Pegylated liposomal irinotecan for treating pancreatic cancer after gemcitabine

Unmet need

4.1 The committee heard from the clinical and patient experts that metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine is associated with a poor prognosis because there are few treatments available. Survival may be less than 6 months. It heard from the patient experts that diagnosis is devastating and that symptoms, which include weight loss, pain, depression and anxiety, can be debilitating and difficult to manage. The committee recognised that extension to life and also quality of life were therefore very important to people with this condition. It understood that there have been few new treatments in this area. The committee concluded that the prognosis for people with metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine is poor and that current treatments are limited in efficacy. It therefore recognised the value of additional treatment options.

Treatment pathway

4.2 The committee noted that the treatment options for untreated metastatic pancreatic cancer include curative surgery (only suitable for 10 to 20% of the population), gemcitabine as recommended in NICE's technology appraisal guidance on gemcitabine for treating pancreatic cancer or FOLFIRINOX (folinic acid, 5‑FU, irinotecan, oxaliplatin). Treatment received at this stage would affect treatment later. The 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, and that 5‑FU plus LV alone is rarely used. The committee also heard from the clinical expert that treatment decisions take into account the balance between the risk and severity of adverse events and the effectiveness of treatment. Double and triple therapies are preferred to monotherapies if the adverse events are tolerable. The clinical and patient experts emphasised the importance of patient choice in treatment decisions. The committee agreed with the company, the 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. The committee concluded that an alternative treatment to oxaliplatin plus 5‑FU and LV would be of value.

Company's indirect treatment comparison with oxaliplatin plus 5‑FU and LV

4.4 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. Issues included different trial populations, incomplete data on patient baseline characteristics and different oxaliplatin plus 5‑FU and LV regimens in the oxaliplatin trials. But, to compare the cost effectiveness of the treatments, the company did an indirect comparison which generated hazard ratios to plot the oxaliplatin plus 5‑FU and LV Kaplan–Meier curve, using the 5‑FU plus LV curve from NAPOLI‑1. The committee acknowledged that the validity of the results relied on an assumption of proportional hazards (that is, the relative risk of an event is fixed irrespective of time) between treatments for overall survival and progression-free survival for all the trials included in the mixed treatment comparison, and that the company and ERG stated this was not true for NAPOLI‑1. The committee considered that for both overall survival and progression-free survival there was a violation of the proportional hazards assumption.

4.5 The committee also noted that the ERG had reviewed the literature given the uncertainties in the indirect treatment comparison. The ERG concluded that, in general, the progression-free survival and overall survival estimates appeared very similar for oxaliplatin plus 5‑FU and LV and for pegylated liposomal irinotecan plus 5‑FU and LV. The clinical expert commented that oxaliplatin plus 5‑FU and LV would be more effective than 5‑FU plus LV, but its relative effectiveness compared with pegylated liposomal irinotecan plus 5‑FU and LV was difficult to estimate. Recognising the uncertainty in the indirect comparison, the committee concluded that the company's approach could not be considered reliable for comparing the relative treatment effect of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV. However the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV could be considered broadly similar to oxaliplatin plus 5‑FU and LV.

Use of parametric modelling

4.7 The committee considered how the company had modelled overall survival, progression-free survival and time to treatment failure data using parametric modelling (a log-normal model for the company's base case). The company assumed that proportional hazards applied, but had fitted a log-normal curve to the results from both the pegylated liposomal irinotecan plus 5‑FU and LV and the 5‑FU plus LV groups. The committee heard that the ERG considered curve fitting to be inappropriate because most of the trial data were complete. It agreed with the ERG that of the 3 approaches explored, the preferred method used the Kaplan–Meier data directly from the trial with extrapolation for the 1 remaining patient in the 5‑FU plus LV group. The committee noted that the company did not provide a biological rationale for using the log-normal model, which estimated a 4.8% greater progression-free survival gain than the trial data when comparing pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV. Modelling time to treatment failure also underestimated the overall time on treatment and the company's modelling showed that benefit continued even after the patient had stopped treatment. The committee concluded that because the data for progression-free survival and time on treatment are complete and virtually complete for overall survival, using the Kaplan–Meier data from NAPOLI‑1 was more appropriate than using the company's parametric modelling.

4.8 When comparing survival on pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV, the committee heard from the ERG that using the company's indirect treatment comparison hazard ratios (assuming proportional hazards) to adjust the parametric curves was unreliable because of the issues with the indirect treatment comparison (see section 4.4). The committee also noted that the total quality-adjusted life years (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 plus LV and is standard clinical practice in the NHS. The committee concluded that the company's approach for modelling survival to compare pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV gave clinically implausible results and lacked robustness for decision-making.

Cost-related model assumptions

4.9 The committee considered the costs of pegylated liposomal irinotecan plus 5‑FU and LV and of the comparators (5‑FU plus LV and oxaliplatin plus 5‑FU and LV) included in the company's model. It noted that the company's model assumed that a reduced or missed dose because of adverse events in NAPOLI‑1 would reduce drug acquisition costs. The committee heard from the clinical expert that in clinical practice, parenteral treatments are often prepared by the pharmacy department when the patient is seen at the outpatient clinic and not when the patient is treated. Therefore planned treatment variations can be accounted for when treatment is given but are difficult to predict in advance. The committee concluded that it was not appropriate to assume that cost savings from dose reductions would always be accounted for in clinical practice and that full costing should be assumed in the base case.

4.10 The committee considered the costs of the generic comparators used in the company's model. It noted that the company used the list prices from the British national formulary, rather than taking costs from the Electronic Market Information Tool (eMit), which provides details of average prices paid by NHS hospitals in England for generic drugs. The committee also heard from the ERG that the company had assumed that only 1 vial size is available for each generic drug; 500 mg for 5‑FU, 50 mg for oxaliplatin and 50 mg for LV. However, the eMit database shows that there are multiple vial sizes for each of these generic drugs and that generally the larger the vial, the lower the cost per mg of the drug. The committee noted that the ERG had recalculated the average cost per dose of the intervention and the comparators using eMit prices, taking into account the range of vial sizes available for the generic drugs and the best combination of vial sizes for the dose needed. The committee 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.

Utility values used in the company's model

4.11 The committee noted that health-related quality-of-life data were collected in NAPOLI‑1 but these were incomplete and not used in the company's economic modelling. The company's health state utility values for all treatments were 0.742 for the pre-progression health state and 0.671 for the post-progression health state, taken from NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles for untreated pancreatic cancer. The committee was aware that the EQ‑5D values were weighted using the general US population tariff but adjusted for the UK population, and incorporated disutility values to account for adverse events of treatment. It also noted that the company used the same utility values regardless of the treatment the patient had (pegylated liposomal irinotecan plus 5‑FU and LV, oxaliplatin plus 5‑FU and LV, or 5‑FU plus LV). The committee heard that the ERG considered these values to overestimate patient health-related quality of life because they were taken from a population who had not had treatment and who were likely to be in better health. The committee heard from the company that it considered the performance status of patients in NAPOLI‑1 to be similar to that of the population in CA046 (the trial considered in NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles for untreated pancreatic cancer), because the patients in NAPOLI‑1 were fitter than those generally seen in clinical practice. Also, the distribution of the performance status scores was similar between the studies. The committee noted that the ERG had explored using utility values from people with gastric cancer, but it heard from the clinical expert that these utility values may not be comparable to people with pancreatic cancer. 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.

Most plausible ICERs

4.12 The committee considered the most plausible incremental cost-effectiveness ratio (ICER) for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV, including the patient access scheme. The committee noted that the company's base-case ICER including the patient access scheme was £96,591 per QALY gained. However, the committee considered that all the ERG's amendments, except the ERG's preferred health state utility values, should be included in the base case. The committee noted it did not have an ICER that reflected all of its preferred assumptions. The ERG's exploratory ICER, combining all ERG amendments, was £162,887 per QALY gained. When only amending the committee's preferred extrapolation of survival, with the remaining assumptions taken from the company's analyses, the ICER was £137,354 per QALY gained. It therefore 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 per QALY gained. The committee considered that the ICER was much higher than would normally be considered a cost-effective use of NHS resources.

4.13 Acknowledging that the analysis in section 4.12 compared pegylated liposomal irinotecan with a treatment (5‑FU plus LV) not considered to be established practice in the NHS, the committee considered the most plausible ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with oxaliplatin plus 5‑FU and LV (the appropriate comparator), including the patient access scheme for pegylated liposomal irinotecan. The committee noted that the company's base-case ICER including the patient access scheme was £54,412 per QALY gained. It also noted that the ERG's exploratory ICER, combining all the ERG's scenarios including the committee's preferred extrapolation of survival, was £106,898 per QALY gained. The committee also noted that because of the uncertain clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV compared with oxaliplatin plus 5‑FU and LV, particularly with the total QALYs for oxaliplatin plus 5‑FU and LV being implausibly lower than 5‑FU plus LV in the company's submission (see section 4.8), the ERG did further exploratory analyses altering the QALY difference between the 2 treatments. When taking into account these scenarios, the ICER ranged from £201,019 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]). The committee concluded that although the analyses comparing pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV were subject to considerable uncertainty, it was confident that pegylated liposomal irinotecan plus 5‑FU and LV would not be considered a cost-effective use of NHS resources.