On 11 January 2017, NICE published evidence-based recommendations on pembrolizumab (Keytruda) for treating PD-L1-positive non-small cell lung cancer (NSCLC) in adults who have had chemotherapy. The NICE guidance states that pembrolizumab is recommended as an option for treating locally advanced or metastatic PD‑L1‑positive NSCLC in adults who have had at least one chemotherapy (and targeted treatment if they have an EGFR- or ALK‑positive tumour), only if:
- pembrolizumab is stopped at 2 years of uninterrupted treatment and no documented disease progression, and
- the company provides pembrolizumab with the discount agreed in the patient access scheme revised in the context of this appraisal.
This guidance is not intended to affect the position of patients whose treatment with pembrolizumab was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.
Pembrolizumab is a humanised monoclonal antibody that acts on the PD‑1. The PD‑1 protein is part of the immune checkpoint pathway, and blocking its activity may promote an anti-tumour immune response.
The most common treatment-related adverse events associated with pembrolizumab include fatigue, decreased appetite, nausea, rash and pruritus. Recommended dose and schedule is 2 mg/kg every 3 weeks by intravenous infusion. The summary of product characteristics recommends treatment with pembrolizumab until disease progression or unacceptable toxicity.
Pembrolizumab is available at a cost of 1,315.00 GBP per 50‑mg vial (excluding VAT; 'British national formulary' [BNF] online, accessed November 2016).
The company has agreed a patient access scheme with the Department of Health. This scheme provides a discount to the list price of pembrolizumab applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.
The appraisal committee concluded that pembrolizumab had an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 based on the KEYNOTE-010 trial data.
The committee noted the uncertainty around the optimal treatment duration and was aware that consultation comments from NHS England stated that data on the optimal treatment duration of checkpoint inhibitors such as pembrolizumab will begin to be available within the next 2 years. NHS England commented during consultation that it was confident that a 2-year stopping rule would be acceptable to both patients and clinicians and would be implementable.
It recalled that the incremental cost-effectiveness ratios (ICERs) are sensitive to a continued treatment effect after stopping treatment, with a range when using the company's preferred assumptions of 61,954 GBP to 44,490 GBP per QALY gained, but concluded that within the uncertainties and with implementation of a 2-year stopping rule, the majority of plausible ICERs are below the range usually considered to be a cost-effective use of NHS resources.
The committee discussed whether, overall, pembrolizumab is a cost-effective use of NHS resources, taking into account the most plausible ICER and the uncertainty that has been identified. It was also aware and that there would be a wider benefit to the NHS because the simple discount agreed in the patient access scheme would apply across all indications. It concluded that pembrolizumab should be recommended for routine use with a 2-year stopping rule, but the guidance should be reviewed 2 years after publication to take in account more mature evidence.
Patients with locally advanced or metastatic NSCLC have a poor prognosis. It is a debilitating condition with many distressing symptoms. Improving quality of life and even small extensions in duration of life are of considerable importance to this patient group.
Patients with NSCLC have limited treatment options and existing treatments such as docetaxel can cause severe adverse effects. Premedication is not needed before pembrolizumab and it is generally well tolerated. Based on clinical trial data, pembrolizumab provides a statistically significant median overall survival gain compared with docetaxel and an important extension-to-life benefit for patients with locally advanced or metastatic NSCLC whose tumours express PD‑L1.
The appraisal committee noted that the marketing authorisation for pembrolizumab states that people should have treatment based on their tumour's expression of PD‑L1 (that is, with a tumour proportion score [TPS] ≥1%), confirmed by a validated test.
Platinum therapy is given as a first treatment for NSCLC in patients whose tumours are not EGFR‑positive, followed by docetaxel or docetaxel plus nintedanib (depending on tumour histology). For patients with EGFR‑positive tumours, treatment starts with a tyrosine kinase inhibitor, followed by a platinum therapy option. For patients with ALK‑positive tumours, platinum combination therapy followed by an ALK inhibitor are the standard treatment choices. The committee heard from the clinical experts that pembrolizumab would be an alternative to docetaxel or to docetaxel plus nintedanib (depending on tumour histology) in patients who have had targeted treatment for EGFR‑ or ALK‑positive tumours.
The committee concluded that pembrolizumab was appropriately positioned in the clinical pathway as a treatment option for people who have had 2 or 3 therapies and as an alternative to docetaxel or to docetaxel plus nintedanib.
The clinical evidence for treating NSCLC came from 3 studies (KEYNOTE-001, KEYNOTE-010 and LUME-LUNG-01). The committee considered that the KEYNOTE-010 evidence was the most applicable to the decision problem because the KEYNOTE-010 population consisted only of patients with PD‑L1‑positive NSCLC, whereas KEYNOTE-001 is a non-randomised cohort study of pembrolizumab which retrospectively identified PD‑L1 status and used the docetaxel arm of KEYNOTE-010 as a comparator; this can lead to a greater risk of bias. The committee concluded that pembrolizumab had an important extension-to-life benefit for patients with locally advanced or metastatic NSCLC whose tumours express PD‑L1 based on the trial data.
The committee heard from the clinical experts that the overall population in KEYNOTE-010 was likely to be the same as those who have pembrolizumab in clinical practice. The committee concluded that the population in KEYNOTE-010 was generalisable to clinical practice in England.
In the overall population in KEYNOTE-010 the median overall survival gain was 10.5 months for pembrolizumab compared with 8.6 months for docetaxel. The committee concluded that pembrolizumab had an important extension-to-life benefit compared with docetaxel.
The committee heard that patients with NSCLC have a life expectancy of less than 24 months. The committee heard that the average number of months of life gained with pembrolizumab, as estimated by the company's economic model, is between 21.2 and 22.8 months, compared with 10.4 months with docetaxel. It agreed that there is significant uncertainty in the overall survival gain, and that this degree of benefit is likely to be optimistic. However, it was reasonable to assume that the benefit is likely to exceed 3 months. The committee therefore concluded that pembrolizumab met the end-of-life criteria and that it can be considered a life-extending, end-of-life treatment.