Avelumab for untreated metastatic Merkel cell carcinoma

Evidence-based recommendations on avelumab (Bavencio) for untreated metastatic Merkel cell carcinoma in adults.

# Recommendation
Avelumab is recommended as an option for treating metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease. It is recommended only if the company provides avelumab according to the commercial arrangement.
Why the committee made this recommendation
This appraisal reviews the additional evidence collected in the Cancer Drugs Fund managed access agreement for avelumab for metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease (NICE technology appraisal guidance 517). The new evidence includes data from clinical trials and from people having treatment in the NHS while this treatment was available in the Cancer Drugs Fund in England.
Avelumab is routinely available in the NHS for treating metastatic Merkel cell carcinoma after chemotherapy. Evidence collected while avelumab was in the Cancer Drugs Fund shows that it is an effective treatment for untreated disease. It shows that, compared with chemotherapy, avelumab improves how long people have before their disease progresses and how long they live.
Avelumab is considered to be a lifeextending treatment at the end of life. Costeffectiveness estimates for avelumab are within what NICE consider an acceptable use of NHS resources. Therefore, it is recommended.# Information about avelumab

# Marketing authorisation indication
Avelumab (Bavencio, Merck/Pfizer) is indicated as monotherapy for 'the treatment of adult patients with metastatic Merkel cell carcinoma'.

# Dosage in the marketing authorisation
The full dosage schedule is available in the summary of product characteristics.
The licensed dose has changed since NICE's technology appraisal guidance on avelumab for treating metastatic Merkel cell carcinoma. The dosage given in the JAVELIN trial was 10 mg/kg. In November 2019, the approved dose was changed to the dose described in the summary of product characteristics.

# Price
The list price of avelumab is 768 per 200-mg vial (excluding VAT; British National Formulary , accessed January 2021). The company has a commercial arrangement. This makes avelumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck, a review of this submission by the evidence review group (ERG), NICE's technical engagement response form, and responses from stakeholders. See the committee papers for full details of the evidence.

# Clinical need and treatment pathway

## Metastatic Merkel cell carcinoma is a rare disease with limited treatment options
Patient groups explained in their written submissions that metastatic Merkel cell carcinoma is an aggressive and frightening cancer for patients. This fear stems from its visibility on the surface of the skin, the potential for disfigurement and rapid observable changes. Because its diagnosis is rare, clinical data and research are limited. This leads people to worry that decision making relating to future treatments and options will be impacted. Merkel cell carcinoma is currently treated with chemotherapy and best supportive care. However, chemotherapy is rarely effective and relapse rates are high with little sustained response. Because of the absence of alternative treatments, people often choose to have chemotherapy despite its limited effectiveness. Avelumab is already routinely used in metastatic Merkel cell carcinoma but only after chemotherapy. Earlier use of avelumab would offer people an alternative to chemotherapy. Benefits include a sustained response, fewer side effects and positive impact on quality of life. The patient expert present at the committee meeting also explained that avelumab makes a huge difference both physically and psychologically to people with metastatic Merkel cell carcinoma and their families. The committee concluded that there is a high unmet need for effective treatments in metastatic Merkel cell carcinoma and that early use of avelumab in the course of the disease would be welcomed by people with the disease and their families.

# Clinical trial evidence from JAVELIN

## Avelumab is an effective treatment for metastatic Merkel cell carcinoma
The clinical-effectiveness evidence came from JAVELIN, a single-arm open-label trial in people with metastatic Merkel cell carcinoma. The trial has 2 parts:
Part A: people with disease relapse after at least 1 line of chemotherapy.
Part B: people who had not had previous systemic therapy for metastatic disease.The first-line cohort (part B) is relevant to this appraisal. The main clinical uncertainties identified by the committee in NICE's technology appraisal guidance on avelumab for treating metastatic Merkel cell carcinoma (from now on, referred to as TA517) were the small numbers of people in the cohort, the short follow up and the immaturity of the progression-free survival (PFS) and overall-survival (OS) data. The committee concluded that more mature OS data from JAVELIN part B would be likely to resolve uncertainty around the treatment effect of avelumab and allow more reliable cost-effectiveness estimates. This appraisal reviews the most recent data from JAVELIN part B, which includes 116 people and has a median follow up of 16 months. The results show a median OS of 20 months, and a median PFS of 4.1 months. OS at 6 months was 75%, decreasing to 60% at 12 months. PFS at 6 months was 41%, decreasing to 31% at 12 months. The committee concluded that the mature data from JAVELIN show that avelumab is an effective treatment for metastatic Merkel cell carcinoma in people who have not had previous systemic therapy for metastatic disease.

## JAVELIN is generalisable to UK clinical practice
The committee discussed the baseline characteristics of people in JAVELIN part B. The ERG's commented that, compared with clinical practice, the population may be slightly younger, and include more men and people with more favourable Eastern Cooperative Oncology Group (ECOG) performance scores. Professional and patient groups at technical engagement also commented that the trial population broadly resembles people in clinical practice, but with more men and a higher than expected proportion of people with an ECOG score of 0 (meaning they are fully active). The clinical experts agreed that the trial population is broadly representative and explained that any differences between the trial and people who have treatment in clinical practice are not unique to metastatic Merkel cell carcinoma. These differences are seen in many cancers, as frailer people are generally excluded from cancer trials. The committee also heard from the company that the efficacy and safety outcomes from JAVELIN are similar to outcomes expected in the clinical setting. The committee concluded that the results from JAVELIN are generalisable to the NHS.

# Clinical evidence from the systemic anticancer therapy (SACT) data

## SACT provides an additional data source to support decision making
Observational data for patients in the Cancer Drugs Fund obtained from the SACT dataset were presented by the company but were not included in its economic analysis. However, the ERG used the SACT dataset in a scenario analysis. The SACT dataset includes 52 people and has a median follow up of 6 months. The results showed a median OS of 11.8 months. OS at 6 months was 58%, decreasing to 50% at 12 months. PFS data were not collected. The committee noted that there were several limitations with the SACT data compared with JAVELIN part B, including a smaller sample size (n=52 versus n=116), data immaturity (median follow up for OS is 6 months versus 16 months), and a reduced number of outcomes collected. The committee concluded that the SACT data are limited by these factors but could be used as an additional data source to support decision making.

# Indirect treatment comparison of avelumab and chemotherapy

## The ERG's adjusted analysis was preferred by the committee
In TA517, the company did a naive (that is, unadjusted) indirect comparison of avelumab against chemotherapy using a retrospective observational study of people with metastatic Merkel cell carcinoma (study 100070Obs001). The company did this study specifically to compare avelumab with chemotherapy. For this appraisal, it updated its naive indirect comparison with the 2019 JAVELIN part B data. No new data for chemotherapy were identified. The results of the naive indirect comparison suggest that avelumab improves overall response rates, PFS and OS compared with chemotherapy. However, the ERG was concerned about the methodological robustness of using a naive unadjusted comparison. It noted that by using a naive pooled analysis of multiple chemotherapy studies, the company was likely to introduce unnecessary heterogeneity into the analysis. The ERG considered the use of the immunocompetent subgroup of study 100070Obs001 more appropriate for a naive comparison with JAVELIN, as JAVELIN only includes people who are immunocompetent. However, the ERG noted that this approach is still potentially unreliable. At clarification, the ERG requested that the company perform propensity score weighting analysis to compare avelumab with chemotherapy efficacy using JAVELIN part B and study 100070Obs001. The ERG's preferred analysis adjusted for age, sex and ECOG performance score and maintained all patients in the analysis while achieving the best balance in baseline characteristics. The committee agreed with the ERG that an adjusted analysis was more appropriate than a naive comparison.

# Cost effectiveness

## The company's updated model uses the committee's preferred assumptions
The committee considered the preferred committee assumptions from TA517. It recalled that the cost-effectiveness estimates were largely dependent on the modelling of PFS and OS, which were uncertain because the trial data were immature. The committee had concluded that there was a plausible potential for avelumab to be cost effective, and that further clinical data from JAVELIN based on a larger number of people with longer follow up could reduce the uncertainty and produce more reliable cost-effectiveness estimates using the original economic model. The ERG explained that the model structure remained the same and was generally in line with the committee's preferred assumptions. The committee was satisfied the company had adhered to the preferred assumptions from TA517.

## The modelling of OS is appropriate
To estimate the expected overall survival for avelumab, the company used a 1knot odds splinebased model. The ERG considered a 1knot splinebased model to be appropriate but preferred the 1knot hazard spline. It highlighted that uncertainties in the naive comparison of the treatment effects of avelumab with chemotherapy meant that a more conservative approach using the hazard-based 1knot spline was appropriate. After technical engagement, the committee heard from the company that all 3 of the 1knot modelling approaches produced estimates in line with clinical advice. Each curve produced was also a near-identical fit to the Kaplan-Meier curve. The company explained that the ERG's preferred 1knot hazard spline, when extrapolated, eventually resulted in an estimated hazard of death that exceeds that of the base-case analysis in TA517 for people who have had 1 or more lines of chemotherapy. This does not align with clinical opinion that a treatment-naive population has better outcomes than those who have had chemotherapy. The ERG acknowledged that all 3 of the 1knot models presented by the company are very similar and, on its own, the selection of model is unlikely to make a difference to decision making. The committee agreed with the ERG's comments and concluded that the modelling of OS is appropriate for decision making.

## The modelling of PFS is appropriate
To extrapolate PFS for avelumab, the company used a 2knot odds splinebased model. The ERG noted that the 2knot odds splinebased model underestimated the Kaplan-Meier data between 0.5 and 1 year and overestimated the Kaplan-Meier data for the tail. The ERG considered the 3knots odds spline to provide a better extrapolation as well as a better fit to the data. After technical engagement, the company commented that there was little evidence to reject one model in favour of the other, and that both models are suitable for decision making with limited impact on the incremental cost-effectiveness ratio (ICER). The committee agreed with these comments and concluded that the modelling of PFS is appropriate for decision making.

## The modelling of time on treatment is appropriate
To extrapolate time on treatment for avelumab, the company used Weibull curves. Extrapolation beyond the minimum follow-up period of 15 months in JAVELIN part B was informed by data from JAVELIN part A (people with relapse after at least 1 line of chemotherapy), in which the minimum follow up was 36 months. Clinical experts advising the company expected most people to stop avelumab within 2 years of initiation, and it was assumed in the model that people remaining on treatment at 5 years would immediately stop. The ERG agreed with this assumption and used it in its preferred analyses. However, the ERG did not agree that the curves fitted to the timeontreatment data should be adjusted using the JAVELIN part A data, as these data are not reflective of a treatment-naive population. The ERG preferred the 3knot hazard spline and did not use the JAVELIN part A data in its approach. After technical engagement, the company stated that its approach was taken to supplement the limited data from JAVELIN part B with mature data from JAVELIN part A while maintaining a model based on a treatment-naive population for the earlier part of the curve. The committee noted that both models resulted in similar mean timeontreatment estimates, and the ICER was not impacted substantially. The clinical experts commented that treatment with avelumab beyond 5 years would be unusual, making the assumptions made about discontinuation of treatment correct. The committee concluded that modelling of time on treatment is appropriate for decision making.

# Cost-effectiveness estimate

## Avelumab is cost effective compared with chemotherapy
The company's base-case ICER was 17,947 per quality-adjusted life year (QALY) gained. Using the ERG's preferred propensity score weighting analysis to compare avelumab with chemotherapy (see section 3.5) and the ERG's preferred assumptions for modelling OS, PFS and time on treatment (see sections 3.7 to 3.9), the ICER was 20,780 per QALY gained. These ICERs are either below or within the range normally considered to be an acceptable use of NHS resources (20,000 to 30,000 per QALY gained). All scenario analyses done by both the company and ERG were also below 25,000 per QALY gained. Therefore, the committee concluded that avelumab is cost effective compared with chemotherapy.

# End of Life

## Avelumab meets the end-of-life criteria
In TA517, the committee concluded that avelumab meets the criteria to be considered a lifeextending end-of-life treatment for first-line treatment of metastatic Merkel cell carcinoma. The committee considered the advice about lifeextending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.

# Conclusion

## Avelumab is a clinically- and cost-effective treatment for metastatic Merkel cell carcinoma
The committee was reassured that avelumab is an effective treatment for metastatic Merkel cell carcinoma. Updated evidence from JAVELIN and the indirect treatment comparison showed that avelumab improves overall response rates, PFS and OS compared with chemotherapy. The modelling approaches taken by the company were also considered appropriate. The costeffectiveness estimates for avelumab are in the range normally considered to be a costeffective use of NHS resources for lifeextending treatments at the end of life. Therefore, the committee recommended avelumab for the treatment of metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease.