NICE Issues Technology Appraisal Guidance for Pegylated Liposomal Irinotecan

NICE does not recommend it for the treatment of metastatic pancreatic cancer after gemcitabine-based therapy

On 26 April 2017, the NICE published technology appraisal guidance [TA440] in which it was stated that pegylated liposomal irinotecan, in combination with 5‑fluorouracil (5-FU) and leucovorin (LV), is not recommended, within its marketing authorisation, for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.

This guidance is not intended to affect the position of patients whose treatment with pegylated liposomal irinotecan was started within the NHS before this guidance was published. Treatment of these 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.

Current practice

Metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine treatment is associated with a poor prognosis because there are few treatments available, and survival may be less than 6 months. Current treatments are limited in efficacy so there is value in more treatment options in this area.

The technology

The appraisal committee heard from the clinical and patient experts that there were few options for treating metastatic adenocarcinoma of the pancreas and that pegylated liposomal irinotecan plus 5‑FU and LV would provide another option. However, the committee concluded that having an extra treatment option did not mean that pegylated liposomal irinotecan plus 5‑FU and LV was innovative. It also concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations.

What is the position of the treatment in the pathway of care for the condition?

The appraisal committee understood from the clinical expert that oxaliplatin plus 5‑FU and LV or capecitabine monotherapy are used in clinical practice in England after gemcitabine treatment. The committee agreed with the company, evidence review group (ERG) and advice from the clinical expert that the most appropriate comparator for pegylated liposomal irinotecan plus 5‑FU and LV in NHS practice would be oxaliplatin plus 5‑FU and LV.

Adverse reactions

In NAPOLI‑1, treatment-emergent serious adverse events (that is, events that first appear during treatment, or worsen during treatment) were more common in the pegylated liposomal irinotecan plus 5‑FU and LV group than in the 5‑FU plus LV group (47.9% compared with 44.8%). The committee noted that health-related quality-of-life data were collected in NAPOLI‑1 and that the results at 6 weeks and 12 weeks showed no real differences between the groups, suggesting no negative effect of pegylated liposomal irinotecan on health-related quality of life.

Evidence for clinical effectiveness

The company's submission presented clinical-effectiveness evidence from NAPOLI-1, comparing pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV.

The company considered that a formal indirect comparison of the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV was not appropriate because the trials were too heterogeneous.

Relevance to general clinical practice in the NHS

The patients in NAPOLI‑1 were fitter than those generally seen in clinical practice.

Uncertainties generated by the evidence

The committee noted that given the uncertainties inherent in the indirect treatment comparison, the ERG reviewed the literature and concluded that, in general, the progression-free survival (PFS) and overall survival (OS) estimates appeared very similar for oxaliplatin plus 5‑FU and LV and pegylated liposomal irinotecan plus 5‑FU and LV. The committee also noted that the relative effectiveness of oxaliplatin plus 5‑FU and LV compared with pegylated liposomal irinotecan plus 5‑FU and LV was difficult to estimate.

Estimate of the size of the clinical effectiveness including strength of supporting evidence: The median extension in OS in NAPOLI‑1 for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was 1.9 months.

Both the company and the ERG were unable to produce a reliable estimate of the difference in OS between pegylated liposomal irinotecan plus 5‑FU and LV and oxaliplatin plus 5‑FU and LV, but when comparing 3 trials of oxaliplatin plus 5‑FU and LV the median OS was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1.

Evidence for cost effectiveness

The company submitted a de novo economic model to estimate the cost effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV, compared with 5‑FU plus LV and with oxaliplatin plus 5‑FU and LV, in patients with metastatic adenocarcinoma of the pancreas after gemcitabine treatment.

The company used an indirect treatment comparison to estimate OS, PFS and time-on-treatment curves for the comparison with oxaliplatin plus 5‑FU and LV.

Uncertainties around and plausibility of assumptions and inputs in the economic model

The company made assumptions about the costs and survival estimates.

The committee noted that the total QALYs for oxaliplatin plus 5‑FU and LV were significantly lower than for 5‑FU plus LV in the company's analysis. It acknowledged that this result was not in agreement with comments from the clinical expert, who stated that oxaliplatin plus 5‑FU and LV is the preferred option; it is more clinically effective than 5‑FU and LV and is standard clinical practice in the NHS.

The committee concluded that because the data were complete for PFS and time on treatment, and virtually complete for OS, using the Kaplan–Meier data from NAPOLI‑1 was more appropriate than using the company's parametric modelling.

The committee concluded that it was not appropriate to assume dose reductions would always apply in the company's model and that full costing should be assumed in the base case. It also concluded that it was not appropriate to assume use of the smallest sized vials in the company's model and that the ERG's method of calculating costs was more appropriate.

Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?

The committee concluded that although there was uncertainty about the most appropriate utility values to use for a second-line treatment population with pancreatic cancer, the values used by the company were acceptable for decision-making.

The committee concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations.

What are the key drivers of cost effectiveness?

For the comparison of pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV the committee considered that all the changes, except the ERG's preferred health state utility values, should be included in the base case. The committee therefore concluded that the incremental cost-effectiveness ratio (ICER) for pegylated liposomal irinotecan plus 5‑FU and LV, compared with 5‑FU plus LV, was over 100,000 GBP per QALY gained.

For the comparison of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV, the ERG carried out scenarios altering the QALY difference between the 2 treatments. When taking into account these scenarios, the ICER ranged from 201,019 GBP per QALY gained (when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% less than for pegylated liposomal irinotecan plus 5‑FU and LV) to pegylated liposomal irinotecan plus 5‑FU and LV being dominated (that is, less effective and more expensive than oxaliplatin plus 5‑FU and LV) when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% more.

Most likely cost-effectiveness estimate (given as an ICER)

The committee concluded that taking into account all of the ICERs presented, the ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was over 100,000 GBP per QALY gained.

Additional factors taken into account

Patient access schemes

The committee considered analyses incorporating the confidential patient access scheme for pegylated liposomal irinotecan plus 5‑FU and LV.

End-of-life considerations

The committee concluded that the criterion for short life expectancy was met.

However, pegylated liposomal irinotecan plus 5‑FU and LV survival estimates from the trial and model showed that the criterion for extension to life was not met for the comparison with 5‑FU plus LV or with oxaliplatin plus 5‑FU and LV. The committee noted that when comparing 3 trials of oxaliplatin plus 5‑FU and LV, the median OS was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1.

Therefore, the committee concluded that pegylated liposomal irinotecan plus 5‑FU and LV did not meet the NICE supplementary advice criteria to be considered as a life-extending, end-of-life treatment.