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

OpdivoOesophageal squamous cell carcinoma, 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 squamous cell carcinoma, 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 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 with cabozantinib
Intravenous

Further information

Yes

Trial or other data

Feb 22Two-year follow-up data from PIII CheckMate -9ER trial improvements in median OS of 37.7 months vs. 34.3 months for Sutent. PFS benefits for the combination were 16.6 months vs. 8.3 months with Sutent and ORR was 55.7% vs. 28.4%. The median DoR of 23.1 months vs. Sutent’s 15.1 months’ and CR was 12.4% vs. 5.2% for Sutent.[13]
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 - second-line 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 - second-line 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

SMC

OpdivoUnresectable pleural mesothelioma - first-line 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 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

SMC

OpdivoAdvanced gastric cancer - first-line with chemotherapy

Information

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

Development and Regulatory status

Launched
Launched
Launched
October 2021
Oct 21New indication approved in the UK by the MHRA for use 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 [14].
Oct 21Approved in EU [13].
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].
Aug 21MHRA grants EAMS status for use in combination with fluoropyrimidine- and platinum-based combination chemotherapy for the first-line treatment of adult patients with HER2 negative (or undetermined) advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma [12].
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 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 monotherapy

Information

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

Development and Regulatory status

Launched
Launched
Launched
May 22MHRA approves a new indication of use as monotherapy for the adjuvant treatment of adults with muscle invasive urothelial carcinoma (MIUC) with tumour cell PD-L1 expression ≥ 1%, who are at high risk of recurrence after undergoing radical resection of MIUC [13].
Apr 22Approved in the EU for the adjuvant treatment of adults with muscle-invasive urothelial carcinoma with tumor cell PD-L1 expression ≥1% who are at a high risk of recurrence after undergoing radical resection [12]
Feb 22Recommended for EU approval by CHMP – the extension to the existing indication is use “ as monotherapy is indicated for the adjuvant treatment of adults with muscle invasive urothelial carcinoma (MIUC) with tumour cell PD-L1 expression ≥ 1%, who are at high risk of recurrence after undergoing radical resection of MIUC” [11].
Aug 21Approved in US for adjuvant treatment of patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC [9].
Jun 21Currently pre-registration in the EU for a licence extension to include adjuvant treatment of adults with muscle invasive urothelial carcinoma (MIUC) who are at high risk of recurrence after undergoing radical resection of MIUC [10].
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 monotherapy
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 with chemotherapy

Information

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

Development and Regulatory status

Launched
Launched
Launched
May 22FDA has approved nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy as a first-line treatment for adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) regardless of PD-L1 status [15]
May 22MHRA approves a new indication of use in combination with fluoropyrimidine- and platinum-based combination chemotherapy for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1% [14].
Apr 22Approved in EU in combination with fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) with tumor cell PD-L1 expression ≥ 1% [13]
Feb 22Recommended for EU approval by CHMP – the extension to the existing indication is use “in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1%” [12].
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 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 with chemotherapy
Intravenous infusion

Further information

Yes

Trial or other data

Feb 22Results of CheckMate 648 reported in the NEJM [11].
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 with ipilimumab

Information

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

Development and Regulatory status

Launched
Launched
Launched
May 2022
May 22FDA has approved nivolumab in combination with ipilimumab as a first-line treatment for adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) regardless of PD-L1 status [15]
May 22Approved in UK. New full indication "OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1%." [14].
Apr 22 Approved in EU in combination with ipilimumab for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) with tumor cell PD-L1 expression ≥ 1% [13]
Feb 22Recommended for EU approval by CHMP – the extension to the existing indication is use “in combination with ipilimumab is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1%” [12].
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 with ipilimumab
Intravenous infusion

Further information

Yes

Trial or other data

Feb 22Results of CheckMate 648 reported in the NEJM [11].
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

OpdivoEarly stage IB−IIIA non-small cell lung cancer (NSCLC) - neoadjuvant therapy with chemotherapy

Information

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

Development and Regulatory status

None
Pre-registration (Filed)
Launched
Mar 22BMS announces that EMA as validated its type II variation application for nivolumab) in combination with chemotherapy for the neoadjuvant treatment of patients with resectable stage IB to IIIA non-small cell lung cancer (NSCLC), based on results from the CheckMate -816 trial. Validation of the application confirms the submission is complete and begins the EMA’s centralized review procedure [12]
Mar 22Approved 4 months ahead of scheduled date in US for use in combination with platinum-doublet chemotherapy for adult patients with resectable NSCLC in the neoadjuvant setting. The review was conducted under Project Orbis, in collaboration with the UK MHRA, the Australian Therapeutic Goods Administration (TGA) and Health Canada. The review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment [10,11].
Feb 22BMS announce the U.S. FDA has accepted the supplemental Biologics License Application for nivolumab plus chemotherapy for the neoadjuvant treatment of patients with resectable NSCLC based on results from the CheckMate -816 trial. The FDA has granted the application Priority Review status and assigned a PDUFA goal date of July 13 2022 [9].
May 20The company has advised NICE that they are no longer pursuing a Marketing Authorisation Application for neoadjuvant treatment of early NSCLC in combination with ipilimumab at this time. They are pursuing use with chemotherapy [5].

Category

Fully human Ig4 monoclonal antibody; programmed cell death-1 receptor (PDCD 1) inhibitor
There are around 47,200 new lung cancer cases in the UK every year, around 130 every day (2014-2016). Lung cancer is the 3rd most common cancer in the UK, accounting for 13% of all new cancer cases (2016) [1].
Early stage IB−IIIA non-small cell lung cancer (NSCLC) - neoadjuvant therapy with chemotherapy
Intravenous infusion

Further information

Yes

Trial or other data

Jun 22In a post hoc analysis of PIII CHECKMATE-816 RCT, among early NSCLC patients who took nivolumab and chemotherapy before surgery and had no trace of tumour in resected tissue, the risk of disease recurrence or death dropped by 82% compared with those who still had traces of tumour at surgery. The result is very suggestive of an association between achieving pathological complete response (pCR) and having a better outcome in event-free survival [14].
Apr 22Results of PIII CHECKMATE-816 RCT (n=505) reported in NEJM [13].
Mar 22US approval was based on efficacy results from PIII CHECKMATE-816. Median event-free survival (EFS) was 31.6 months (95% CI: 30.2, not reached) in the nivolumab plus chemotherapy arm and 20.8 months (95% CI: 14.0, 26.7) for those receiving chemotherapy alone. The hazard ratio was 0.63 (97.38% CI: 0.43, 0.91; p=0.0052). The pathologic complete response (pCR) rate was 24% (95% CI: 18.0, 31.0) in the nivolumab plus chemotherapy arm and 2.2% (95% CI: 0.6, 5.6) in the chemotherapy alone arm. The most common adverse reactions (incidence ≥20%) occurring in patients were nausea, constipation, fatigue, decreased appetite, and rash. The addition of nivolumab to chemotherapy did not result in more frequent delays or cancellations of surgery. The median lengths of hospital stays following definitive surgery and the rates of adverse reactions identified as surgical complications were similar for patients in both arms of the trial [10].
Dec 21No update posted on US trial registry for PIII CheckMate 816 [8].
Nov 21Interim analysis of PIII CheckMate 816 shows nivolumab + chemotherapy showed significant improved event-free survival vs chemotherapy alone. [7]
Apr 21Company announces data from CheckMate-816 trial showed three cycles of nivolumab plus chemotherapy significantly improved pathologic complete response in pts with resectable stage Ib to IIIa non-small cell lung cancer (24%) vs chemotherapy alone (2.2%). It had a tolerable safety profile, and no new safety signals were observed. Grade 3–4 treatment-related adverse events were reported in 34% vs. 37% in the nivolumab plus chemotherapy group vs. chemotherapy. Surgery was rarely cancelled due to adverse events, only affecting two patients in each arm of the trial. [6]
Oct 20BMS announce PIII Checkmate 816 trial (n=358) meets primary endpoint of pathologic complete response in patients who received Opdivo plus chemotherapy before surgery [4].
Feb 20PIII neodjuvant CheckMate 816 study has three arms - nivolumab plus ipilimumab vs. nivolumab plus platinum-doublet chemo vs. chemo. It also has multiple primary endpoints; the first primary completion date of Pathological Complete Response is anticipated to be reached Apr 20. The completion date for all primary outcome measures is expected May 2023 [3].
Jan 17PIII CheckMate 816 trial to evaluate the safety and efficacy of nivolumab and ipilimumab compared to chemotherapy, in the treatment of early stage non-small cell lung cancer (NCT02998528). The primary endpoint is major pathological response (MPR) rate and secondary response includes event-free survival, overall survival and complete pathological response. 326 patients will be recruited in countries such as the US, Canada, France, Hungary, Spain (not UK). Collection of primary outcome data is expected to complete Apr 20 [2].

Evidence based evaluations

Opdivo PD-L1-positive urothelial cancer - first-line 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 with ipilimumab
Intravenous infusion

Further information

Yes

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

Evidence based evaluations