Paclitaxel as albumin-bound nanoparticles with gemcitabine for untreated metastatic pancreatic cancer

Evidence-based recommendations on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel; Abraxane) for untreated metastatic pancreatic cancer in adults.

# Recommendations
Paclitaxel as albumin-bound nanoparticles (nabpaclitaxel) with gemcitabine is recommended as an option for untreated metastatic adenocarcinoma of the pancreas in adults, only if:
-ther combination chemotherapies are unsuitable and they would otherwise have gemcitabine monotherapy and
the company provides nabpaclitaxel with the discount agreed in the patient access scheme.
This recommendation is not intended to affect treatment with nabpaclitaxel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
NICE reviewed its technology appraisal guidance on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel) in combination with gemcitabine for previously untreated metastatic pancreatic cancer (TA360) because the company submitted more evidence and proposed a patient access scheme that would make nabpaclitaxel available with a confidential price discount.
Nabpaclitaxel plus gemcitabine would normally be considered for people with metastatic adenocarcinoma of the pancreas who would otherwise have gemcitabine.
Evidence shows that nab-paclitaxel plus gemcitabine is more effective in increasing survival than gemcitabine monotherapy, but is less effective than FOLFIRINOX (a combination of fluorouracil, leucovorin, irinotecan and oxaliplatin) and similarly effective to gemcitabine plus capecitabine (although the results were uncertain).
Nabpaclitaxel plus gemcitabine met NICE's end-of-life criteria when compared with gemcitabine monotherapy, but not when compared with gemcitabine plus capecitabine or FOLFIRINOX because it did not improve survival.
The most likely estimate of cost effectiveness compared with gemcitabine monotherapy is 41,000 to 46,000 per quality-adjusted life year (QALY) gained. Nabpaclitaxel plus gemcitabine is not cost effective compared with gemcitabine plus capecitabine or FOLFIRINOX.
Nabpaclitaxel plus gemcitabine can therefore be recommended for people with metastatic pancreatic cancer only if other combination chemotherapies are not suitable, and they would otherwise have gemcitabine monotherapy.# The technology
Paclitaxel as albumin-bound nanoparticles (nab-paclitaxel; Abraxane, Celgene)
Marketing authorisation
Paclitaxel as albumin-bound nanoparticles with gemcitabine is indicated 'for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas'.
Recommended dose and schedule
Dosage
Nab-paclitaxel: 125 mg/m2 intravenous infusion on days 1, 8 and 15 of a 28day cycle.
Gemcitabine: 1,000 mg/m2 intravenous infusion immediately after each nab-paclitaxel administration.
Average length of a course of treatment
Treatment should be continued until disease progression or unacceptable toxicity (median time in pivotal trial 15 weeks).
Price
The UK list price is 246.00 per 100mg vial.
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of nab-paclitaxel, with the discount 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 does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Celgene and a review of this submission by the evidence review group (ERG). It took into account the evidence and committee considerations in NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel) in combination with gemcitabine for previously untreated metastatic pancreatic cancer (TA360) and the new evidence submitted as part of this review of that guidance. See the committee papers for full details of the evidence.

# Clinical need and patient perspective

## Clinicians and patients would value additional options for pancreatic cancer
The committee understood that untreated metastatic adenocarcinoma of the pancreas is associated with a poor prognosis because many people are not diagnosed until the cancer is very advanced, and survival may be only 2 to 6 months. The patient expert explained that a diagnosis of pancreatic cancer can have a devastating effect on patients and their families. The committee recognised that extension to life is therefore very important to people with this condition and their families. The committee understood that current treatment options for pancreatic cancer have a number of limitations. In particular, FOLFIRINOX (a combination of fluorouracil, leucovorin, irinotecan and oxaliplatin) can be associated with serious adverse effects. Some people are unable to take FOLFIRINOX or choose not to do so, whereas gemcitabine monotherapy is better tolerated but less effective. The patient expert explained that many patients would be willing to accept some additional side effects if it resulted in longer life expectancy. The committee acknowledged that the prognosis for people with untreated metastatic pancreatic cancer is poor and that current treatments are limited in efficacy or associated with significant adverse events. It therefore recognised the value of additional treatment options in this area.

# Current practice and comparators

## FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy are potentially relevant comparators for nab-paclitaxel
The clinical experts explained that FOLFIRINOX is the preferred choice in clinical practice for untreated pancreatic cancer, because it has the most favourable survival compared with the other available treatments. The committee heard that patients for whom FOLFIRINOX is unsuitable would normally be offered gemcitabine monotherapy, which, although more tolerable, is associated with poorer overall survival than FOLFIRINOX. The clinical experts explained that there is a group of patients in clinical practice for whom FOLFIRINOX is unsuitable but who would be fit enough to tolerate a doublet therapy such as nabpaclitaxel plus gemcitabine. The committee understood that the suitability of FOLFIRINOX could not be defined by specific criteria, and would depend on a number of factors, including age, performance status, comorbidities and patient choice. It understood that some patients for whom FOLFIRINOX is otherwise suitable would choose not to have this treatment because of its considerable toxicity. The clinical experts explained that gemcitabine plus capecitabine is rarely used in practice, but the committee was aware of evidence that showed there is some use of gemcitabine doublet chemotherapy for pancreatic cancer in the NHS in England. The committee was also aware that the NICE scope and company decision problem listed FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy as comparators, and considered that all 3 were options in the NHS for the population covered by this appraisal. The committee took into account its decision in TA360. It concluded that FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy were all potentially relevant comparators for nabpaclitaxel plus gemcitabine.

## Gemcitabine monotherapy is the most appropriate comparator if other combination chemotherapies are unsuitable
The committee acknowledged that the company considered gemcitabine monotherapy to be the most relevant comparator, because nabpaclitaxel plus gemcitabine would not displace FOLFIRINOX or gemcitabine plus capecitabine in clinical practice.
The company stated that FOLFIRINOX is an intensive and toxic therapy that is only suitable for a clinically defined group of patients, for whom nabpaclitaxel would not be considered and who would continue to have this regimen despite the availability of nabpaclitaxel. However, the committee recalled that the suitability of FOLFIRINOX could not be defined by specific criteria, and would depend on a number of factors including patient choice (see section 3.2). It therefore considered that there may be some people for whom nabpaclitaxel plus gemcitabine is an option who would otherwise have had FOLFIRINOX.
The company also stated that gemcitabine plus capecitabine has not shown a significant survival benefit over gemcitabine monotherapy and is only used in a few UK centres. The committee heard that the clinical experts did not consider gemcitabine plus capecitabine to be an alternative to nabpaclitaxel plus gemcitabine. However, the committee did not hear how patients who would be offered gemcitabine plus capecitabine or nabpaclitaxel were distinct.The committee heard from the clinical experts that nabpaclitaxel plus gemcitabine would be considered for people for whom other combination chemotherapies are unsuitable (and hence would otherwise have gemcitabine monotherapy) but who would be fit enough to tolerate nabpaclitaxel plus gemcitabine. It recalled that such patients could be identified in clinical practice (see section 3.2). The committee concluded that although all 3 currently used treatments are potentially relevant comparators, gemcitabine monotherapy is the most appropriate comparator in people for whom other combination chemotherapies are unsuitable.

# Nab-paclitaxel compared with gemcitabine

## Nab-paclitaxel plus gemcitabine is more effective than gemcitabine monotherapy
The committee noted that study CA046 showed that nabpaclitaxel plus gemcitabine had statistically significantly longer overall survival and progression-free survival, and higher response rates, than gemcitabine monotherapy. In the most recent data cut (May 2013), median overall survival increased by 2.1 months (the mean increase was 2.4 months) with nabpaclitaxel plus gemcitabine compared with gemcitabine monotherapy (median overall survival: 8.7 months compared with 6.6 months; hazard ratio  0.72; 95% confidence interval  0.62 to 0.83, p<0.0001). Data from the September 2012 data cut showed that progression-free survival increased by 1.8 months with nabpaclitaxel plus gemcitabine compared with gemcitabine monotherapy (median progression-free survival: 5.5 months compared with 3.7 months; HR 0.69; 95% CI 0.58 to 0.82, p<0.001). The committee noted that the ERG expressed concerns about the generalisability of CA046 to UK clinical practice, because older patients were under-represented. The committee was aware that the summary of product characteristics states that for patients aged 75 years and older, no benefit for nabpaclitaxel plus gemcitabine compared with gemcitabine monotherapy has been shown, but there were more serious adverse reactions and adverse reactions that led to stopping treatment. However, the committee understood that this was based on a small subgroup. The committee understood that clinicians would be cautious about using nabpaclitaxel plus gemcitabine in older patients, and considered that the evidence from CA046 was suitable for decision-making. The committee concluded that nabpaclitaxel plus gemcitabine was more clinically effective than gemcitabine monotherapy.

# Nab-paclitaxel compared with gemcitabine plus capecitabine and FOLFIRINOX

## The indirect comparison is uncertain but suitable for decision-making
The company presented a mixed treatment comparison using a fixed-effects model to compare nabpaclitaxel plus gemcitabine with FOLFIRINOX and with gemcitabine plus capecitabine. The committee noted that this model was updated from that used in TA360, including 2 more trials and focusing only on the population with metastatic pancreatic cancer (consistent with the committee's preference in TA360). It also noted that the updated results were very similar to the results of the mixed treatment comparison in TA360. It noted the ERG's comments that the validity of the results relied on the overall survival and progression-free survival hazards being proportional for all the trials included in the mixed treatment comparison, and that the ERG stated this was not true for CA046. The ERG also noted that the base-case mixed treatment comparison included a number of additional comparators, and stated that restricting the comparators to those in the decision problem would be more appropriate. The committee agreed that, taking into account the uncertainty from the proportional hazards assumption not being met, the mixed treatment comparison was preferable to having no data on which to make a decision. The committee, although recognising the uncertainty, concluded that the mixed treatment comparison could be used to compare nabpaclitaxel plus gemcitabine with gemcitabine plus capecitabine and with FOLFIRINOX.

## Nab-paclitaxel plus gemcitabine is less effective than FOLFIRINOX and similarly effective to gemcitabine plus capecitabine
The committee noted that the results of the mixed treatment comparison showed that FOLFIRINOX improved overall survival compared with nabpaclitaxel plus gemcitabine, although this result was not statistically significant (company base case: HR 0.77; 95% credible interval  0.58 to 1.01). It also noted that the results of the mixed treatment comparison showed there was no evidence to suggest a difference in overall survival between nabpaclitaxel plus gemcitabine and gemcitabine plus capecitabine (company base case: HR 0.97; 95% CrI: 0.64 to 1.47). The committee concluded that nabpaclitaxel plus gemcitabine was likely to be less clinically effective than FOLFIRINOX, and similarly effective to gemcitabine plus capecitabine.

# Adverse events

## Nab-paclitaxel plus gemcitabine may cause more adverse events than gemcitabine monotherapy or gemcitabine plus capecitabine
The company presented adverse event data from CA046 and the SIEGE trial. The committee understood that combining therapies was likely to increase the rate of adverse events, and noted that nabpaclitaxel plus gemcitabine was associated with more adverse events than gemcitabine monotherapy, including higher rates of peripheral neuropathy, neutropenia and fatigue. It noted that the company had presented adverse event data from the mixed treatment comparison analysis in TA360, which showed that the rates of neutropenia, febrile neutropenia, fatigue, peripheral neuropathy and leukopenia were higher for people who had nabpaclitaxel plus gemcitabine than for people who had gemcitabine plus capecitabine. It recognised that it was difficult from the data available to draw firm conclusions about the rates of adverse events between nabpaclitaxel plus gemcitabine and gemcitabine plus capecitabine. The committee recalled its consideration in TA360 that, based on the adverse event profiles in the pivotal studies, both nabpaclitaxel plus gemcitabine and FOLFIRINOX were associated with considerable toxicity, and that a difference in their adverse event profiles could not be reliably determined from the data available. The committee recognised that in clinical practice the dosage and administration schedules of combination therapies are modified to maintain efficacy but minimise adverse events. The clinical expert explained that the adverse effects associated with nabpaclitaxel, although serious, were mainly manageable. The committee concluded that nabpaclitaxel plus gemcitabine may be associated with more adverse events than gemcitabine or gemcitabine plus capecitabine.

# Cost-effectiveness evidence

## The model structure is appropriate for decision-making
The committee considered the company's model, the associated assumptions and the ERG's critique. It noted that the company had updated the model in TA360. It also noted its conclusions in TA360 that the model structure was largely appropriate. The committee therefore agreed that the structure of the company's model appropriately captured the aspects of untreated metastatic pancreatic cancer and was appropriate to use for decision-making.

# Model assumptions

## The assumptions in the economic model are generally reasonable, and the committee accepts the ERG's amendments
The committee discussed the company's assumptions for survival estimates, utilities and costs. It noted that the revised model incorporated the confidential discount for nabpaclitaxel proposed in the company's patient access scheme. The committee heard from the company that it had aimed to keep its base case as close as possible to NICE's preferred base case from TA360. The committee noted that the company had modelled overall survival, progression-free survival and time on treatment using parametric distributions, but the ERG proposed to use the KaplanMeier data where available and extrapolate the 'tails' of the curves only. The committee recalled its consideration in TA360 that neither method could be considered more appropriate, but recognised that the choice of method made very little difference to the cost-effectiveness estimates.
The committee noted that the company had used utility estimates from the Romanus study (with UK adjustment) in its base-case analysis, and the company and ERG had used estimates based on EQ-5D-5L from SIEGE in scenario analyses. The committee also noted that the ERG had disputed some of the company's costing assumptions, in particular that drug costs were based on a single average body surface area for all patients (rather than a different body surface area estimate for men and women) and that not all available vial and pack sizes were included. The committee noted that the ERG amended these assumptions in its exploratory analysis, and considered this amendment reasonable. The ERG also explored the costs associated with adverse events (diarrhoea, dehydration and vomiting of grade 3 or higher) in a scenario analysis. The ERG noted that the company base-case analysis includes adverse event disutilities (decreases in utility values because of adverse events) alongside health-state utility values from a clinical trial. The ERG considered this to be double counting and therefore proposed removing the disutilities; the committee accepted this approach. The committee concluded that the assumptions in the economic model were generally reasonable, and accepted the ERG's amendments to the company's assumptions.

# Cost-effectiveness estimates

## The most plausible ICER for nab-paclitaxel plus gemcitabine compared with gemcitabine is between 41,000 and 46,000 per QALY gained
The committee noted that in the company's base case, the incremental cost-effectiveness ratio (ICER) for nabpaclitaxel plus gemcitabine compared with gemcitabine was 46,657 per quality-adjusted life year (QALY) gained. It noted that in the ERG's preferred exploratory analysis the ICER was 41,250 per QALY gained. This analysis included the ERG's proposed changes:
to the modelling of overall survival, progression-free survival and time on treatment
to the costs, to use all available vial and pack sizes
to use different body surface areas for men and women and
to remove adverse event disutilities (see section 3.9).The committee also noted that the results of the ERG scenario analyses, which adjusted the costs of adverse events and used alternative utility values, increased the ICER to 45,571 per QALY gained. The committee was aware that the ICER remained below 50,000 per QALY gained in all of the ERG's scenarios, and almost all of the company's scenarios. Recalling that it accepted the ERG's amendments to the company's assumptions (see section 3.9), the committee it concluded that the most plausible ICER compared with gemcitabine was in the range of 41,000 to 46,000 per QALY gained.

## Nab-paclitaxel plus gemcitabine is not cost effective compared with FOLFIRINOX or gemcitabine plus capecitabine
The committee noted that the company's base case showed that nabpaclitaxel plus gemcitabine was dominated by FOLFIRINOX (that is, nabpaclitaxel plus gemcitabine was less effective and more costly). Nabpaclitaxel plus gemcitabine remained dominated by FOLFIRINOX in the ERG's exploratory analysis and scenario analyses. The company's base case also showed that nabpaclitaxel plus gemcitabine was dominated by gemcitabine plus capecitabine. The committee noted that the ERG's preferred exploratory analysis (in which the model was amended as outlined in sections 3.9 and 3.10) for nabpaclitaxel plus gemcitabine compared with gemcitabine plus capecitabine had an ICER of 99,837 per QALY gained. This increased to 107,898 per QALY gained in the scenario analyses that adjusted the costs of adverse events and used alternative utility values. The committee recognised the uncertainty associated with these ICERs, particularly given that they were based on the results of the mixed treatment comparison. The committee concluded that although the analyses comparing nabpaclitaxel plus gemcitabine with gemcitabine plus capecitabine and with FOLFIRINOX were subject to uncertainty, it was confident that nabpaclitaxel plus gemcitabine would not be considered a cost-effective use of NHS resources compared with these treatments.

# End of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods.

## Nab-paclitaxel plus gemcitabine meets the end-of-life criteria compared with gemcitabine monotherapy
The committee noted that the average life expectancy of people with pancreatic cancer was up to 6 months and therefore concluded that the short life expectancy criterion was met. It also noted that, compared with gemcitabine monotherapy, nabpaclitaxel plus gemcitabine had been shown to increase overall survival by a mean of 2.4 months in CA046. The committee noted that the survival data were mature and therefore considered that the survival gain estimate was robust. It recognised that this survival gain should be considered in the context of the very poor prognosis for metastatic pancreatic cancer. The committee noted that the survival gain was below what is normally considered appropriate for the extension-to-life criterion to be met (that is, it was less than 3 months). However, it agreed that the survival gain was particularly important relative to the average survival of people with this condition, and therefore this criterion could be accepted as met in this circumstance. The committee concluded that, for the comparison with gemcitabine monotherapy, nabpaclitaxel plus gemcitabine met the criteria to be considered a life-extending end-of-life treatment.

## Nab-paclitaxel plus gemcitabine does not meet the end-of-life criteria compared with FOLFIRINOX or gemcitabine plus capecitabine
The committee understood that both end-of-life criteria had to be met for the advice to be applied. The committee recalled that the mixed treatment comparison showed that FOLFIRINOX had a greater survival benefit than nabpaclitaxel plus gemcitabine and there was no difference in survival between nabpaclitaxel plus gemcitabine and gemcitabine plus capecitabine (see section 3.6). It concluded that the extension-to-life criterion had not been met for the comparison of nabpaclitaxel plus gemcitabine with FOLFIRINOX or gemcitabine plus capecitabine, because there was no survival benefit with nabpaclitaxel compared with these comparators. It further concluded that nabpaclitaxel plus gemcitabine did not meet the criteria to be considered a life-extending end-of-life treatment compared with gemcitabine plus capecitabine or with FOLFIRINOX.

# Other factors
No equalities issues were identified.
The Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of nabpaclitaxel.
The committee discussed how innovative nabpaclitaxel plus gemcitabine is in its potential to have a significant and substantial effect on health-related benefits. It understood that nabpaclitaxel is a novel formulation of paclitaxel and there is a high level of unmet need in terms of clinically effective treatment options for metastatic pancreatic cancer. The committee concluded that all health-related benefits had been adequately captured by the QALYs in the model.

# Conclusion

## Nab-paclitaxel is recommended when other combination chemotherapies are unsuitable
The committee recognised that, although gemcitabine and combination chemotherapies were appropriate comparators, clinicians could identify patients for whom combination chemotherapies were unsuitable (and who would otherwise have gemcitabine) but for whom nabpaclitaxel plus gemcitabine could be considered. It is this population who would have treatment with nabpaclitaxel plus gemcitabine in clinical practice. The committee noted that nabpaclitaxel plus gemcitabine was more effective than gemcitabine monotherapy. Taking into account the patient access scheme, the most plausible ICER was between 41,000 and 46,000 per QALY gained. The committee considered that the end-of-life criteria were met, because the survival gain of 2.4 months was particularly important relative to the average survival of people with this condition. Therefore, nabpaclitaxel plus gemcitabine could be considered a cost-effective use of NHS resources. Compared with combination chemotherapies (FOLFIRINOX and gemcitabine plus capecitabine), nabpaclitaxel plus gemcitabine did not provide a survival benefit, and could not be considered cost effective. The committee therefore concluded that nabpaclitaxel plus gemcitabine was recommended for people with adenocarcinoma of the pancreas for whom other combination chemotherapies were unsuitable and who would otherwise have gemcitabine monotherapy.