LONDON, September 17, 2021 – MSD (tradename of Merck & Co., Inc., Kenilworth, N.J., USA (NYSE: MRK)) has today announced that the National Institute for Health and Care Excellence (NICE) has approved the use of pembrolizumab – MSD’s checkpoint inhibitor immunotherapy – in combination with platinum- and fluoropyrimidine-based chemotherapy as an option for untreated locally advanced unresectable (inoperable) or metastatic carcinoma of the oesophagus or HER-2 negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a combined positive score (CPS) of 10 or more.[i]
Oesophageal cancer is one of the six ”less survivable cancers”[ii] where only 21% of patients will typically live beyond a year after being diagnosed with stage 4 disease.[iii] Until this year there had been little innovation in treatment options for oesophageal cancer patients.[iv]
The pembrolizumab-chemotherapy combination was shown to extend the lives of certain patients newly diagnosed with late stage oesophageal cancer in a phase III clinical trial – reducing the risk of growth and spread of patients’ tumours compared with standard of care chemotherapy, with a manageable safety profile. Twice as many patients were alive after two years or more since they began treatment with pembrolizumab plus chemotherapy compared to those who received only chemotherapy [31% vs 15%, respectively, n=186/197, HR 0·62 (95% CI 0·49–0·78) p < 0.0001]. In patients whose tumours expressed PD-L1 with a CPS of 10 or above, the risk of their cancer continuing to grow while receiving treatment was almost halved if they received pembrolizumab plus chemotherapy (n=186), compared to chemotherapy (n=197) [HR=0.51 (95% CI, 0.41-0.65) p < 0.0001]. Overall, more patients responded to pembrolizumab plus chemotherapy (n=168/373) compared to chemotherapy alone (n=110/376) – 45.0% (95% CI, 39.9-50.2), compared to 29.3% (95% CI, 24.7-34.1), respectively. The two treatment groups also showed manageable safety profiles, with 67.6% (n=250/370) of patients treated with chemotherapy alone experiencing grade 3-5 drug-related side effects compared to 71.9% of patients who received pembrolizumab plus chemotherapy (n=266/370). Immune-related side effects were consistent with previous pembrolizumab clinical trials. [v]
Professor Was Mansoor, Consultant Medical Oncologist at The Christie NHS Foundation Trust, said:
“Advanced oesophageal cancer can be very aggressive, with limited treatment options which offer only modest benefits for patients. Improvements in treatments for these patients has been in urgent need for the last half century. This approval from NICE is a major step forward in addressing these needs – offering a new type of treatment in immunotherapy for this group of patients for the first time on the NHS.
“The KEYNOTE-590 clinical trial, which we at The Christie were a part of, showed that adding pembrolizumab to chemotherapy stopped the tumours from growing for longer than chemotherapy alone, and more than doubled the number of patients alive two years after beginning treatment. This represents a paradigm-shift in the treatment of oesophageal cancer and will likely change clinical practice for oncologists.”
Mimi McCord, Chairman of Heartburn Cancer UK, said:
“The prognosis for late stage oesophageal cancer patients is appalling. Surgery is not a viable option for these patients so treatment was severely limited. To now have pembrolizumab combined with chemotherapy for suitable patients is a welcome and significant step forward.”
There are approximately 8,000 new cases of oesophageal cancer diagnosed in England and Wales every year.[vi]Of these new cases, approximately 40% of patients are diagnosed as metastatic.[vii]Within the phase III KEYNOTE-590 trial, the proportion of patients with a PD-L1 CPS of 10 or above was around 50%.[viii]This means that around 1,600 patients across England and Wales could potentially benefit from the pembrolizumab-chemotherapy combination each year, plus any additional eligible patients who are diagnosed with locally advanced disease for whom surgery isn’t an option to remove their cancer.
David Long, Oncology Business Unit Director, MSD UK, said:
“We at MSD are delighted that NICE has approved pembrolizumab combined with chemotherapy for people with oesophageal cancer that has begun to spread. When diagnosed at stage 3 or 4, oesophageal cancer is deadly and, unlike other cancers, there has been very little innovation in treatment options for patients – contributing to the disease’s status as one of the ‘least survivable cancers’. I am proud that MSD has been able to contribute to filling this void.”
Julie Thompson, Information Manager at Guts UK, said:
“It is extremely important that people living with oesophageal cancer enjoy time with their family and this treatment could help give this valuable time. This treatment works by a different mechanism and offers another option where there are few options available. Patients will always look for hope in new treatments or trials for themselves and to benefit others going forward. Hope is a vital and powerful ingredient on a patient’s journey.“
The phase III KEYNOTE-590 clinical trial upon which this approval was based, involved 749 patients across 26 countries worldwide. In the UK, patients were enrolled from The Christie NHS Foundation Trust in Manchester, St Luke's Cancer Centre in the Royal Surrey NHS Foundation Trust, and Lothian University Hospitals NHS Trust in Edinburgh. In the trial, patients diagnosed with locally advanced oesophageal cancer who were not suitable for surgery, or those with metastatic disease, were randomly assigned to receive either pembrolizumab plus chemotherapy or to the control arm of the trial where patients received a placebo plus chemotherapy. The trial was designed to primarily assess whether the pembrolizumab-chemotherapy combination both kept patients’ tumours from getting worse and helped patients live longer, compared with chemotherapy.[ix]
The pembrolizumab-chemotherapy combinationwas granted a UK licence in July 2021 from the MHRA for the first-line treatment of patients with locally advanced ‘unresectable’ (inoperable) or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥10[x] and has been recommended by NICE shortly after, following its first appraisal committee meeting. Pembrolizumab plus chemotherapy will shortly be undergoing review by the Scottish Medicines Consortium for routine use in Scotland for this group of patients.
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Notes to editors
Data Supporting NICE Approval[xi]
The approval was based on data from KEYNOTE-590 (NCT03189719), a multicentre, randomised, double-blind placebo-controlled trial that enrolled 749 patients with locally advanced unresectable or metastatic oesophageal or GEJ carcinoma (Siewert Type I) who were not candidates for surgical resection or definitive chemoradiation. Patients were randomised (1:1) to receive either pembrolizumab (200 mg on Day 1 every three weeks) or placebo (on Day 1 every three weeks) in combination with cisplatin (80 mg/m2 on Day 1 every three weeks for up to six cycles) plus 5-FU (800 mg/m2 per day on Days 1 to 5 every three weeks, or per local standard for 5-FU administration, for up to 24 months); all study medications were administered via intravenous infusion.
Randomisation was stratified by tumour histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs. 1).
Treatment with pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression or a maximum of 24 months. Patients could be treated with pembrolizumab for up to 24 months in the absence of disease progression. Patients randomised to pembrolizumab were permitted to continue beyond the first RECIST v1.1-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least four weeks later with repeat imaging. Assessment of tumour status was performed every nine weeks.
The dual primary efficacy outcome measures were OS and PFS, as assessed by the investigator according to RECIST v1.1 in squamous cell histology, PD-L1 expression (CPS ≥10), and in all patients. Secondary efficacy outcome measures were ORR and duration of response (DOR), as assessed by the investigator according to RECIST v1.1.
In a pre-specified analysis of KEYNOTE-590 in patients whose tumours expressed PD-L1 (CPS ≥10) (n=383), pembrolizumab plus 5-FU and cisplatin showed a median OS of 13.5 months (95% CI, 11.1-15.6) versus 9.4 months (95% CI, 8.0-10.7) for patients treated with 5-FU and cisplatin alone. Additionally, pembrolizumab plus 5-FU and cisplatin showed a median PFS of 7.5 months (95% CI, 6.2-8.2) versus 5.5 months (95% CI, 4.3-6.0) for patients treated with 5-FU and cisplatin alone. Median DOR was 8.3 months (range, 1.2+ to 31.0+) with pembrolizumab plus 5-FU and cisplatin versus 6 months (range, 1.5+ to 25+) with 5-FU and cisplatin alone.
The pembrolizumab plus 5-FU and cisplatin treatment group and the 5-FU and cisplatin treatment group demonstrated comparable safety profiles overall. For patients treated with pembrolizumab plus 5-FU and cisplatin (N=370), grade 3-5 drug-related adverse event (AE) rates were 71.9% versus 67.6% for patients treated with 5-FU and cisplatin alone (N=370). For patients treated with pembrolizumab plus 5-FU and cisplatin (N=370), discontinuation rates from drug-related AEs were 19.5% versus 11.6% for patients treated with 5-FU and cisplatin alone (N=370). For patients treated with pembrolizumab plus 5-FU and cisplatin (N=370), immune-mediated AEs and infusion reactions were 25.7% versus 11.6% for patients treated with 5-FU and cisplatin alone (N=370).
Additionally, for patients treated with pembrolizumab plus 5-FU and cisplatin (N=370), rates of treatment-related AEs which led to death were 2.4% versus 1.4% for patients treated with 5-FU and cisplatin alone (N=370).
Clinicians should refer to the SmPC and Educational Risk Minimisation Materials before prescribing pembrolizumab plus chemotherapy.
The wall of the oesophagus is made of several layers of tissue. These include the inner layer (mucosa), muscle, and connective tissue. Oesophageal cancer starts in the inner lining of the oesophagus and spreads outward through the other layers.
Oesophageal cancer is the 14th most common cancer in the UK and the 7th most common cause of cancer death in the UK. There are around 8,000 new oesophageal cancer cases and around 7,000 oesophageal cancer deaths in England and Wales every year.
Pembrolizumab is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Pembrolizumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment.
Our Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At MSD Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new options to people with cancer.
For more than 125 years, MSD has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. MSD is a trade name of Merck & Co., Inc., with headquarters in Kenilworth, N.J., U.S.A. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, MSD continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.msd-uk.com and connect with us @MSDintheUK on Twitter, Instagram, LinkedIn, YouTube and Facebook.
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This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.
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You may find the Summary of Product Characteristics for pembrolizumab at: www.medicines.org.uk/emc/product/2498/smpc
Patient Information for pembrolizumab at:
Educational Risk Minimisation Materials for pembrolizumab at: www.medicines.org.uk/emc/product/2498/rmms
[i] National Institute for Health and Care Excellence (2021). Pembrolizumab with platinum-based chemotherapy for untreated advanced oesophageal cancer. Available here: https://www.nice.org.uk/guidance/indevelopment/gid-ta10613
[iii] Cancer Research UK (2018). Oesophageal cancer survival by stage at diagnosis. Available: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/oesophageal-cancer/survival#heading-Three [Accessed 25 August 2021]
[iv] National Institute for Health and Care Excellence (updated 2021). Palliative management for people with oesophageal and gastric cancer. Available: https://pathways.nice.org.uk/pathways/oesophageal-and-gastric-cancer#path=view%3A/pathways/oesophageal-and-gastric-cancer/palliative-management-for-people-with-oesophageal-and-gastric-cancer.xml&content=view-index [Accessed 14 September]
[v] Jong-Mu Sun et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. The Lancet, Volume 398, Issue 10302,
2021, Pages 759-771, https://doi.org/10.1016/S0140-6736(21)01234-4
[vi] Cancer Research UK (2017). Oesophageal cancer incidence by sex and UK country. Available: https://www.cancerresearchuk.org/health-professional/cancer-stat istics/statistics-by-cancer-type/oesophageal-cancer/incidence#heading-Zero Accessed 25 August 2021.
[vii] Cancer Research UK Early Diagnosis Data Hub (2018). Proportion Diagnosed by Stage (stacked chart). Available: https://crukcancerintelligence.shinyapps.io/EarlyDiagnosis/ [Accessed 25 August 2021]
[viii] Jong-Mu Sun et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. The Lancet, Volume 398, Issue 10302,
2021, Pages 759-771, https://doi.org/10.1016/S0140-6736(21)01234-4
[ix] Jong-Mu Sun et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. The Lancet, Volume 398, Issue 10302,
2021, Pages 759-771, https://doi.org/10.1016/S0140-6736(21)01234-4
[x] Medicines and Healthcare products Regulatory Agency (2021). SUMMARY OF PRODUCT CHARACTERISTICS – KEYTRUDA. Available: https://mhraproducts4853.blob.core.windows.net/docs/bf11c53380abd4b4232123f376ed756466b4385b
[xi] Kato K, Sun J-M, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 Study. Slide deck presented at: European Society for Medical Oncology (ESMO) Virtual Congress; September 19-21, 2020.
[xii] Cancer Research UK. What is oesophageal cancer? https://www.cancerresearchuk.org/about-cancer/oesophageal-cancer/about. [Accessed July 2021]
[xiii] Cancer Research UK. Oesophageal cancer statistics. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/oesophageal-cancer#heading-One. [Accessed July 2021]
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