UK Medicines and Healthcare Products Regulatory Agency issues an Early Access to Medicines Scheme positive scientific opinion for Avelumab as First-Line Maintenance Treatment for patients with Locally Advanced or Metastatic Urothelial Carcinoma

Merck and Pfizer announced today that the UK Medicines and Healthcare Products Regulatory Agency (MHRA) has issued an Early Access to Medicines Scheme (EAMS) positive scientific opinion for avelumab for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy.¹ With this approval, the MHRA have confirmed a positive benefit-risk of avelumab in this patient population under EAMS.

 

The positive scientific opinion approval is based on results from the Phase III JAVELIN Bladder 100 study, which demonstrated a significant 7.1-month improvement in median overall survival (OS) with avelumab as first-line maintenance plus best supportive care (BSC) compared with BSC alone: 21.4 months (95% CI: 18.9 to 26.1) vs. 14.3 months (95% CI: 12.9 to 17.9).^1,2 This statistically significant improvement in OS represents a 31% reduction in the risk of death in the overall population (HR 0.69; 95% CI: 0.56 to 0.86; 2-sided P=0.001).² OS was measured from the time of randomisation, after patients were treated with four to six cycles of gemcitabine plus cisplatin or carboplatin over a period of approximately four months.² The JAVELIN Bladder 100 interim analysis results were presented at the ASCO 2020 Virtual Scientific Meeting.³

                                                                                

Platinum-based chemotherapy is currently the first-line standard of care for eligible patients with advanced disease based on high initial response rates. However, most patients will ultimately experience disease progression within nine months of initiation of treatment^4,5 and only 5% of patients with metastatic disease will live longer than five years.⁶

 

Dr Mike England, Medical Director, Merck UK & Ireland said: “Bladder cancer is the eleventh most common cancer in the UK, with urothelial carcinoma being the most common type of bladder cancer, accounting for 90 percent of all cases. However, treatment options are limited and survival rates are poor. Therefore, we are delighted by the MHRA’s positive decision to provide early access to avelumab, as there is a significant unmet need in this therapy area for new treatment options for these patients. We believe this is a major advance in the existing standard of care and will improve patient outcomes.”

 

Dr Olivia Ashman, Oncology Medical Director, Pfizer UK said: “Avelumab is the first immunotherapy to demonstrate in a clinical trial a statistically significant improvement in overall survival as a first-line treatment for patients with advanced urothelial carcinoma. It is our greatest hope that our maintenance approach can eventually become part of routine clinical practice and significantly prolong survival for these patients.”

 

Avelumab is now available in the UK through the EAMS scheme for the first-line maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy.¹

 

Avelumab is not licensed in the UK for locally advanced or metastatic urothelial carcinoma and a marketing authorisation application for this indication is currently under review by the European Medicines Agency (EMA).

 

Notes to Editors

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse events.  Reporting forms and information can be found at mhra.gov.uk/yellowcard. Adverse events should also be reported to Merck Serono Limited on 0208 818 7373 (email: medinfo.uk@merckgroup.com).

 

About the JAVELIN Bladder 100 Study

JAVELIN Bladder 100 (NCT02603432) is a Phase III, multicentre, multinational, randomised, open-label, parallel-arm study investigating first-line maintenance treatment with avelumab plus BSC versus BSC alone in patients with locally advanced or metastatic UC that did not progress with first-line platinum-containing chemotherapy as per RECIST v1.1. A total of 700 patients were randomly assigned to receive either avelumab (10 mg/kg intravenous infusion every 2 weeks) plus BSC (n=350) or BSC alone (n=350). The primary endpoint was OS in the two primary populations of all randomised patients and patients with PD-L1+ tumours defined by the Ventana SP263 assay. Secondary endpoints included progression-free survival, anti-tumour activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers and patient-reported outcomes in the two primary populations. All primary and secondary endpoints are measured from the time of randomisation, after completion of four to six cycles of chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded.^2,3

 

In PD-L1+ patients (n=358, 51%), the risk of death was reduced by 44% in the avelumab arm versus the control arm (HR 0.56; 95% CI: 0.40 to 0.79; 2-sided p-value <0.001). Consistent results were observed across the pre-specified subgroups of complete or partial response versus stable disease to first-line chemotherapy.^2,3 In an exploratory analysis of patients with PD L1 negative tumours (n=271, 39%), the OS hazard ratio was 0.85 (95% CI: 0.62, 1.18).²

 

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient receiving avelumab plus BSC. Serious adverse reactions occurred in 28% of patients receiving avelumab plus BSC. Serious adverse reactions in ≥1% of patients included urinary tract infection (including kidney infection, pyelonephritis, and urosepsis) (6.1%), pain (including abdominal, back, bone, flank, extremity, and pelvic pain) (3.2%), acute kidney injury (1.7%), haematuria (1.5%), sepsis (1.2%), and infusion-related reaction (1.2%). The most common adverse reactions (≥20%) in patients receiving avelumab plus BSC were fatigue, musculoskeletal pain, urinary tract infection, and rash.²

 

About the Early Access to Medicines Scheme (EAMS)

The Early Access to Medicines Scheme (EAMS) aims to provide earlier availability of promising new unlicensed medicines to UK patients with high unmet clinical need. A positive scientific opinion is issued by the Medicines and Healthcare Products Regulatory Agency (MHRA) if the criteria for the EAMS are fulfilled, which includes demonstrating a positive benefit risk balance (quality, safety and efficacy assessment) and the ability of the company to supply a medicine according to a consistent quality standard.⁷ A full assessment of the quality, safety and efficacy of the medicine is conducted by the MHRA’s assessment teams, including pharmacists, toxicologists, statisticians, pharmacokinetic and medical assessors. EAMS medicines are unlicensed medicines.⁷ The term ‘unlicensed medicine’ is used to describe medicines that are used outside the terms of their UK licence or which have no licence for use in the UK. GMC guidance on prescribing unlicensed medicines can be found at: https://www.gmc-uk.org/ethical-guidance/ethical-guidance-for-doctors/prescribing-and-managing-medicines-and-devices/prescribing-unlicensed-medicines. The opinion is based on assessment of the information supplied to the MHRA on the benefits and risks of the medicine. As such this is a scientific opinion and should not be regarded as a licensed indication or a future commitment by the MHRA to licence such a medicine.⁷ The scheme is voluntary and the opinion from MHRA does not replace the normal licensing procedures for medicines.⁷

 

About Urothelial Carcinoma (UC)

Bladder cancer is the eleventh most common cancer in the United Kingdom (UK), accounting for 3% of all new cancer cases (10,233 cases [16.6 per 100,000 population] in 2017).⁸ Bladder cancer consists of urothelial carcinoma (UC) and non-urothelial cancers, of which UC is the most common type, accounting for >90% of cases in the UK.⁸ UC originates in the urothelium or transitional epithelium, and is caused by genetic alterations in urothelial cells.⁹ As patients with early UC can have no apparent symptoms, cases may be diagnosed as advanced/metastatic (Stage IV) disease (between 15.4% and 17.8% of cases in the UK).^6,11,12 Bladder cancer is the ninth most common cause of cancer deaths in the UK, with 5,612 deaths in 2017 (3% of all cancer deaths), corresponding to age-standardised mortality rates of 14.8 and 5.0 per 100,000 population for men and women, respectively.¹³ Prognosis is associated with stage at diagnosis, and survival is especially poor for patients with locally advanced or metastatic UC.  

 

About Avelumab

Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, Avelumab has been shown to release the suppression of the T cell-mediated anti-tumour immune response in preclinical models.^14-16 In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialise Avelumab.

 

Bavencio(Avelumab) Approved Indications

The European Commission has authorised the use of avelumab in combination with axitinib for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). In September 2017, the European Commission granted conditional marketing authorisation for avelumab as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (MCC).

 

Avelumab Safety Profile from the EU Summary of Product Characteristics (SmPC)

The special warnings and precautions for use for avelumab monotherapy include infusion-related reactions, as well as immune-related adverse reactions that include pneumonitis and hepatitis (including fatal cases), colitis, pancreatitis (including fatal cases), myocarditis (including fatal cases), endocrinopathies, nephritis and renal dysfunction, and other immune-related adverse reactions. The special warnings and precautions for use for avelumab in combination with axitinib include hepatotoxicity.

 

The SmPC list of the most common adverse reactions with avelumab monotherapy in patients with solid tumours includes fatigue, nausea, diarrhoea, decreased appetite, constipation, infusion-related reactions, weight decreased and vomiting. The list of most common adverse reactions with avelumab in combination with axitinib includes diarrhoea, hypertension, fatigue, nausea, dysphonia, decreased appetite, hypothyroidism, cough, headache, dyspnoea, and arthralgia.

 

About programmed death-ligand 1 (PD-L1)

PD-L1 is a protein expressed on the surface of cells, which binds to PD-1 receptors on T cells of the immune system to stop them from attacking them. Some tumour cells also have PD-L1 proteins on their surface (‘PD-L1 positive’ status), preventing the immune T cells from recognising and attacking them. Avelumab (MSB0010718C) is a human antibody (calculated molecular weight of 143,832 Dalton) of the immunoglobulin G1 (IgG1) isotype that specifically binds to PD-L1 on tumour cells and blocks it from binding to the PD-1 receptors on T cells, allowing the immune system T cells to recognise and kill the cancer cells.

 

 

About the Merck-Pfizer Alliance

Immuno-oncology is a top priority for Merck and Pfizer. The global strategic alliance between Merck and Pfizer enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an anti-PD-L1 antibody initially discovered and developed by Merck. The immuno-oncology alliance is jointly developing and commercialising avelumab. The alliance is focused on developing high-priority international clinical programs to investigate avelumab as a monotherapy as well as combination regimens, and is striving to find new ways to treat cancer.

 

About Merck

Merck, a leading science and technology company, operates across healthcare, life science and performance materials. Around 52,000 employees work to make a positive difference to millions of people’s lives every day by creating more joyful and sustainable ways to live. From advancing gene editing technologies and discovering unique ways to treat the most challenging diseases to enabling the intelligence of devices – Merck is everywhere. In 2019, Merck generated sales of €16.2 billion in 66 countries.

 

Scientific exploration and responsible entrepreneurship have been key to Merck’s technological and scientific advances. This is how Merck has thrived since its founding in 1668. The founding family remains the majority owner of the publicly listed company. Merck holds the global rights to the Merck name and brand. The only exceptions are the United States and Canada, where the business sectors of Merck operate as EMD Serono in healthcare, MilliporeSigma in life science, and EMD Performance Materials.

 

Pfizer: Breakthroughs that change patients’ lives

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world's best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. In the UK, Pfizer has its business headquarters in Surrey and is a major supplier of medicines to the NHS. To learn more about our commitments, please visit us at www.pfizer.co.uk or follow us on Twitter (@Pfizer_UK) and Facebook (@PfizerUK).

 

Forward-looking statements

This release contains forward-looking information about avelumab, including a potential indication for first-line maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma in the EU for avelumab. Such statements involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. The Merck-Pfizer Alliance disclaims any obligation to update these forward-looking statements contained in this release as the result of new information or future events or developments.

 

References

1. Early Access to Medicines Scientific Opinion - Public Assessment Report – Avelumab (EAMS number 11648/0003) Available at: https://www.gov.uk/government/publications/early-access-to-medicines-scheme-eams-scientific-opinion-avelumab-in-the-treatment-of-bladder-cancer. Accessed September 2020.
2. Pfizer Inc. Interim Clinical Study Report: JAVELIN Bladder 100/B9991001, 2020.
3. Powles T, et al. “Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma: JAVELIN Bladder 100 phase III results.” 2020 ASCO Annual Meeting, 31 May 2020, oral presentation (virtual) Abstract LBA1. Conference Presentation.
4. Bukhari N, et al. Update on the treatment of metastatic urothelial carcinoma. Scientific World Journal. 2018;2018:5682078.
5. Von der Maase H, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. Journal of Clinical Oncology. 2005;23(21):4602-4608.
6. Queen's University Belfast. Cancer incidence, prevalence and survival statistics for Northern Ireland: 1993-2017. Bladder cancer (C67), 2019.
7. Early access to medicines scheme (EAMS): how the scheme works. Available at https://www.gov.uk/government/publications/early-access-to-medicines-scheme-eams-how-the-scheme-works. Accessed September 2020.
8. Cancer Research UK. Bladder cancer incidence statistics. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer/incidence. Accessed September 2020.
9. Boustead GB, Fowler S, Swamy R, Kocklebergh R, Hounsome L. Stage, grade and pathological characteristics of bladder cancer in the UK: British Association of Urological Surgeons (BAUS) urological tumour registry. BJU Int 2014; 113(6): 924-30.
10. Zhao M, He XL, Teng XD. Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview. Chin J Cancer Res 2016; 28(1): 92-8.
11. National Cancer Registration and Analysis Service. TNM stage group by CCG by tumour type for 10+3 tumour types, 2012-2017, 2019.
12. Welsh Cancer Intelligence and Surveillance Unit. Cancer incidence in Wales, 2001-2017, 2019.
13. Cancer Research UK. Bladder cancer mortality statistics. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer/mortality. Accessed September 2020.
14. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21(3):231-237.
15. Dahan R, Sega E, Engelhardt J, et al. FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell. 2015;28(3):285-295.
16. Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. 2015;3(10):1148-1157.