov 18PIII CheckMate-227 study is recruiting with primary outcome data collection due to complete Jan 19 [2].
Aug 15PIII CheckMate-227 study to evaluate the efficacy of first-line nivolumab or a combination of nivolumab and ipilimuma, or a a combination of nivolumab and platinum doublet chemotherapy in patients with advanced NSCLC (squamous or non-squamous) starts (CA209-227, 2014-003630-23; NCT02477826). The open-label, randomised, parallel-assignment trial will assess improvement in progression free survival and/or overall survival compared with chemotherapy in 1 980 patients in the US, France, Germany, Italy, Spain, the Netherlands and the UK. Collection of data should complete Jan 18 [1].