Olaratumab (1) – Lartruvo®

• Clinical trials
  • The JGDG trial is an open-label, multicentre Phase 1b/2 trial that enrolled adult patients with advanced or metastatic soft tissue sarcoma who were not eligible for curative treatment (surgery or radiotherapy) and who had not yet received anthracycline.
  • The benefit assessment is based on Phase 2 of the JGDG trial, in which olaratumab plus doxorubicin was compared with doxorubicin monotherapy.

Patients with advanced soft tissue sarcoma who are not suitable for curative treatment (surgery or radiotherapy) and who have not previously been treated with doxorubicin

• For patients with advanced soft tissue sarcoma who are not suitable for curative treatment (surgery or radiotherapy) and who have not previously been treated with doxorubicin, there is considerable additional benefit.
• Consequently, the G-BA classifies the extent of the additional benefit of olaratumab in combination with doxorubicin as ‘considerable’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease, as considerable.
• Mortality – Overall survival
  • For the endpoint of overall survival, there was a statistically significant prolongation of overall survival in the treatment group receiving olaratumab plus doxorubicin compared with doxorubicin monotherapy (median 26.5 months versus 14.7 months), resulting in a median survival benefit of 11.8 months (hazard ratio: 0.46 [0.30; 0.71], p = 0.0003).
  • This result was confirmed by sensitivity analyses addressing the influence of subsequent treatments, baseline characteristics or the number of treatment cycles.
• Morbidity – Progression-free survival
  • For the endpoint of progression-free survival (PFS), there was no statistically significant difference between the treatment groups: a median of 8.2 months (olaratumab + doxorubicin) versus 4.4 months (doxorubicin) (hazard ratio: 0.67 [0.40; 1.12], p = 0.1208).
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories.
  • The morbidity component – radiologically confirmed disease progression according to the RESIST criteria – was not assessed on the basis of symptoms, but exclusively by means of imaging procedures.
• Morbidity – Symptoms
  • The effects of the treatments in the JGDG study on disease-specific symptoms were not investigated.
  • No data on symptoms are available for the benefit assessment of the combination of olaratumab and doxorubicin compared with doxorubicin monotherapy.
• Health-related quality of life
  • Health-related quality of life was not investigated in the JGDG study.
  • No data are available for the benefit assessment on the effects of olaratumab plus doxorubicin on quality of life compared with doxorubicin monotherapy.
• Side effects
  • Almost every patient in this study experienced adverse events at least once, including both those treated with the combination of olaratumab and doxorubicin and those treated with doxorubicin monotherapy.
  • Adverse events classified as ‘severe adverse events’ (CTCAE grade ≥ 3) occurred at least once in the vast majority of patients in both treatment groups, with no statistically significant difference (79.7% and 69.2%, respectively).
  • ‘Serious adverse events (SAEs)’ affected 42.2% of patients in the olaratumab plus doxorubicin group and 38.5% of patients in the doxorubicin monotherapy group at least once.
  • No statistically significant difference was observed for any of the endpoints either.
  • Furthermore, there was no statistically significant difference between the treatment groups in terms of therapy discontinuations due to adverse events.
  • With regard to frequently documented adverse events (≥ 10% of patients in a study arm), severe neutropenia (CTCAE grade ≥ 3) were observed more frequently; however, this was not associated with an increased incidence of febrile neutropenia or severe infections.
  • When interpreting these results, the longer follow-up period for adverse events in the intervention group receiving olaratumab plus doxorubicin must be taken into account; consequently, the present analysis of event frequencies yields a conservative result, as the longer observation period in the intervention group alone may lead to more frequent reporting of adverse events.
• Overall assessment
  • To assess the extent of the additional benefit of olaratumab in combination with doxorubicin for the treatment of advanced soft tissue sarcoma, the JGDG registration trial provides results on mortality (overall survival), morbidity and side effects compared with doxorubicin monotherapy.
  • The results for the overall survival endpoint show that treatment with olaratumab in combination with doxorubicin, compared with doxorubicinmonotherapy, a statistically significant prolongation of survival of 11.8 months (median) is achieved, which is assessed as a significant improvement of considerable extent.
  • There is a lack of data for an assessment of health-related quality of life.
  • Statements regarding quality of life are considered particularly important in the context of palliative care, as is the case here.
  • Furthermore, no data are available on disease-specific symptoms.
  • The endpoints relating to side effects show neither an advantage nor a clear disadvantage.
  • The increase in severe neutropenia (CTCAE grade ≥ 3) in the olaratumab plus doxorubicin treatment group was not associated in the study with an increased incidence of febrile neutropenia or severe infections.
  • Taking an overall view of the available results on patient-relevant endpoints, olaratumab in combination with doxorubicin is found to provide additional benefit compared with doxorubicin monotherapy due to the prolongation in overall survival achieved, the extent of which is assessed as considerable.
  • The limitations described regarding the validity of the available study results give rise to significant uncertainties in the interpretation of the findings.
  • However, the extent of these uncertainties is not considered such that they would prevent the quantification of the additional benefit.
  • The assessment result is, however, subject to significant uncertainties.

Courtesy translation only, please refer to the German original.