NICE Issues Technology Appraisal Guidance on Olaratumab in Combination with Doxorubicin for Treating Advanced STS

Ongoing ANNOUNCE trial is expected to address the uncertainty in the data

On 9 August 2017, NICE issued technology appraisal guidance [TA465] and granted a conditional marketing authorisation for olaratumab for the treatment of adult patients with advanced soft tissue sarcoma (STS) who are not amenable to curative treatment with surgery or radiotherapy and who have not been previously treated with doxorubicin.

Olaratumab is recommended in combination with doxorubicin, for use within the Cancer Drugs Fund as an option for STS in adults, only if they have not had any previous systemic chemotherapy for advanced STS, cannot have curative treatment with surgery or disease does not respond to radiotherapy and the conditions in the managed access agreement for olaratumab are followed.

This recommendation is not intended to affect treatment with olaratumab 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.

The recommended dose of olaratumab is 15 mg/kg, given by intravenous infusion on days 1 and 8 of each 3‑week cycle until disease progression or unacceptable toxicity.

Olaratumab is given with doxorubicin for up to 8 cycles of treatment, followed by olaratumab alone in patients whose disease has not progressed.

Doxorubicin is given on day 1 of each cycle, after the olaratumab infusion.

People with advanced STS having doxorubicin alone are expected to live for 12 to 16 months after starting treatment. Evidence from JGDG study suggests that having olaratumab plus doxorubicin increases the length of time people live by 11.8 months. This amount of survival gain in advanced sarcoma is unprecedented and potentially represents a step-change in its treatment. However, there are not enough long-term data to know the overall length of time people having olaratumab plus doxorubicin live compared with doxorubicin alone because a confirmatory phase III trial (ANNOUNCE) is still ongoing.

Olaratumab plus doxorubicin met NICE's criteria to be considered a life-extending treatment at the end of life. The criteria are that life expectancy for people with the condition should be less than 24 months and that the treatment should extend life by more than 3 months.

The estimate of the cost effectiveness of olaratumab plus doxorubicin varied primarily because of the uncertainties in the data. The incremental cost-effectiveness ratios (ICERs) ranged between 46,000 GBP and 60,000 GBP per quality-adjusted life year (QALY) gained. The most plausible ICER is likely to be close to 60,000 GBP per QALY gained. This is not cost effective based on what NICE normally considers acceptable for end-of-life treatments.

More long-term data would reduce uncertainty in the clinical effectiveness of olaratumab plus doxorubicin and allow a more certain cost effectiveness estimate. The ongoing ANNOUNCE trial is expected to address the uncertainty in the data. Olaratumab is therefore recommended for use within the Cancer Drugs Fund while further data are collected.

As a condition of the positive recommendation and the managed access arrangement, the company is required to collect efficacy data from the ANNOUNCE trial. Data on treatment duration and survival will also be collected via the Systemic Anti-Cancer Therapy data set.

The guidance will be updated when the data collection period has ended (expected to be December 2020).

The JGDG study 

The clinical evidence for olaratumab plus doxorubicin is from the JGDG (2016) trial, which was an open-label multicentre study of 133 people with advanced STS not amenable to treatment with surgery or radiotherapy. People were randomised to have either olaratumab plus doxorubicin or doxorubicin alone for up to 8 cycles. Beginning with cycle 9, patients randomised to the combination arm received olaratumab monotherapy until disease progression or discontinuation for any other reason. In the trial, 65% of people had no previous systemic chemotherapy and none had previously had doxorubicin.

Olaratumab has a modest effect on progression-free survival

In the JGDG trial, olaratumab plus doxorubicin increased median progression-free survival (PFS) in the intention-to-treat population by 2.5 months compared with doxorubicin alone (olaratumab plus doxorubicin 6.6 months, doxorubicin alone 4.1 months; hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.44 to 1.02 p=0.06). The appraisal committee noted that the results were similar for the subpopulation of people who had no previous systemic chemotherapies, which was 65% of the trial population (HR 0.77; 95% CI 0.48 to 1.25 p=0.28). The appraisal committee concluded that olaratumab was associated with an improvement in PFS in both the intention-to-treat and in the subpopulation of people who had no previous systemic chemotherapies, and that the trial data are mature.

Olaratumab improves overall survival but the data are immature

In the JGDG trial, olaratumab plus doxorubicin increased median overall survival (OS) in the intention-to-treat population by 11.8 months compared with doxorubicin alone (olaratumab plus doxorubicin 26.5 months, doxorubicin alone 14.7 months; stratified HR 0.46; 95% CI 0.30 to 0.71 p=0.0003). The results were similar in the subpopulation of people who had no previous systemic chemotherapies (stratified HR 0.47; 95% CI 0.27 to 0.81 p=0.0051). The appraisal committee noted that the OS data are limited (as a high proportion of patients were still alive at the end of the trial follow‑up), but the OS gain appeared to be much greater than the PFS gain. It considered the clinical plausibility of a PFS benefit of 2.5 months translating into an OS benefit of 11.8 months. It discussed the potential relationship between PFS and OS but, given the limited number of events, it agreed that the relationship is unclear. It noted that the ANNOUNCE trial is in progress and expected to address key areas of clinical uncertainty in the JGDG trial.

Olaratumab has an acceptable adverse-event profile

There were more adverse events in the olaratumab plus doxorubicin arm of JGDG than in the doxorubicin-alone arm. This may relate to the higher cumulative dose of doxorubicin in the olaratumab plus doxorubicin arm compared with doxorubicin monotherapy (median 7.1 cycles and 4.1 cycles respectively). The appraisal committee heard from the clinical and patient experts that olaratumab seems to be very well-tolerated.