Avelumab (2) – Bavencio®

• Clinical trials
  • For the benefit assessment of avelumab in combination with axitinib, the pharmaceutical manufacturer submitted the randomised, open-label Phase III trial Javelin Renal 101.

a) Adult patients with untreated, advanced renal cell carcinoma with a favourable or intermediate risk profile (IMDC score 0–2)

• Consequently, the G-BA concluded that, for avelumab in combination with axitinib as first-line therapy in adults with advanced renal cell carcinoma with a favourable or intermediate risk profile (IMDC score 0–2) compared with the appropriate comparator therapy, sunitinib, that the additional benefit is not proven.
• mortality
  • For the endpoint of overall survival, there was no statistically significant difference between the treatment arms.
  • By the time of the underlying data cut-off, 74 patients (20.3 per cent) and 84 patients (22.6 per cent) in the sunitinib arm had died; the median survival time had not yet been reached in either treatment arm.
• morbidity
  • The PFS endpoint is defined as the time from randomisation to the first documented disease progression or death from any cause, whichever occurs first.
  • There was a statistically significant advantage between the study arms in favour of avelumab plus axitinib (hazard ratio (HR): 0.72; 95% confidence interval (CI) [0.59; 0.88]; p-value: 0.0016).
  • The available data from the Javelin Renal 101 trial show no differences between the treatment groups in the endpoint category of morbidity.
  • The participants’ disease symptoms were assessed using the FKSI-DRS (Functional Assessment of Cancer Therapy – Kidney Symptom Index – Disease-Related Symptoms) questionnaire.
  • No statistically significant difference was observed between the study arms.
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • No statistically significant difference was observed between the study arms.
  • Overall, in the morbidity endpoint category, avelumab in combination with axitinib showed neither an advantage nor a disadvantage compared with sunitinib.
• quality of life
  • To assess health-related quality of life, the pharmaceutical manufacturer provided analyses of the FKSI-19 measurement tool.
  • The six additional questions in the FKSI-15, which go beyond those in the FKSI-DRS, are not suitable for comprehensively assessing the complex construct of health-related quality of life.
  • Against this background, the analyses submitted by the pharmaceutical manufacturer based on the FKSI-19 are not used to assess the additional benefit in the category of quality of life.
  • No data on health-related quality of life are available.
• Side effects
  • In the Javelin Renal 101 study, the planned follow-up period, as specified in the study protocol, was up to 90 days after the last dose of the study medication for all endpoints in the ‘side effects’ category, or until the start of follow-up therapy in the case of non-serious side effects (whichever occurred first).
  • For the endpoints SAE and severe AEs (CTCAE grade ≥ 3), no statistically significant differences were observed between the treatment arms.
  • There was a statistically significant difference between the treatment arms, with a disadvantage for avelumab + axitinib. This is based on 86 events (24.0 %) in the avelumab + axitinib arm and 49 events (13.3 %) in the sunitinib arm.
  • The operationalisation of the endpoint ‘immune-mediated AEs’ adopted in the study is assessed as insufficiently reliable due to the causal link with the treatment administered and the absence of a clear alternative aetiology, as it does not guarantee that all immune-mediated AEs are captured.
  • For other specific AEs, advantages and disadvantages of avelumab plus axitinib compared with sunitinib can be identified.
  • In detail, advantages are evident in the endpoints ‘Blood and lymphatic system disorders’ (SOC, severe AEs [CTCAE grade ≥ 3]) as well as ‘Dyspepsia’ and ‘Taste disturbance’ (in each case: PT, AEs).
  • Disadvantages are evident for the combination therapy compared with sunitinib for the endpoints ‘Diarrhoea’ and ‘Elevated alanine aminotransferase’ (both: PT, severe AEs [CTCAE grade ≥ 3]), ‘chills’, ‘pruritus’ and ‘dysphonia’ (each: PT, AE) as well as ‘injuries, poisoning and procedural complications’ (SOC, AE).
  • Overall, the results regarding side effects for avelumab + axitinib compared with sunitinib show a disadvantage for the endpoint of therapy discontinuations due to adverse events.
• Overall assessment
  • Results are available for the endpoint categories of mortality, morbidity and adverse events, based on the Javelin Renal 101 study, for the assessment of the additional benefit of avelumab in combination with axitinib as first-line therapy in adult patients with advanced renal cell carcinoma with a favourable or intermediate risk profile (IMDC score 0–2), results are available for the endpoint categories of mortality, morbidity and side effects based on the Javelin Renal 101 study.
  • In this ongoing study, avelumab in combination with axitinib is being compared with the appropriate comparator therapy, sunitinib.
  • For the endpoint of overall survival, there is no statistically significant difference between the treatment arms. Uncertainties remain due to the still preliminary results based on relatively minor event numbers.
  • In the morbidity endpoint category, analyses are available for disease-specific symptoms using the FKSI-DRS measurement tool and for health status using the EQ-5D VAS. With regard to both the patients’ disease-related symptoms and their health status, neither advantages nor disadvantages of the combination therapy compared with sunitinib can be identified.
  • No data on health-related quality of life are available. It is therefore not possible to assess the impact of avelumab in combination with axitinib on patients’ quality of life.
  • With regard to side effects, the combination of avelumab and axitinib shows a moderate disadvantage compared with sunitinib in terms of therapy discontinuations due to adverse events. In terms of specific adverse events, there are both advantages and disadvantages of the combination therapy compared with sunitinib.
  • In the overall assessment of the available results on patient-relevant endpoints, there is a moderate disadvantage for avelumab in combination with axitinib in terms of adverse events leading to therapy discontinuation. However, this disadvantage does not reach an extent that would justify less benefit.

b) Adult patients with previously untreated, advanced renal cell carcinoma with an unfavourable risk profile (IMDC score ≥ 3)

• mortality
  • There is a statistically significant difference between the treatment arms in favour of avelumab + axitinib (HR: 0.50, 95% CI [0.31; 0.81]; p-value: 0.005). The median survival time is 21.2 months in the intervention arm and 11.0 months in the control arm, representing an absolute difference of 10.2 months.
  • Furthermore, there is an effect modification for the endpoint of overall survival due to the characteristic ‘region’.
  • Despite the observed effect modification, no separate statement on additional benefit is made on the basis of the subgroup analyses for the ‘region’ characteristic, as the subgroup analysis is considered unreliable given the current data situation.
  • The extent of the effect of the combination therapy of avelumab + axitinib compared with sunitinib is assessed as a significant improvement in overall survival.
• morbidity
  • The PFS endpoint is defined as the time from randomisation to the first documented disease progression or to death from any cause, whichever occurs first.
  • There is a statistically significant advantage between the study arms in favour of avelumab plus axitinib (HR: 0.54, 95% CI [0.36; 0.84]; p-value: 0.0049).
  • The participants’ disease symptoms were assessed using the FKSI-DRS questionnaire (Functional Assessment of Cancer Therapy – Kidney Symptom Index – Disease-Related Symptoms).
  • A statistically significant advantage was observed between the study arms in favour of avelumab + axitinib. However, it cannot be concluded with sufficient certainty that this represents a clinically relevant effect.
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • A statistically significant advantage was observed between the study arms in favour of avelumab + axitinib. However, it cannot be concluded with sufficient certainty that this represents a clinically relevant effect.
  • Overall, within the morbidity endpoint category, statistically significant differences were observed between the treatment arms in terms of disease-specific symptoms and health status, in favour of avelumab in combination with axitinib. However, it cannot be concluded with sufficient certainty that these are clinically relevant effects in each case.
• quality of life
  • For the assessment of health-related quality of life, the pharmaceutical manufacturer submitted analyses of the FKSI-19 measurement tool.
  • The six additional questions in the FKSI-15, which go beyond those in the FKSI-DRS, are not suitable for comprehensively assessing the complex construct of health-related quality of life.
  • Against this background, the analyses submitted by the pharmaceutical manufacturer based on the FKSI-19 are not used for the assessment of additional benefit in the category of quality of life.
  • No data on health-related quality of life are available.
• Side effects
  • In the Javelin Renal 101 study, the planned follow-up period, as specified in the study protocol, was up to 90 days after the last dose of the study medication for all endpoints in the ‘side effects’ category, or until the start of follow-up therapy in the case of non-serious side effects (whichever occurred first).
  • No statistically significant differences were observed between the treatment arms for the endpoints SAE, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
  • The operationalisation of the endpoint ‘immune-mediated AEs’ chosen in the study is assessed as insufficiently reliable due to the causal link with a previous treatment and the absence of a clear alternative aetiology, as it does not guarantee that all immune-mediated AEs are captured.
  • For other specific AEs, advantages and disadvantages of avelumab + axitinib compared with sunitinib can be identified.
  • In detail, advantages are evident for the two endpoints ‘disorders of the blood and lymphatic system’ and ‘disorders of the gastrointestinal tract’ (in each case: SOC, severe AEs [CTCAE grade ≥ 3]).
  • This is offset by disadvantages of the combination therapy compared with sunitinib for the endpoints ‘hypertension’ (PT, severe AE [CTCAE grade ≥ 3]) and ‘hypothyroidism’ (PT, AE).
  • In the overall assessment of the results regarding side effects, neither an advantage nor a disadvantage can be identified for avelumab + axitinib compared with sunitinib.
• Overall assessment
  • For the assessment of the additional benefit of avelumab in combination with axitinib as first-line therapy in adult patients with advanced renal cell carcinoma with an unfavourable risk profile (IMDC score ≥ 3), results are available for the endpoint categories of mortality, morbidity and side effects are available from the Javelin Renal 101 trial.
  • In this ongoing study, avelumab in combination with axitinib is being compared with the appropriate comparator therapy, sunitinib.
  • The combination therapy of avelumab and axitinib results in a statistically significant, marked advantage in overall survival compared with sunitinib.
  • In the morbidity endpoint category, assessments are available for disease-specific symptoms using the FKSI-DRS measurement tool and for health status using the EQ-5D VAS. Advantages of avelumab in combination with axitinib over sunitinib can be identified in terms of disease-specific symptoms and health status. However, it cannot be concluded with sufficient certainty that these are clinically relevant effects in each case.
  • No data on health-related quality of life are available. It is therefore not possible to assess the impact of avelumab in combination with axitinib on patients’ quality of life.
  • With regard to side effects, neither an advantage nor a disadvantage can be identified for avelumab in combination with axitinib compared with sunitinib. In terms of specific adverse events, there are detailed advantages and disadvantages of the combination therapy compared with sunitinib.
  • Taking the available results on patient-relevant endpoints as a whole, the clear advantage in overall survival is not offset by any disadvantages in terms of morbidity and side effects.

Courtesy translation only, please refer to the German original.