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21st October 2024
Consultant clinical oncologist Dr John Conibear speaks to Kathy Oxtoby about the changing treatment landscape of non-small cell lung cancer, durvalumab’s latest approval by the MHRA for the resectable form, and his hopes for the future management of the condition.
The UK has one of the worst five-year survival rates for lung cancer in Europe, and new treatment options are urgently needed to offer patients a better chance of long-term survival.
This July, the Medicines and Healthcare products Regulatory Agency (MHRA) granted marketing authorisation in Great Britain for durvalumab (brand name Imfinzi) for the treatment of adults with resectable non-small cell lung cancer (rNSCLC).
This anti-programmed death ligand 1 monoclonal antibody is now indicated in combination with platinum-based chemotherapy as a neoadjuvant treatment before surgery, followed by durvalumab as adjuvant monotherapy after surgery, in those who have no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements or aberrations.
This joins durvalumab’s existing indication for the treatment of adult patients with locally advanced, unresectable NSCLC, meaning the drug is now approved in Great Britain for both resectable and unresectable forms.
The latest approval from the MHRA is based on positive data from the AEGEAN Phase III trial in rNSCLC, which showed that durvalumab-based treatment before and after surgery reduced the risk of recurrence, progression events or death by 32% versus neoadjuvant chemotherapy alone.
Dr John Conibear is a consultant clinical oncologist and clinical director for thoracic oncology at Barts Cancer Centre, London, and oncology lead for the National Lung Cancer Audit (NLCA). He says the AEGEAN Phase III trial represents ‘a promising step forward in the management of patients with resectable lung cancer’.
‘The trial demonstrates that the combination of immunotherapy with traditional chemotherapy, in both the neoadjuvant and the adjuvant setting improves pathological response rates and disease-free survival,’ he says. ‘That could potentially lead to better long-term outcomes and increased survival rates for these resectable patients.’
The use of durvalumab in combination with chemotherapy for treating rNSCLC is still pending approval from the National Institute of Health and Care Excellence (NICE) and is currently not recommended by the organisation in its initial draft guidance, which has been out for consultation and is now being considered by the committee.
Dr Conibear says the results of the trial show that ‘the addition of this drug does seem to reduce the relapse of patients with lung cancer in this resectable setting, and it increases the rates of complete responses’. For him, there is ‘clearly synergism between chemotherapy and immunotherapy in this setting’, and Dr Conibear is in favour of durvalumab being available on the NHS for routine use in this patient group.
‘From a clinician’s point of view, I want to do what’s best for my patients, and it’s a shame if durvalumab is considered unsuitable on the basis of financial availability rather than clinical benefit,’ he says.
Whether NICE changes its current stance, only time will tell.
Dr Conibear’s insight into the importance and value of durvalumab for lung cancer patients comes from more than 20 years of working in oncology, including thoracic oncology.
It was during the early part of his training as a junior doctor in 2003 that he chose this specialism. ‘As a medical specialty, oncology is dynamic, and always seems to evolve, because of the nature of the treatment we can offer patients,’ says Dr Conibear.
Patients with cancer require ‘a compassionate and thoughtful approach to their care’, he says. ‘Oncology fuses both the science and compassion of medical care into one specialty, which I find attractive.’
His particular interest in thoracic oncology was sparked towards the end of his oncology training. ‘I was involved in clinical trials looking at improving outcomes in patients with locally advanced lung cancer, and through that I began to appreciate the complexities in diagnosing and treating lung cancers.’
During the last decade since Dr Conibear became a consultant, the treatment landscape of NSCLC, in both the UK and Europe, has evolved significantly. ‘That’s been driven by advancements in targeted therapies, immunotherapy and the more personalised approach to patient care,’ he says.
Understanding the molecular biology of NSCLC has made a huge difference, with clinicians ‘now able to identify specific gene mutations, which allows us to use specific targeted therapies, and these offer better efficacy and often fewer side effects compared to traditional chemotherapy’.
Then there is the advent and evolution of immunotherapy. ‘This has revolutionised NSCLC treatment, both in the early, locally advanced and metastatic settings. This has become the standard of care for many patients with NSCLC, and led to significant improvements in survival rates,’ he says.
‘Through these advances in treatment, and the combination of these treatments, whereby you create a personalised multimodality approach, we’ve seen improvements in patient survival. We see patients not only cured of their disease, but also living with their disease for much longer than we ever saw in the past,’ he adds.
However, in the UK, what is clear from ongoing data analysis – such as the National Lung Cancer Audit’s ‘State of the Nation 2024’ report – is that much more needs to be, and potentially can be, done. ‘There is still an unmet need when it comes to treating patients with both early and advanced lung cancer in regard to the number of patients who don’t seem to be receiving optimal cancer-driven care’, Dr Conibear says.
‘We’re trying to explore the reasons behind that – the potential biases and inequalities that are causing these differences to occur, both within regions of the UK, and also the UK compared to our European brothers and sisters.’
The AEGEAN Phase III trial is evolving the treatment landscape further, says Dr Conibear.
Durvalumab has become ‘a cornerstone in the management of unresectable locally advanced NSCLC’, and ‘the AEGEAN trial potentially, as the data matures, could reveal durvalumab to have a similar role in resectable patients,’ he suggests.
Until now, treatment has been focused on just the neoadjuvant use of chemoimmunotherapy in resectable patients before they have surgery.
‘What this trial demonstrates is expanding that treatment beyond surgery, so that patients then come back after surgery to receive further immunotherapy,’ Dr Conibear says. ‘Essentially, we’re intensifying the patient’s treatment to see an improved long-term outcome – we hope.’
Dr Conibear would like durvalumab to ‘translate into a meaningful improvement in long-term survival and push the bar higher in what we consider to be standard outcomes for these patients’, and he believes there is certainly potential for this to happen.
While clinicians and multidisciplinary teams (MDTs) working in lung cancer care understand the role of durvalumab in treating patients with unresectable lung cancer, Dr Conibear says ‘there is a knowledge gap now for people in those teams to understand the role of durvalumab in that resectable patient group, following the results of the AEGEAN trial’.
If NICE’s final ruling is in favour of durvalumab for treating rNSCLC ‘then there will be a need to target education towards these clinicians to expand that knowledge base’, he says. This could include educational initiatives such as workshops, seminars and webinars focused on the role of durvalumab in non-small cell lung cancers. And guidelines and protocols will need to be updated to reflect these evolutions of approaches to patient care.
Ongoing professional development should be encouraged, ensuring that the MDT attends training sessions to stay up to date with the latest practices and treatment recommendations, he says.
As patients are becoming increasingly complex in terms of the personalised approach required for their care, Dr Conibear sees a greater need for case discussions and the sharing of ‘knowledge and experience between multidisciplinary team meetings’. There is also a role for direct peer-to-peer learning and encouraging experienced oncologists to share insights through mentorship programmes or peer-led discussions, he adds.
‘And what mustn’t be forgotten is the dissemination of information to patients, arming them with the knowledge of what’s available, and what’s potentially suitable for them so they can also be an advocate for their own care,’ he says. ‘Patient education and advocacy are also important to dispel the limitations on what we offer our patients.’
As to further developments in the management of NSCLC beyond durvalumab, attention is turning to new mutations, which Dr Conibear says are ‘potentially druggable’ and ‘could form further aspects of that personalised approach to patient care in the resectable and unresectable lung cancer setting’.
Then there are advances in diagnostics, in particular liquid biopsies – the ability to collect and analyse circulating tumour DNA and circulating tumour cells. ‘We can use these measures to understand resistance patterns to treatment so that we potentially have a more dynamic and adaptive treatment plan that we can offer our patients,’ he says.
‘We can see at a microscopic level whether the treatment is working or not, so that we can make clinical management decisions more quickly than we have done historically.’
Dr Conibear also highlights the integration of artificial intelligence and machine learning into clinical practice. ‘These tools are capable of analysing large data sets, including imaging, genomic data and clinical data,’ he says. ‘It seems with the right algorithms you’re capable of predicting patient outcomes and responses to therapy, and possibly even unwanted adverse events or effects more accurately. This technology could help us to enhance this personalised treatment approach to patients.’
And with the AEGEAN trial showing the benefit of immunotherapy and chemotherapy before, and now also after surgery, ‘it’s demonstrating, again, the importance of a multimodality approach to these patients’, Dr Conibear says. ‘As we move on, we’ll see the potential of other treatments added into this approach.’
It’s no secret that Dr Conibear would like durvalumab to be available to real-world rNSCLC patients who are eligible for the treatment. ‘And it would be great to not see it as the final step, but a stepping stone in terms of improving things further for these patients,’ he says.
‘Ultimately, I hope durvalumab plays a pivotal role in advancing lung cancer treatment, thereby contributing to higher survival rates, improved quality of life and pushing the bar higher on the idea of a personalised approach to these patients’ care. I’m optimistic we’ll see that.’
Update:
On 6 December 2024, AstraZeneca announced that NICE has published final draft guidance recommending durvalumab in combination with platinum-based chemotherapy as a neoadjuvant treatment before surgery, followed by durvalumab as adjuvant monotherapy after surgery for the treatment of adults with rNSCLC (tumours ≥4 cm and/or node-positive) and no known EGFR mutations or ALK rearrangements, for NHS use in England and Wales.
25th July 2024
The UK’s medicines regulator has approved the use of semaglutide (brand name Wegovy) for cardiovascular prevention in obese and overweight patients with established cardiovascular disease (CVD).
The Medicines and Healthcare products Regulatory Agency (MHRA) granted the authorisation on Tuesday this week, making it the first weight loss drug to be prescribed as a preventative treatment for cardiovascular events.
The drug, supplied by Novo Nordisk, is already approved and recommended by the National Institute for Health and Care Excellence for use as a treatment for obesity, alongside lifestyle changes and support.
It can now be used to reduce the risk of overweight and obese adults suffering events such as cardiovascular death, non-fatal heart attacks and non-fatal strokes, in people with established cardiovascular disease and a body mass index (BMI) higher or equal to 27 kg/m2.
The MHRA has granted this authorisation based on data from a clinical trial which found that semaglutide reduces the incidence of major adverse cardiovascular events (MACE) by 20% when compared with a placebo.
There were over 17,600 participants in the multi-national, double-blind trial who were randomly assigned either Wegovy or a placebo.
Novo Nordisk first revealed headline figures from this study a year ago, with full results since published in the New England Journal of Medicine.
At the time, the company said it expected to file for regulatory approvals for a label indication expansion of semaglutide 2.4mg during 2023.
MHRA deputy director of innovative medicines Shirley Hopper said the safety of Wegovy will be kept ‘under close review’ but that the MHRA is ‘assured that the appropriate regulatory standards of safety, quality and effectiveness for the approval of this medicine have been met.
‘This treatment option that prevents heart disease and strokes is an important step forward in tackling the serious health consequences of obesity.’
Professor John Wilding, professor in the department of cardiovascular medicine at the University of Liverpool, said the approval is ‘good news’ based on evidence from the trial.
He said: ‘Semaglutide is already approved for treatment of obesity, but despite a favourable NICE appraisal since 2023, many people living with obesity in England and Wales are still unable to access this treatment due to funding restrictions and limited availability of NHS services for the treatment of obesity.
‘It is hoped that this new widened indication will help funders of services to understand the benefits of treatment for people living with obesity, and provide appropriate support for clinical services to provide treatment.’
Dr Martin White, associate professor in metabolic medicine at the University of Surrey, said that data from the trial also showed that there was ‘no difference in cardiovascular outcomes in those who did or did not achieve 5% weight loss’ after 20 weeks of semaglutide.
‘This hints that weight loss per se may not be a crucial factor, but any benefit may instead relate to benefits on blood pressure, glucose and body inflammation,’ he suggested.
Semaglutide, which is a GLP-1 receptor agonist, was launched on the NHS as a weight-loss drug in September.
The drug is available via specialist NHS weight management services for people who meet NICE criteria, or privately through a registered healthcare professional, but has been in short supply due to global demand.
A recent study indicated that weight loss in patients on semaglutide can be sustained for up to four years and that the drug can cut CVD risk.
And further research has shown that semaglutide could be beneficial in helping to treat patients with type 2 diabetes and obesity-related heart failure.
A version of this article was originally published by our sister publication Pulse.
19th July 2024
The AKT inhibitor capivasertib (brand name Truqap) has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) for treating eligible patients with advanced breast cancer.
Capivasertib is indicated in combination with the hormone therapy fulvestrant for treating advanced hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced breast cancer with specific biomarker alterations (PIK3CA, AKT1 or PTEN) following recurrence or progression on or after an endocrine-based regimen.
This follows the marketing authorisation of capivasertib by the European Commission (EC) in June 2024 for the same indication.
The first-in-class drug is taken orally at a starting dose of 400 mg twice a day for four days followed by three days of rest, then repeated.
The MHRA and EC approvals were based on the results of the phase 3, randomised, double-blind CAPItello-291 trial, which included 708 patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer. Of these, 289 patients (40.8%) had AKT pathway alterations.
Patients were randomised to receive either capivasertib or a placebo, both in combination with fulvestrant. The dual primary endpoint was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway–altered (PIK3CA, AKT1, or PTEN) tumours.
In the overall population, the median progression-free survival was 7.2 months in the capivasertib–fulvestrant group, as compared with 3.6 months in the placebo–fulvestrant group (HR 0.60; 95% CI, 0.51 to 0.71; P<0.001).
In the AKT pathway–altered population, the median progression-free survival was 7.3 months in the capivasertib–fulvestrant group, as compared with 3.1 months in the placebo–fulvestrant group (HR 0.50; 95% CI, 0.38 to 0.65; P<0.001).
Potential side effects of capivasertib included high blood sugar, diarrhoea, rash and other skin drug reactions, urinary tract infection, low level of haemoglobin in blood, loss of appetite, nausea, vomiting, mouth sores or ulcers with gum inflammation, itching, and tiredness.
The most frequent adverse events of grade 3 or higher in patients receiving capivasertib–fulvestrant were rash (12.1% vs in 0.3% of those receiving placebo–fulvestrant) and diarrhoea (9.3% vs 0.3%).
Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo.
Professor Nicholas Turner, professor of molecular oncology at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, who led the CAPItello-291 trial, said the MHRA approval is ‘wonderful development in the treatment of the most common type of advanced breast cancer’.
He added: ‘Around half of patients with this kind of breast cancer have mutations in one or more of the genes PIK3CA, AKT1 or PTEN, and for these patients, capivasertib provides an exciting, new targeted treatment which can keep their cancer from progressing for longer.
‘We hope NICE will recommend the use of capivasertib in combination with fulvestrant for patients on the NHS.’
Speaking about the EC marketing authorisation of this AKT inhibitor, Dr Mafalda Oliveira, senior clinical investigator of the Vall d’Hebron Institute of Oncology’s Breast Cancer Group in Barcelona, Spain, said: ‘Patients with advanced [HR]-positive breast cancer typically experience tumour progression or resistance with widely used endocrine-based treatment regimens, and there is an urgent need to provide them more time with their disease under control.
‘[This] approval is welcome news for approximately half of [HR]-positive breast cancer patients in Europe who have tumours with these biomarkers, and it is important for clinicians to test and identify eligible patients who may be able to benefit from this combination.’
4th April 2024
Cladribine tablets (brand name Mavenclad) have been granted a label extension by the Medicines and Healthcare products Regulatory Agency (MHRA) to expand access for additional patient populations with multiple sclerosis (MS), its manufacturer Merck has announced.
It is now indicated for the treatment of adult patients in Great Britain with relapsing forms of MS with active disease as defined by clinical or imaging features.
The expanded label means more newly diagnosed patients will be eligible for treatment with cladribine earlier in their disease course. Since 2017 it has been approved for use in patients with highly active relapsing MS as defined by clinical or imaging features.
Its latest approval makes cladribine the only short-course oral treatment for active relapsing MS available in Europe.
Cladribine tablets, which can be taken at home, are taken for a maximum of 20 treatment days in each of years 1 and 2 with no further treatment required in years 3 and 4.
This low administrative burden can offer advantages to a patient’s quality of life over other types of MS treatment, which can require drugs to be administered via regular self-injections, as an infusion in hospital, or as daily tablets, Merck said.
Speaking about the approval, Dr Wallace Brownlee, consultant neurologist and multiple sclerosis specialist, said: ‘The expansion of the label for cladribine tablets could improve patient outcomes and quality of life for many MS patients with active relapsing MS in Great Britain by allowing us to use cladribine tablets earlier in the treatment pathway.
‘This will be the first high-efficacy oral short-course treatment to be available for this patient group in Europe and could provide clinicians with an additional treatment option which also provides patients with treatment which has a low monitoring and administration burden.’
This approval by the MHRA follows a robust review of the current evidence around the benefit-risk profile of cladribine tablets for this patient group. The pre- and post-approval studies considered in the review included:
The review concluded that there is a favourable benefit-risk profile to warrant use in this wider population.
Dr Doina Ionescu, managing director of Merck Healthcare UK and Ireland, said: ‘We know from our long history of working in the field of MS that there is still an unmet need for many patients to have access to a high-efficacy oral treatment which can be used early in the course of the disease.
‘Since the NICE approval in 2017, cladribine tablets have treated globally over 80,000 patients which has been supported by data from both our pivotal studies and real-world evidence we have shared. More patients could benefit from cladribine tablets than before, so we look forward to applying for NHS reimbursement with urgency.’
14th March 2024
Etrasimod (brand name Velsipity) has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) and recommended by the National Institute for Health and Care Excellence (NICE) for treating eligible patients with ulcerative colitis (UC).
It is approved for patients aged 16 years and older with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biological agent.
The recommended dose of etrasimod is one 2 mg tablet taken once daily with food for the first three days. After this, it can be taken each day with or without food.
The approval of etrasimod in the UK follows its marketing authorisation by the European Commission in February 2024 for the same indication.
This was the first time an oral advanced UC therapy had been approved for use in older adolescents.
Commenting on the recommendation, Helen Knight, director of medicines evaluation at NICE, said: ‘Severe ulcerative colitis is a debilitating lifelong condition; etrasimod provides a new convenient and effective treatment option that will make a positive difference for thousands of people.
‘I’m very pleased we have been able to publish our final guidance recommending the treatment on the day the MHRA granted it a licence. We are determined to continue getting the best care to patients fast.’
NICE has noted that just over 25,000 people in England are now eligible to receive the new treatment, which was evaluated using a simpler technology appraisal process.
As a result, the full final NICE guidance was available up to eight weeks faster than would have been the case under standard process.
The MHRA and NICE approvals of etrasimod were based on results from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials.
These randomised, double-blind, placebo-controlled trials involved 743 patients aged 16 years and over for whom standard treatment or other treatments did not work well enough or could not be used.
They evaluated the safety and efficacy of etrasimod 2 mg once daily on clinical remission.
The coprimary endpoints in ELEVATE UC 52 were the proportion of patients who achieved clinical remission at Week 12 (induction period) and Week 52 (maintenance period).
The primary endpoint for ELEVATE UC 12 was the proportion of patients in clinical remission at the end of the 12-week induction period.
Taken together, the results from the studies showed that, after 12 weeks of treatment, 26% (129/496) of those who received etrasimod had achieved clinical remission compared with 11% (27/247) of those who received the placebo.
ELEVATE UC 52 also found that 32% (88/274) of people taking etrasimod achieved clinical remission after 52 weeks compared with 7% (9/135) for those receiving the placebo.
Both studies also achieved all key secondary efficacy endpoints, with a favourable safety profile consistent with previous studies of etrasimod.
The most common side effects of the were found to be bradycardia, hypertension, urinary tract infection and lower respiratory tract infection.
NICE also noted that indirect comparisons suggest etrasimod is likely to work better than adalimumab and may be similarly effective to other usual treatments for moderately to severely active UC.
9th February 2024
Momelotinib (brand name Omjjara) has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) to treat adult myelofibrosis patients who have anaemia.
The Janus kinase (JAK) inhibitor is now indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with moderate to severe anaemia who have primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis and who are Janus Kinase (JAK) inhibitor naive or have been treated with ruxolitinib.
The MHRA approval follows the positive opinion from the European Medicines Agency‘s Committee for Medicinal Products for Human Use in November 2023 for the same indication.
Momelotinib is taken in tablet form, once daily, at the same time each day.
Julian Beach, MHRA interim executive director, healthcare quality and access, said: ‘Myelofibrosis patients often rely on blood transfusions to counter their anaemia, but studies have shown that these transfusions are often linked to reduced quality of life and survival.
‘Keeping patients safe and enabling their access to high quality, safe and effective medical products are key priorities for us.
‘We’re assured that the appropriate regulatory standards for the approval of this medicine have been met.’
He added: ‘As with all products, we will keep the safety of this medicine under close review.’
This approval is supported by evidence from the randomised, double-blind phase 3 MOMENTUM trial involving 195 patients with myelofibrosis and anaemia, who had previously been treated with a JAK inhibitor.
The patients were given either 200mg momelotinib once daily, or 300mg of danazol twice daily, for 24 weeks.
Momelotinib demonstrated a statistically significant response with respect to constitutional symptoms, splenic response and transfusion independence compared to danazol at Week 24.
Some 25% of patients on momelotinib saw their symptoms reduce by at least half (against 9% on danazol) and 22% saw their enlarged spleen volume decrease by at least 35% (against 2% on danazol).
Momelotinib was also associated with favourable safety at Week 48 in a follow-up analysis.
The most common adverse reactions were diarrhoea, thrombocytopaenia, nausea, headache, dizziness, fatigue, asthenia, abdominal pain and cough.
2nd February 2024
Rezafungin (brand name Rezzayo) has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of invasive candidiasis in adults.
This follows its approval by the European Commission in late December 2023 for the same indication.
An antimycotic, rezafungin selectively inhibits the fungal enzyme 1,3-β-D-glucan synthase, inhibiting formation of 1,3-β-D-glucan, an essential component of the fungal cell wall. This, in turn, results in rapid and concentration-dependent fungicidal activity in Candida species.
Rezafungin is administered once a week by a drip into the vein until at least 14 days after the last day Candida is found in the bloodstream.
Julian Beach, MHRA interim executive director, healthcare quality and access, said: ‘Keeping patients safe and enabling their access to high quality, safe and effective medical products are key priorities for us.
‘We’re assured that the appropriate regulatory standards for the approval of this medicine have been met.
‘As with all products, we will keep its safety under close review.’
The MHRA marketing authorisation was given to Napp Pharmaceuticals and is based on results from the randomised, double-blind, controlled phase 3 ReSTORE clinical trial.
This compared the efficacy and safety of intravenous rezafungin with intravenous caspofungin – the current standard of care – in patients with candidaemia and invasive candidiasis.
Chosen at random, 93 of the patients with invasive candidiasis were given a weekly dose of rezafungin and the other 94 were given a daily dose of caspofungin, for between two to four weeks.
A total of 55 of the patients on rezafungin were cured at day 14, and 57 patients on caspofungin. Some 22 patients had died from any cause by day 30 on rezafungin, compared with 20 on caspofungin.
The trial therefore demonstrated statistical non-inferiority for rezafungin, dosed once weekly, when compared to caspofungin dosed once daily.
The most common side effects of rezafungin, which may affect more than 1 in 10 people, include hypokalaemia, diarrhoea and pyrexia.
3rd January 2024
The combined cancer treatment nivolumab-relatlimab (brand name Opdualag) has been granted marketing authorisation by the Medicines and Healthcare products Regulatory Agency (MHRA) for advanced melanoma.
The monoclonal antibody treatment manufactured by Bristol-Myers Squibb is now approved for adults and children from the age of 12 years.
Administered via a drip over 30 minutes every four weeks in a hospital under specialist medical supervision, nivolumab-relatlimab is continued for as long as clinical benefit is observed by the doctor, or until side effects become too severe.
Nivolumab attaches to the target protein PD 1 and relatlimab to LAG-3, blocking their actions and helping to increase T-cell activity against the melanoma.
This nivolumab-relatlimab approval was granted through Project Orbis, a global partnership between the MHRA, the Therapeutics Goods Administration in Australia, Health Canada, the Health Sciences Authority in Singapore, Swissmedic, Agência Nacional de Vigilância Sanitária in Brazil and Israel’s Ministry of Health, coordinated by the US Food and Drug Administration.
This programme reviews and approves promising cancer drugs, helping patients to access treatments more quickly.
The Project Orbis decision on nivolumab-relatlimab was based on the results of a phase 2/3 randomised, double-blind clinical trial involving 714 patients with previously untreated advanced melanoma.
Patients were given either 480 mg nivolumab with 160 mg of relatlimab, or 480mg of nivolumab alone, every four weeks.
The primary endpoint was progression-free survival as assessed by blinded independent central review.
The researchers concluded that the combined nivolumab-relatlimab treatment was more effective at slowing the progression of the disease over those given nivolumab alone.
The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with nivolumab-relatlimab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab alone (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P=0.006 by the log-rank test).
Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with nivolumab-relatlimab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab alone.
Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the nivolumab-relatlimab group and in 9.7% of patients in the nivolumab group.
The most common adverse events experienced with nivolumab-relatlimab were tiredness; pain in muscles, bones and joints; skin rash (sometimes with blisters) and itching; decreased appetite; headache; diarrhoea; constipation; nausea; vomiting; stomach pain; fever; cough; difficulty breathing; underactive thyroid gland; skin colour change in patches (vitiligo); urinary tract infection; and decreased number of red and white blood cells.
In September 2023, nivolumab (brand name Opdivo) was approved by the European Commission for use as a monotherapy for the adjuvant treatment of stage IIB or IIC melanoma.
17th November 2023
The licence of the cystic fibrosis (CF) medicines ivacaftor-tezacaftor-elexacaftor (Kaftrio) and ivacaftor (Kalydeco) have been extended by the Medicines and Healthcare products Regulatory Agency (MHRA) to include children aged two to five years old.
These medicines, which are manufactured by Vertex Pharmaceuticals, are already authorised for use in the long-term treatment of CF with at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in adults and children aged six years and older.
F508del is the most common CF causing mutation.
Taken together, the CFTR modulator therapies work by interacting with certain abnormal CFTR proteins so they open more often to improve chloride movement in and out of cells.
They are available as sachets of granules to be mixed with 5ml of soft food and consumed immediately, just before or after a fat-containing meal or snack.
The license extension was based on the results of a study looking at this combination of drugs in patients aged 12 years and older in addition to data from a 24-week, phase 3 clinical study involving 75 patients aged 2-5 years old with a confirmed diagnosis of CF and at least one F508del mutation.
Participants continued their CF therapies, such as bronchodilators or inhaled antibiotics, but came off any CFTR modulator therapies other than the study drugs.
Safety was assessed by observing side effects to the medication and the effect of the treatment was assessed using the change in chloride concentrations in sweat.
Chloride concentrations in sweat reduced by 57.9 mmol/L over the course of the study in those aged two to five. This effect was comparable to the effect on sweat chloride in older children and adults where clinical efficacy and a comparable safety profile was demonstrated.
The most common side effects are a common cold, including sore throat and nasal congestion; headache, dizziness; diarrhoea; stomach pain; changes in the types of bacteria in the mucus; increased liver enzymes; and a rash.
Commenting on the license extension, John Stewart, national director for specialised commissioning at NHS England, said: ’Children as young as two years old with CF will now be eligible to receive the triple therapy if determined to be suitable by their treating clinician.
’We anticipate that as many as 600 children could benefit from this approval under the terms of the existing commercial agreement, and NHS England will publish an updated policy confirming this expansion in access and funding to coincide with stock arriving in England, which is anticipated in a few weeks.
’Patients, families and carers should be assured that NHS CF centres across the country have plans in place to ensure that all eligible children can be initiated on treatment while the NICE review of the CFTR modulators remains ongoing – meaning that all children eligible today can be confident about their long term access to these life-changing treatments.’
Earlier this month, the National Institute for Health and Care Excellence (NICE) published a first-stage draft recommendation for Kaftrio and two further CF treatments, which highlighted their clinical effectiveness.
However, it also stated that the ’most likely cost-effectiveness estimates’ were ’above the range that NICE considers an acceptable use of NHS resources. So they are not recommended’.
Commenting on the ’disappointing’ news, David Ramsden, CEO of Cystic Fibrosis Trust, said: ’It is important to emphasise that those already taking any of the modulator drugs are not affected by the NICE process because of the agreements already in place but this update creates uncertainty for those not yet on treatment.
’Vertex, NICE and the NHS must now urgently work together to find a solution to make these treatments available for all those who could potentially benefit. We must never return to a situation where people with CF die far too young, knowing there’s a treatment that could change that.’
The draft guidance is out for consultation until 24 November and a second evaluation meeting will be held on 14 December. Final publication is expected in March 2024.
The first-of-its-kind gene-editing treatment exagamglogene autotemcel (exa-cel, brand name Casgevy) has been granted conditional marketing authorisation by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of sickle cell disease and transfusion-dependent beta thalassemia (TDT).
Exa-cel is now approved for use in eligible patients aged 12 and over with sickle cell disease who have recurrent vaso-occlusive (VOC) crises, or TDT for whom a human leukocyte antigen-matched related hematopoietic stem cell donor is not available.
A genetically modified autologous CD34+ cell-enriched population, exa-cel contains human hematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 at the erythroid-specific enhancer region of the BCL11A gene.
The edited stem cells are then infused back into the patient to restore healthy haemoglobin production.
The innovative gene-editing tool CRISPR gained its inventors the Nobel Prize in 2020.
Professor Josu de la Fuente, professor of practice (cellular and gene therapy) at Imperial College London, and consultant haematologist at Imperial College Healthcare NHS Trust, said: ’This is a world-first and a significant moment for researchers, clinicians and, most of all, people with sickle cell disease and beta thalassaemia.
’These are inherited blood disorders which have a huge impact on people’s lives, including many people from our local community. This authorisation offers a new option for eligible patients who are waiting for innovative therapies.’
He added: ’I look forward to patients having access to this therapy as quickly as possible.’
The UK is the first country in the world to approve gene editing as a potential cure for these two inherited blood disorders. There are an estimated 2,000 patients eligible for Casgevy treatment across the country.
The MHRA approval was based on the results of two global clinical trials. Looking at exa-cel in both sickle cell disease and TDT, the trials met their respective primary outcome of becoming free from severe VOCs or transfusion independent for at least 12 consecutive months.
Once achieved, these benefits were potentially expected to be life-long.
The safety profile of 97 patients with SCD and TDT treated to date with Casgevy in these ongoing studies is generally consistent with the traditional treatments of myeloablative conditioning with busulfan and hematopoietic stem cell transplant.
Professor de la Fuente, who was also the chief national investigator of the UK arm and steering committee member of the two studies, said: ’I’m proud to have contributed to the development of the studies and be leading the UK arm. I am very grateful to my colleagues both at the Trust and the other centres involved in the trials and patient selection for their hard work, but most of all to the patients for their willingness to explore innovative therapies and their daily inspiration.’
Julian Beach, interim executive director of healthcare quality and access at the MHRA, added: ’Both sickle cell disease and beta thalassemia are painful, life-long conditions that in some cases can be fatal. To date, a bone marrow transplant – which must come from a closely matched donor and carries a risk of rejection – has been the only permanent treatment option.
He added: ’The MHRA will continue to closely monitor the safety and effectiveness of Casgevy, through real-world safety data and post-authorisation safety studies being carried out by the manufacturer.
’I would like to thank the patients with lived experiences who engaged with us as part of the assessment process and gave us valuable insight into their lives and the challenges of managing their condition.’
The manufacturer Vertex Pharmaceuticals is working closely with the National Institute for Health and Care Excellence to secure access for patients as soon as possible.
Exa-cel is also under review by the European Medicines Agency and other global regulators.
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