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Beth benderfynodd Grŵp Asesu Meddyginiaethau Cymru’n Un?

Gellir rhoi infliximab i drin llid yn y llwybr treulio (enterocolitis) a achoswyd gan driniaeth canser gyda meddyginiaethau a elwir yn atalyddion pwynt gwirio imiwnedd. Gellir rhoi infliximab os yw'r symptomau'n gymedrol ('gradd 2'), yn ddifrifol ('gradd 3') neu'n bygwth bywyd ('gradd 4') ac nad ydynt wedi ymateb i corticosteroidau (steroidau). Gellir rhoi infliximab hefyd ar gyfer symptomau enterocolitis graddau 2-4 sy'n ymateb i steroidau ar y dechrau, ond yna'n gwaethygu pan fydd y dos steroid yn cael ei leihau a dim ond yn setlo pan fydd y dos steroid yn cael ei gynyddu. 

Bydd infliximab ar gael i gleifion cymwys sydd wedi cofrestru gyda phractis meddyg teulu yng Nghymru, hyd yn oed os oes angen iddynt dderbyn eu triniaeth y tu allan i Gymru.

Nid yw infliximab wedi'i drwyddedu i drin enterocolitis, felly os caiff ei ddefnyddio i drin enterocolitis fe’i gelwir yn ddefnydd “all-drwydded”. Pan gaiff meddyginiaeth ei defnyddio yn “all-drwydded”, rhaid i'ch meddyg esbonio'n glir i chi y risgiau a'r manteision o gymryd y feddyginiaeth. Dylai eich meddyg roi gwybodaeth glir i chi, siarad â chi am eich opsiynau a gwrando'n ofalus ar eich barn a'ch pryderon. Darllenwch ein taflen wybodaeth i gleifion am ddefnydd di-drwydded ac all-drwydded o feddyginiaethau.

Mae Grŵp Asesu Meddyginiaethau Cymru'n Un ac AWTTC yn adolygu'r penderfyniad hwn yn rheolaidd i weld a oes unrhyw dystiolaeth newydd a allai effeithio ar y penderfyniad hwn.

Am ragor o wybodaeth, ewch i: Checkpoint inhibitors | Types of immunotherapy | Cancer Research UK (Saesneg yn unig)

 

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What did the One Wales Medicines Assessment Group decide?

Infliximab can be given to treat inflammation of the digestive tract (enterocolitis) that has been caused by cancer treatment with medicines called immune checkpoint inhibitors. Infliximab can be given if symptoms are moderate (‘grade 2‘), severe (‘grade 3’) or life‑threatening (‘grade 4’) and have not responded to corticosteroids (steroids). Infliximab can also be given for enterocolitis symptoms grades 2–4 that respond to steroids at first, but then flare again when the steroid dose is reduced and only settle when the steroid dose is increased. 

Infliximab will be available to eligible patients who are registered with a GP practice in Wales, even if they need to receive their treatment outside Wales.

Infliximab is not licensed to treat enterocolitis, so using it to treat enterocolitis is called “off-label” use. When a medicine is used “off-label”, your doctor must clearly explain to you the risks and benefits of taking the medicine. Your doctor should give you clear information, talk with you about your options and listen carefully to your views and concerns. Read our patient information leaflet about unlicensed and off-label use of medicines.

The One Wales Medicines Assessment Group and AWTTC review this decision regularly to see if there is any new evidence that may affect this decision.

For more information on immune checkpoint inhibitors visit: Checkpoint inhibitors | Types of immunotherapy | Cancer Research UK

Medicine: infliximab

Indication: Reassessment of OW21 to extend the indication to include:

• patients with ICI-induced grade 2 enterocolitis when symptoms have not responded to first-line immunosuppression with corticosteroids, as an alternative to vedolizumab
• patients with grade 2–4 enterocolitis who are corticosteroid-dependent requiring multiple challenges with corticosteroids 
• dose escalation to 10 mg/kg when there has been an inadequate response to standard 5 mg/kg dosing in patients with grade 2-4 enterocolitis.

Meeting date: 19 August 2024

Criterion: Clinical effectiveness and safety

OWMAG opinion OWMAG note that the current One Wales decision (OW21) recommends infliximab to treat ICI-induced enterocolitis grade 3–4 that had not responded to corticosteroids. This reassessment is in response to 12-month review of OW21 which identified change to European Society for Medical Oncology (ESMO) guidelines for treating ICI-induced enterocolitis. The One Wales Medicines Assessment Group (OWMAG) proposed that, in accordance with the new treatment guidelines, infliximab should be reassessed for the broader indication of treating ICI-induced grade 2–4 enterocolitis that had not responded to corticosteroid treatment and to consider the use of a higher (10 mg/kg) dose of infliximab. This proposal was supported by Welsh clinicians who also requested that patients with grade 2-4 disease whose condition is settling and re-flaring and requires multiple steroid escalations be included in the expanded indication being considered. OWMAG note that there is limited new clinical effectiveness evidence to that already presented and considered as part of the original assessment and the 12-month review. New evidence presented that includes grade 2 enterocolitis and dose escalation is limited and consists of 3 retrospective studies, interim results of an ongoing clinical trial and a case series investigating 10 mg/kg infliximab for refractory enterocolitis. For the treatment of grade 2 enterocolitis, the group notes that infliximab dosage used (when reported) was consistent with the 5 mg/kg dose recommended in national and international guidelines while dosing schedule frequency varied with generally no more than three doses received. However, results were generally reported for the mixed colitis group (grade 1-4) with no stratification by grade.  All studies showed a clinical benefit in terms of enterocolitis symptom improvement and partial or complete response to treatment with infliximab and reflected the results of previous studies. OWMAG note that for the dose escalation study, 50% of patients with severe enterocolitis who had not responded to the standard 5 mg/kg dose of infliximab had a clinical response to the 10 mg/kg dose although the number of patients included in the study was small. OWMAG note the evidence provided by clinical experts, both in the ESR and at the meeting, who reported positive clinical outcomes for patients that had been treated with infliximab. Clinicians highlighted that the majority of patients with grade 2 enterocolitis unresponsive to steroid treatment progress to grade 3. At this point, such patients will become eligible for treatment with infliximab or vedolizumab via OW21 and OW22. Allowing use of infliximab earlier in the pathway prevents the worsening of symptoms and lessens steroid burden by allowing rapid steroid weaning. Clinicians also highlight that 90% of patients with grade 2 enterocolitis who are successfully treated with either infliximab or vedolizumab are able to resume their cancer-treatment with ICIs; this compares to 25- 33% of patients with grade 3 enterocolitis. The detrimental impact of the prolonged use of high dose corticosteroids was also discussed; this can result in a range of serious adverse events including some that are irreversible, prevention or delay of cancer-related treatments or surgery and a decrease in quality of life. Clinicians also highlight that some patients with enterocolitis are steroid-dependent and require multiple treatment courses with steroids for relapses. They note concerns regarding the increase risk of steroid-related adverse events due to repeated exposure and would welcome the option to use infliximab for these patients to prevent future relapses and lessen steroid burden. OWMAG note that no new safety signals have been observed for the use of infliximab to treat ICI-induced enterocolitis. OWMAG considers that the evidence provided demonstrated clinical effectiveness.

Criterion: Cost-effectiveness

OWMAG opinion There is no published cost‑effectiveness evidence available for infliximab for the extended indication. OWMAG considered the cost-consequence analysis, threshold analysis and scenario analyses presented. The group acknowledged the limited scope of the analyses in terms of capturing all costs and effects, in particular longer term costs and effects. Clinicians shared their experiences in treating this patient group, suggesting that: the majority of patients not responding to corticosteroids would progress to grade 3 if grade 2 patients are treated successfully, then approximately 90% can be rechallenged with ICI compared with 25% or 33% of patients who experience grade 3 ICI-induced enterocolitis Grade 3 patients tend to be treated as day-cases rather than in-patients Monitoring is intensive for patients with steroid burden ICI-induced enterocolitis is very different to ulcerative colitis (UC), and that unlike UC, it is reversible with limited treatment options. Therefore, they would expect that the likely expected gain in benefits would be higher for patients with ICI-induced enterocolitis. On consideration of these factors OWMAG consider it is likely that the cost of infliximab for these additional patient groups is a reasonable use of NHS resources.

Criterion: Budget impact

OWMAG opinion OWMAG consider the clinical estimate of patient numbers reported to be reasonable. The group note that the majority of eligible patients with ICI-induced enterocolitis in Wales can already receive infliximab through the existing OW21 recommendation for grade 3–4 colitis. The group also note that, as the first review of OW21 indicated the actual number of patients receiving infliximab was lower to that predicted in the original assessment, the estimated population who will receive infliximab has been revised down even after accounting for the additional patients covered by the expanded indication. This has resulted in a lower budget impact range than that calculated for the original assessment. Based on outcome data provided by Welsh clinicians for patients treated with infliximab for grade 3 enterocolitis, OWMAG note that it’s likely that the majority of patients will receive three doses and so the yearly budget impact is likely to be at the higher end of the estimate. The group note that mortality rates and additional screening and monitoring for bacterial, viral and fungal infections and adverse event costs have not been included in the budget impact. OWMAG acknowledge that a proportion of patients with grade 2 ICI induced enterocolitis in Wales are already  receiving infliximab through local agreement routes. Also, as ICI usage grows, it is acknowledged that patient numbers are anticipated to increase over the coming years, resulting in additional budgetary impact in Wales. This will be monitored as part of the review process. OWMAG consider that the base case provided in the report is a reasonable estimate of the associated cost to NHS Wales.

Criterion: Other factors

OWMAG opinion OWMAG acknowledges that although grade 2 colitis is milder than grade 3, it can still significantly impact patients’ quality of life. This may include malnutrition, poor sleep, inability to work, lethargy and chronic dehydration. In addition, OWMAG also acknowledge that long term and/or high dose steroid exposure is associated with increased risk of a wide range of adverse effects including infections, fractures, high blood sugar, cardiovascular and cerebrovascular events and that there are clinical, cost and quality of life benefits in reducing steroid burden and repeated exposure to corticosteroids. It was noted that many patients are elderly and these effects may be more severe. The use of infliximab may help a rapid wean from steroids. OWMAG also considers that earlier intervention and resolution of enterocolitis enables resumption of cancer treatment with ICIs for the majority of patients which offers an increased possibility of durable outcomes.   It was noted that for patients with a low albumin level, the higher dose of infliximab may be required to achieve an adequate response. There are no licensed alternative treatment options routinely available.

Final recommendation

OWMAG recommends that the existing recommendation for the use of off-label infliximab for the treatment of ICI-induced grade 3-4 enterocolitis unresponsive to corticosteroids and outlined in OW21 be updated to include the expanded indication considered in this reassessment. Therefore, the updated recommendation is as follows: Infliximab can be made available within NHS Wales: for the treatment of ICI-induced grade 2-4 enterocolitis, where symptoms have not responded to first line immunosuppression with corticosteroids. for the treatment of grade 2–4 enterocolitis in patients who are corticosteroid-dependent requiring multiple challenges with corticosteroids for the treatment of grade 2-4 enterocolitis in patients requiring dose escalation to 10 mg/kg when there has been an inadequate response to standard 5 mg/kg dosing. This recommendation is subject to the development of appropriate start/stop criteria.

Summary of rationale

There is some limited evidence to support the use of infliximab as a clinically effective option for the treatment of ICI induced grade 2-4 enterocolitis, where symptoms have not responded to first line immunosuppression with corticosteroids, and for patients who are steroid-dependent and require multiple treatment courses with steroids for relapses and for dose escalation to 10 mg/kg when there has been an inadequate response to standard 5 mg/kg dosing. There are no licensed alternative treatment options and recent updates to international guidelines recommend the use of infliximab for these additional populations. Allowing the use of infliximab earlier in the pathway may prevent the worsening of symptoms, lessen steroid burden by allowing rapid steroid weaning, allow resumption of ICIs to treat the patient’s cancer and maintain or improve their quality of life. A proportion of the extended patient population in Wales is already receiving this treatment via local agreement routes, supporting the extension on an All Wales basis would ensure equity of access. The review after 12 months will provide more clarity around patient numbers and the number of doses of infliximab administered.

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Key findings

Licence status: Infliximab is not licensed for treating immune checkpoint inhibitor (ICI)-induced grade 2–4 enterocolitis, when symptoms have not responded to first-line immunosuppression with corticosteroids or require multiple challenge with corticosteroids and dose escalation following inadequate response to standard dose. The use of infliximab for this indication is off-label.

Clinical evidence: The clinical evidence for the use of infliximab in this setting comes from interim results from an ongoing clinical trial, a systematic review with meta analysis, and retrospective studies. Despite limitations of retrospective study design, in most studies, infliximab showed clinical benefit in terms of symptom improvement or symptom response to infliximab (complete or partial). Patient deaths were typically from other causes (infection or cancer progression).

Safety: No new safety signals have been observed for infliximab in this indication.

Patient factors: Infliximab is administered by intravenous infusion over a two-hour period. Due to risk of acute infusion related reactions, patients should be monitored during and for at least one to two hours post infusion.

Cost effectiveness: There are no published studies on the cost-effectiveness of infliximab in combination with oral corticosteroids for treating immune checkpoint inhibitor (ICI) induced grade 2 enterocolitis, when symptoms have not responded to first-line immunosuppression with corticosteroids or require multiple challenges with corticosteroids. AWTTC cost analyses identified that this intervention is associated with an incremental cost of [commercial in confidence figure removed].

AWTTC threshold analysis, with a limited cost perspective, identified that treatment with infliximab in combination with corticosteroids would require an improvement of [commercial in confidence figure removed] QALYs to be considered cost-effective. There is insufficient evidence to inform a decision on cost-effectiveness.

Budget impact: Clinicians consulted by AWTTC estimate that 12 people in Wales per year would be likely to be eligible to receive infliximab in this setting. It is assumed that people would have one to three 5 mg/kg infliximab doses although one patient is predicted to require dose escalation to 10 mg/kg due to lack of response. All doses are assumed to be received within a single year. This is associated with an annual cost of between [commercial in confidence figure removed], depending on which infliximab product is used. The number of eligible patients is likely to increase over time as more people receive ICIs. The budget impact is subject to uncertainty.

Impact on health and social care services: Patients with ICI-induced grade 3–4 enterocolitis (not responding to corticosteroids) in Wales are currently receiving infliximab through a One Wales recommendation (OW21) issued in February 2023. Patients with grade 2 colitis may receive infliximab through local agreements.

Innovation and/or advantages: Infliximab may reduce the need for more invasive interventions for this condition, and may improve patients’ quality of life and allow them to be discharged earlier. Infliximab treatment may help patients to receive subsequent cancer treatments, titrate steroids down, and carry on with their lives at home. Managing the toxicity of cancer treatments improves the chance for cancer to be cured for this cohort of patients.

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Background

In 2023 AWTTC reviewed the One Wales recommendation to use infliximab to treat ICI-induced enterocolitis grade 3–4 that had not responded to corticosteroids. The review identified a change to the European Society for Medical Oncology (ESMO) guidelines for treating ICI colitis. The One Wales Medicines Assessment Group (OWMAG) proposed that, in accordance with the new treatment guidelines, infliximab should be reassessed for the broader indication of treating ICI-induced grade 2–4 enterocolitis that had not responded to corticosteroid treatment or to multiple challenges with corticosteroids, and to consider the use of a higher (10 mg/kg) dose of infliximab.

The All Wales Therapeutics and Toxicology Centre (AWTTC) sought opinions from clinical experts in Wales, who said the incidence of immune checkpoint inhibitor (ICI) induced enterocolitis will increase over the next few years as the use of cancer immunotherapies increases. Clinical experts expressed a need for effective ICI toxicity management, with infliximab considered standard of care for severe or steroid refractory ICI-induced enterocolitis, and supported the reassessment of infliximab for the proposed broader indication.

Patients with ICI-induced grade 2 enterocolitis in Wales currently receive infliximab through local agreements. In the absence of other licensed treatments, a One Wales decision would ensure equity of access to this treatment across the country.

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Target group

The indication under consideration is an extension to the current One Wales recommendation to include:

• patients with ICI-induced grade 2 enterocolitis when symptoms have not responded to first-line immunosuppression with corticosteroids, as an alternative to vedolizumab
• patients with grade 2–4 enterocolitis who are corticosteroid-dependent requiring multiple challenges with corticosteroids
• dose escalation to 10 mg/kg when there has been an inadequate response to standard 5 mg/kg dosing.

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Marketing authorisation date

Not applicable, off-label. Infliximab is not licensed for the treatment of ICI-induced grade 2–4 enterocolitis, when symptoms have not responded to first-line immunosuppression with corticosteroids, or to multiple challenges with corticosteroids or dose escalation following inadequate response for this indication.

There are no plans to license infliximab for the indication under consideration. 

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Dosing information

The recommended dose is 5 mg/kg given as an intravenous infusion¹. A second dose may be repeated 14 days later, with a maximum of three infusions to be given (weeks 0, 2 and 6). The ESMO guidelines recommend considering a higher dose of 10 mg/kg to treat refractory colitis². 

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Clinical background

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Incidence

Incidence of ICI-induced enterocolitis will vary greatly depending on the ICI treatment and dosage used⁶. Incidence of all grade diarrhoea is estimated to be 10% and 33% with anti‑programmed cell death protein (PD)‑1 and anti‑cytotoxic T‑lymphocyte-associated protein (CTLA)‑4 treatment, respectively. Incidence of all grade colitis is estimated to be 2% and 7%, respectively. Incidence of grade 1–4 and severe (grades 3–4) colitis is estimated to be 1.2% and 0.2%, respectively, with anti‑PD‑1 treatment, 0.3% and 0.04% with anti‑PD‑L1 treatment, and 11.2% and 4.9% with anti‑CTLA‑4 treatment⁶. The proportion of people who develop steroid-refractory colitis is not known but has been estimated to be between 33.3% and 66.6% of those receiving anti‑CTLA‑treatment and approximately 12.5% of those receiving anti‑PD‑1 treatment⁷.

Clinicians consulted by AWTTC estimated that twelve people in Wales per year would be likely to be eligible to have infliximab for ICI-induced grade 2–4 enterocolitis that has not responded to corticosteroids.

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Current treatment options and relevant guidance

Treatment of ICI-induced grade 2 enterocolitis that has not responded to corticosteroids is currently treated off‑licence in Wales with infliximab through local agreements. Treatment of ICI-induced grade 3–4 enterocolitis unresponsive to corticosteroids is treated in Wales by infliximab or vedolizumab under the One Wales recommendations OW21 and OW22^8,9.

The Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up were updated in 2022². For patients presenting with grade 2 symptoms, ICI therapy should be withheld and symptomatic management with oral corticosteroids at 40–60 mg/day should be initiated, tapered over 4–8 weeks. Upon remission, ICI may be considered taking into account the risk of enterocolitis recurrence and the oncological benefit of restarting the ICI. In the case of relapse or where the patient is found to be refractory to corticosteroids, ESMO recommends infliximab or vedolizumab treatment and rapid corticosteroid tapering. Vedolizumab is recommended for more moderate disease (grade 2) and infliximab for more severe disease (grade 3–4). This seems to be due to vedolizumab taking longer to elicit a response and therefore being less suitable when time to treatment success is critical. The updated ESMO guidelines also include the option of switching between biologics, or considering a higher dose of infliximab (10 mg/kg) for refractory colitis².

The current One Wales recommendation states that infliximab at a dose of 5 mg/kg for up to three doses may be used if a patient’s condition is not responsive to corticosteroids for grade 3–4 enterocolitis. Vedolizumab may be used for patients whose condition is unresponsive to infliximab or for whom infliximab is not appropriate.

Clinicians in Wales said that they would welcome the opportunity to extend the group of patients receiving infliximab to include patients with grade 2 disease. Dose escalation to 10 mg/kg may be considered when there is no response to the 5 mg/kg dose, and this would be discussed with gastroenterology colleagues. 

A number of national and international guidelines have been published on this topic with some variation in their recommendations^3,4,10-15.

The UK Oncology Nursing Society’s Acute Oncology Initial Management Guidelines (version 4.0) include Guideline 21: immune-related adverse event: diarrhoea and colitis. The guideline recommends screening on Day 1 for suitability for infliximab administration in cases of severe or life-threatening colitis (grades 3 and 4) and also for moderate colitis (grade 2)¹².

For milder forms of disease, the British Society of Gastroenterology (BSG) recommend initiating treatment with oral corticosteroids². Should there be no response within 3–5 days, BSG advise switching to intravenous methylprednisolone. If there is still no response within three days, they then recommend to escalate to infliximab at 5 mg/kg for a maximum of three infusions. For patients with high-risk endoscopic features there may be a lower threshold for early escalation to infliximab. In acute severe enterocolitis, there are safety concerns about sequential use of powerful immunosuppressive agents immediately after infliximab failure³. For severe enterocolitis that is refractory to treatment, or following intestinal perforation, surgical management might be required³.

A single dose of infliximab 5 mg/kg is effective in at least 65% of cases but a second dose may be required due to symptomatic relapse or incomplete response³. The BSG advise completing the standard induction regimen of 5 mg/kg at weeks zero, two and six to maximise the opportunity for complete mucosal healing. The value of additional doses of infliximab following the standard three infusions has not been established³.

Clinical experts advise that patients would initially have clinical review and investigations including routine blood tests, stool cultures and faecal calprotectin. They would then undergo radiology assessment and start primary immunosuppression with intravenous methylprednisolone followed by endoscopy. If the enterocolitis does not respond to primary treatment then infliximab would be considered after three to five days.

For patients receiving intravenous corticosteroids, or for patients with high‑risk endoscopic features, screening for tuberculosis, varicella zoster virus, HIV and hepatitis B and C should take place in anticipation of treatment escalation; however, this should not delay treatment initiation³.

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Summary of evidence on clinical effectiveness

For the review of the OW21 recommendation and for reassessment of the broader use of infliximab to include grade 2 enterocolitis and dose escalation with infliximab, AWTTC conducted a literature search for additional evidence, and excluded studies that had very small numbers of patients, or in which the grade of colitis was not specified by treatment. Evidence identified included a case series investigating the use of 10 mg/kg infliximab for refractory enterocolitis, three retrospective studies, and interim results from an ongoing clinical trial were identified. All are discussed below.

Efficacy

Safety

Discussion

Most of the evidence for the off-label use of infliximab to treat ICI-induced grade 2–4 enterocolitis, where symptoms have not responded to first-line immunosuppression with corticosteroids comes from retrospective studies. When reported, the infliximab dosage used was consistent with that recommended in national and international guidelines (5 mg/kg). The dosing schedule frequency varied between studies although generally no more than three doses were administered. Patient selection and grading, as well as outcome measurements are inconsistently reported across the studies (due to the nature of their design and limitations in the most widely used grading tool CTCAE). Interim data have also been reported from 15 patients in a clinical study comparing infliximab with vedolizumab to treat grade 2 or higher ICI‑related colitis.

The evidence for dose escalation to 10 mg/kg is limited. Three studies included a dose  of 10 mg/kg but only one reports specifically on its use where standard dose has failed. In this group success rate was 50% with the remainder going on to receive either vedolizumab or faecal microbiota transplantation with good response.

The National Institute for Health and Care Excellence (NICE) recommends infliximab (or adalimumab) for adults with severe active Crohn’s disease whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy (TA187)²⁷. NICE recommends infliximab for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contraindicated or clinically inappropriate, based on a careful assessment of the risks and benefits of treatment in the individual patient (TA163)²⁸. It is acknowledged that the acute treatment strategy for ICI-induced enterocolitis may follow a similar pathway to the treatment for Crohn’s and ulcerative colitis. However, there are differences in terms of patient and disease characteristics, the length of treatment, morbidity and mortality rates. Therefore, comparing the use of infliximab for these indications and trying to predict clinical and cost effectiveness for ICI induced enterocolitis from the data used for Crohn’s and ulcerative colitis is subject to significant uncertainty. 

It is reported that the early use of immunotherapies such as vedolizumab and infliximab to treat ICI-induced enterocolitis may ensure a more favourable overall patient outcome when compared to steroids alone as immunotherapy use is associated with a shortened course of steroid treatment¹⁸. A retrospective review by Wang et al. (2018) assessing the impact of ICI-induced diarrhoea and colitis and their immunosuppressive treatment on patient outcomes found that patients who received long duration of steroid treatment (> 30 days) had a numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, p = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, p = 0.089)¹⁸.

Clinicians have stated that there are some patients who require multiple treatment courses with steroids for relapses and note concerns regarding the increased risk of steroid-related adverse events due to repeated exposure^29-35. They would welcome the option to use infliximab in this patient group to with the aim to prevent future relapses.

Patients with grade 2 enterocolitis who are unresponsive to corticosteroids are likely to progress to stage 3 disease. At this point they will become eligible for treatment with either infliximab or vedolizumab under the One Wales recommendations OW21 and OW22^8,9. Higher doses of corticosteroids are associated with a greater risk of fractures, developing diabetes/hyperglycaemia, cataracts, glaucoma, cardiovascular and cerebrovascular events. Psychiatric disturbances are also more common with higher dose corticosteroid use³². In addition, cumulative doses of corticosteroids are associated with an increased risk of fractures, high blood sugar, cataracts, weight gain, skin and sleep problems³⁶. Short-term oral corticosteroid use has cumulatively been associated with osteoporosis, hyperglycaemia and muscle weakness, even when given for <7 days³⁴. Allowing use of infliximab earlier in the pathway may prevent the worsening of symptoms requiring hospitalisation, lessen steroid burden and maintain or improve the quality of life for these patients.  

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Cost-effectiveness evidence

An AWTTC literature review did not identify any cost-effectiveness studies of infliximab for treating ICI-induced grade 2 enterocolitis, when symptoms have not responded to first-line immunosuppression with corticosteroids or require multiple challenges with corticosteroids.

Cost-consequence analysis

An AWTTC cost-consequence analysis compares the cost and clinical outcomes of intravenous infliximab in combination with the current standard of care in the treatment of ICI-induced grade 2 enterocolitis with current standard of care alone. Standard of care in this setting consists of symptomatic management with oral corticosteroids at 40–60 mg/day.

The cost-consequence analysis includes the costs of infliximab procurement and administration. The analysis adopts a lifetime horizon and an NHS Wales/Personal and Social Services perspective. The analysis accounts for the costs and outcomes associated with the acute disease in addition to considering longer term clinical and cost impacts. The recommended dose of infliximab is 5 mg/kg¹. A second dose may be repeated 14 days later, with a maximum of three infusions to be given (weeks 0, 2 and 6). The ESMO guidelines recommend considering a higher dose of 10 mg/kg to treat refractory colitis¹⁴.

Cost of intervention and comparator

Infliximab procurement costs are informed by a confidential NHS Wales contract price with a unit cost of a 100 mg vial ranging between [commercial in confidence figures removed]. NHS Wales prescribing figures from 2023 for infliximab 100 mg are used to calculate a weighted average procurement cost. The weighted average cost per 100 mg vial is [commercial in confidence figure removed] excluding VAT.

The average patient weight is calculated using population averages with an equal percentage of males and females. The recommended dose of 5 mg/kg for an average patient weight of 77.25 kg results in 4 vials per administration^38,39. There is an assumption of no vial sharing; wastage is applied. The total infliximab procurement cost for a single administration is [commercial in confidence figure removed] excluding VAT.

The administration cost for the delivery of infliximab is sourced from the NHS reference costs 2021/22 with cost code SB12Z used for the first administration and SB15Z for additional delivery. The first administration cost is £207.59. Delivery of subsequent dose is costed at £326.46⁴⁰. The total cost for an initial dose of 5 mg/kg of infliximab is [commercial in confidence figure removed] excluding VAT. Whilst not included in the base case, treatment with 10 mg/kg is recommended to treat refractory colitis by the ESMO guidelines; this dose would cost [commercial in confidence figure removed] excluding VAT per subsequent delivery (maximum 2)².

The base case distribution of patients across the differing delivery modalities has been informed by clinical experts. It is assumed patients receive three doses of infliximab at 5 mg/kg. The cost for the delivery of infliximab is [commercial in confidence figure removed] excluding VAT. The delivery costs of corticosteroids are assumed equal in the intervention and comparator arm the net intervention cost is therefore [commercial in confidence figure removed] excluding VAT.

Comparative clinical effectiveness

The summary of evidence on clinical effectiveness section outlines the clinical literature searches from which the effectiveness outcomes included in the cost‑consequence analysis, are taken. Clinical outcomes associated with infliximab for grade 2 enterocolitis are broad and evidence is heterogenous. Seventeen studies across the severity grade (grades 1–4) found that infliximab showed a clinical benefit in terms of symptom improvement or symptom response (complete or partial). Evidence from a network meta-analysis calculates the pooled response rate of infliximab in combination with corticosteroids to be 81% (95% CI: 73% to 87%)²⁵. There is a lack of evidence as to the clinical efficacy for patients in the comparator arm who continue treatment with corticosteroids and who are corticosteroid dependent.

The curative potential of infliximab may allow for a reduction in continued oral corticosteroid use, either in reduction of dose for those achieving partial response or in treatment discontinuation for those with complete response. The Summary of evidence on clinical effectiveness section outlines the wide range of adverse events associated with continued oral corticosteroids. Steroid burden is associated with an increase in continued care costs estimated to be £165 in 2007 per patient per year, the cost inflated using the PSSRU inflation indexes to 2022/23 prices is £252⁴¹. This cost was calculated by applying the oral corticosteroid relative risk of seven adverse events (AEs) to the prevailing incidence rate and then multiplying by associated costs³⁶. Fractures were the main cost driver across the seven discrete AEs. The seven AEs are chosen due to the availability of relative risk estimates as opposed to severity ranking or incidence rates.

In addition to the seven relative risks included in the steroid burden economic study there is an increased infection risk associated with prolonged steroid use. A retrospective study pooling colitis grade 2 and 3 identified a relationship between longevity of steroid treatment and infection rates. The study findings suggest that early intervention with infliximab in combination with corticosteroids offers favourable outcomes compared to a longer duration of steroid without infliximab with infection rates of 14.3% and 42.9%, respectively; this finding was not statistically significant (P = 0.089)²³.

Adverse events associated with infliximab which were very common (observed in greater than 1 in 10 patients), have been listed in the safety section of the clinical review; they are viral infection (e.g. influenza, herpes virus infection), headache, upper respiratory tract infection, sinusitis, abdominal pain, nausea, infusion‑related reaction and pain.

Clinical experts highlighted benefits in terms of a reduction in symptoms and an overall increase to patient health-related quality of life (HRQoL). This HRQoL impact is described in the patient organisation submission in terms of a disruption to usual activities and pain or discomfort. In addition to the curative impact on enterocolitis, a reduction in continued oral steroid use may also have an overall net HRQoL impact.

ESMO guidance and clinical experts have highlighted the need for hospital monitoring for grade 3–4 enterocolitis². Welsh clinical experts suggest that intervention at grade 2 with infliximab in combination with corticosteroids may reduce progression to grade 3–4 and therefore result in a lower overall hospitalisation rate. The prudent healthcare element to the use of infliximab for the treatment of grade 2 ICI enterocolitis is centred upon the timely treatment which avoids progression to more severe grades of enterocolitis. Clinical experts have informed that patients with grade 2 who are unresponsive to steroids may progress to grade 3–4 at which point they can routinely access infliximab. The proportion of patients who would progress from grade 2 to grade 3–4 is unknown. Offering treatments with a high partial/full curative rate may avoid subsequent progression or exacerbation. The cost consequence analysis is summarised in Table 1.

Table 1. Infliximab cost-consequence analysis (opens image in new tab)

Threshold analysis

Using this net cost of infliximab, AWTTC conducted a threshold analysis to estimate the minimum required quality-adjusted life year (QALY) gain for infliximab to be deemed cost-effective. Applying a cost-effectiveness threshold of £20,000 per quality-adjusted life year to the net intervention cost of [commercial in confidence figure removed] requires a minimum QALY gain of [commercial in confidence figure removed]. A disease burden QALY is calculated to contextualise the threshold; this consists of disease duration and health-related quality of life (HRQoL) decrement.

An AWTTC literature review identified a recent study that reports a median time to resolution with grade 2 colitis of 52 days¹⁷; however, no direct evidence of impact on HRQoL for this indication was identified.

An alternative method to inform the scale of disease burden is to utilise literature from comparable conditions. An AWTTC literature search identified one relevant publication reporting no significant difference between ICI colitis and two conventional inflammatory bowel diseases (ulcerative colitis and Crohn’s disease) for a range of quality of life measures⁴². A subsequent targeted literature review was therefore undertaken to search for evidence on the HRQoL burden of ulcerative colitis and Crohn’s disease. Two publications were identified, offering relevant data.

The HRQoL decrement associated with ICI enterocolitis is the difference between the immunotherapy patient cohort HRQoL and those experiencing ICI colitis. Mapping EQ-5D figures from an assessment of ulcerative colitis patients in remission compared to moderate or severe disease status suggests a HRQoL decrement of 0.20⁴³. Applying the median grade 2 colitis duration of 52 days offers a QALY decrement of 0.028.

Alternative HRQoL figures are offered by NICE TA342 which reported estimates of 0.88 for ulcerative colitis remission and 0.42 for active disease⁴⁴. Applying the median duration of 52 days to the utility decrement of 0.46 results in a disease burden estimate of 0.065.

An alternative approach to estimating the HRQoL decrement associated with ICI colitis was undertaken to assess the robustness of the previous HRQoL decrement estimation approach. A targeted literature search aimed to identify publications on the EQ-5D burden of adverse events in patients undergoing immunotherapy, one paper was identified which reports the disutility associated with treatment-related adverse events of any grade as −0.005⁴⁵. This generic adverse event disutility can be multiplied by the median duration of 52 days to offer a QALY reduction of 0.001.

The disease burden estimates of 0.028 and 0.065 incorporate evidence which is specific to ulcerative colitis as opposed to the more general approach of adverse events; the disease specific estimates are considered more plausible. 

Scenario analyses

AWTTC undertook a range of scenario analyses to assess the influence of key variables and assumptions. The main cost driver is the acquisition cost of infliximab. Currently the price of 100 mg vial of infliximab ranges between [commercial in confidence figure removed] and [commercial in confidence figure removed]. The lowest cost delivery of 3 cycles of 5 mg/kg with administration is [commercial in confidence figure removed]; the highest cost is [commercial in confidence figure removed]. Guidance for clinicians is to prescribe the lowest cost option. Prescribing data from Wales suggests that the lowest cost option is the most frequently delivered.

The base-case analysis assumes 3 cycles of infliximab at 5 mg/kg, to assess the robustness of the cost estimates to the delivery modality the minimum delivery dosing and maximum doses are calculated. The minimum dose is 1 cycle of infliximab at 5 mg/kg, with administration cost equalling [commercial in confidence figure removed]; the maximum dose is 5 mg/kg followed by 2 cycles of 10 mg/kg, with administration cost equalling [commercial in confidence figure removed].

The QALY burden in the main analysis uses a HRQoL decrement of 0.20 with a duration of 52 days to offer a QALY reduction of 0.028. Varying the duration by ±20% results in a QALY burden of 0.034 when increased by 20% and by 0.024 when decreased by 20%. There is a high level of uncertainty in the assumptions and figures used to calculate the QALY burden approach. Caution should be applied when incorporating this metric into decision making.

Cost-effectiveness evidence limitations

• There are no published cost-effectiveness studies for this intervention.
• The clinical effectiveness estimate is reported without the context of a comparator curative rate; this is due to the uncertainty as to the curative rate for patients who have previously not responded to corticosteroids. There may be patients achieving partial/total symptom reduction with oral steroids who continue treatment with corticosteroids and who are corticosteroid dependent.
• The cost consequence analysis is limited to intervention and administration costs. The cost impact of adverse events and ongoing healthcare resource use are not included as there is insufficient supporting evidence. Total costs are therefore underestimated for the intervention and the comparator.
• The meta-analysis informing the clinical evidence pools studies from across the disease grade, including grade 1–4²⁵. Including other disease grades may be misleading if there is a significant interaction between severity and curative rates. There is evidence suggesting that less severe grades respond more quickly to therapeutic intervention¹⁷.
• The time horizons in the included clinical studies are insufficient to capture any potential intermediate or longer-term clinical effects; this prohibits drawing any robust conclusions as to the lifetime cost-effectiveness.  
• The HRQoL estimates are sourced from ulcerative colitis, whilst the equality of impact is supported by the published evidence; direct immune checkpoint inhibitor-induced enterocolitis data would be preferred, and therefore the estimates should be treated with caution. A further limitation is equality of impact evidence, in that the data was collected during the SARS-CoV-2 pandemic where impacts to daily routines may have masked the influence of the study health conditions.
• The burden of disease data is highly uncertain; the three estimates of the impact of enterocolitis in this patient group are inconsistent. This uncertainty and heterogeneity mean it is not possible to draw robust conclusions.
• The time to symptom resolution for grade 2 ICI-induced enterocolitis figure of 52 days includes the broader population and not those who have not responded to first‑line immunosuppression. The time horizon may be longer in those who are less likely to respond to steroid treatment.
• Outcomes include evidence from clinical opinion in the absence of published literature. Whilst clinical expert opinion is an important component in the evidence hierarchy it is more susceptible to bias and uncertainty than well conducted randomised control trials.
• Net costs are highly sensitive to the delivery modality, particularly the amount of cycles administered. Variation in delivery modality may result in significant changes to the net intervention cost.

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Budget impact

Welsh clinicians estimate that around 12 people in Wales per year would receive treatment with infliximab. This includes patients with grade 3–4 enterocolitis who are eligible under the existing One Wales recommendation (OW21) plus those eligible under the extensions for use considered in this reassessment. This is a reduction from the 20 patients per year estimated for the original assessment.

The infliximab treatment regimen is typically 5 mg/kg given as an intravenous infusion up to a maximum of three doses. Clinicians estimate that 1 of the 12 patients would require dose escalation to 10 mg/kg due to lack of response to the first 5 mg/kg dose. It is assumed that all eligible patients would receive between one and three doses of infliximab within a single year. Medicine and administration costs per patient are shown in Table 2. The total annual costs for 12 patients are given in Table 3.

Table 2. Estimated annual costs for infliximab per patient in Wales (opens image in new tab)

Table 3. Range of total annual costs for infliximab for 12 patients in Wales (opens image in new tab)

Budget impact issues

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Additional factors

Prescribing unlicensed medicines

Infliximab is not licensed to treat this indication and is therefore prescribed ‘off label’. Prescribers should consult their relevant guidelines on prescribing unlicensed medicines before any off-label medicines are prescribed.

  

Care has been taken to ensure the information is accurate and complete at the time of publication. However, the All Wales Therapeutics and Toxicology Centre (AWTTC) do not make any guarantees to that effect. The information in this document is subject to review and may be updated or withdrawn at any time. AWTTC accept no liability in association with the use of its content. An Equality and Health Impact Assessment (EHIA) has been completed in relation to this assessment and this found there to be a positive impact. 

Information presented in this document can be reproduced using the following citation: All Wales Therapeutics & Toxicology Centre. Evidence Status Report. Reassessment of infliximab for the treatment of immune checkpoint inhibitor induced enterocolitis OW21. 2024.
Copyright AWTTC 2024. All rights reserved.

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• Reassessment (to include grade 2 enterocolitis): One Wales Interim Decision with starting and stopping criteria September 2024 PDF 56KB
• Reassessment (to include grade 2 enterocolitis): Decision rationale September 2024 PDF 39KB
• Reassessment (to include grade 2 enterocolitis): Evidence Status Report September 2024 PDF 245KB
• Reassessment (to include grade 2 enterocolitis): Equality and Health Impact Assessment September 2024 PDF 142KB 
• Original assessment (grades 3-4 enterocolitis): One Wales Interim Decision with starting and stopping criteria February 2023 PDF 87KB
• Original assessment (grades 3-4 enterocolitis): Evidence Status Report February 2023 PDF 164KB