Nivolumab (12) – Opdivo®

a) Adult patients with previously untreated advanced renal cell carcinoma with an intermediate risk profile (IMDC score 1–2)

• Overall, there is an indication of considerable additional benefit.
• Consequently, the G-BA has determined that nivolumab in combination with ipilimumab provides considerable additional benefit for first-line treatment of advanced renal cell carcinoma in adults with an intermediate-risk profile (IMDC score 1–2).
• Consequently, the certainty of the evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • overall survival
  • Nivolumab in combination with ipilimumab results in a statistically significant advantage in overall survival compared with treatment with sunitinib (hazard ratio (HR): 0.70; 95% confidence interval (CI) [0.55; 0.88]; p-value: 0.003). There were 124 events (37.1%) in the nivolumab + ipilimumab arm and 159 events (47.7%) in the sunitinib arm. In the intervention arm, the median survival time has not yet been reached.
  • The combination therapy of nivolumab and ipilimumab achieves a significant improvement in overall survival compared with sunitinib.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival (PFS)
  • The PFS endpoint is defined as the time from the date of randomisation to the date of the first documented progression according to the Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1), or the date of death from any cause, whichever occurs first. The results underlying this benefit assessment, taken from the second planned interim analysis of 6 August 2018, are based on data provided by the investigator.
  • For PFS, there is a statistically significant difference in favour of nivolumab + ipilimumab (HR: 0.816, 95% CI [0.685; 0.972]; p-value: 0.0217). With regard to the median time to event, there is an absolute difference of 0.23 months (8.18 months vs. 8.41 months). The proportion of patients experiencing an event was higher in the sunitinib arm (81.7%) than in the intervention arm (71.6%).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. In this study, the mortality component of the endpoint was assessed as a standalone endpoint via the overall survival endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (in accordance with RECIST v1.1). Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Quality of life – FACT-G
  • FACT-G
  • Health-related quality of life was assessed using the generic FACT-G (Functional Assessment of Cancer Therapy – General) questionnaire.
  • Based on the difference in mean scores, the FACT-G total score shows a statistically significant advantage for the combination therapy of nivolumab + ipilimumab compared with treatment with sunitinib, which corresponds to an improvement in health-related quality of life (MD: 3.64, 95% CI [2.05; 5.24]; p-value: < 0.001). The improvement in health-related quality of life is considered clinically relevant, as the 95% CI of the standardised mean difference (Hedges’ g) lies entirely above the irrelevance range [–0.2; 0.2].
• Side effects – Serious adverse events (SAEs)
  • Serious adverse events (SAEs)
  • There is a statistically significant difference between the treatment arms to the detriment of nivolumab + ipilimumab (HR: 1.38, 95% CI [1.11; 1.71]; p-value: 0.004). The median time to the occurrence of a SAE is 9.13 months in the intervention arm and 20.83 months in the control arm. Consequently, a SAE occurs, on a median basis, 11.70 months earlier with nivolumab + ipilimumab than with sunitinib.
• Overall assessment
  • For the assessment of the additional benefit of nivolumab in combination with ipilimumab for first-line treatment of advanced renal cell carcinoma in adults with an intermediate-risk profile (IMDC score 1–2), results are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • Treatment with nivolumab in combination with ipilimumab results in a statistically significant, marked advantage in overall survival compared with sunitinib. There are uncertainties regarding the observed effect on overall survival due to effect modifications by the characteristics ‘PD-L1 status’ and ‘age’.
  • Further advantages of combination therapy compared with sunitinib can be observed in the endpoint categories of morbidity and quality of life. Here, positive effects are evident due to a reduction in disease-related symptoms and an improvement in health-related quality of life.
  • In the endpoint category of side effects, both positive and negative effects of combination therapy are evident when compared with sunitinib. The advantage in terms of severe adverse events (CTCAE Grade 3–4) is offset by disadvantages regarding the occurrence of severe adverse events and therapy discontinuations due to adverse events. With regard to specific adverse events, nivolumab in combination with ipilimumab shows both advantages and disadvantages compared with sunitinib.
  • In its overall assessment of the available results on patient-relevant endpoints, the G-BA has reached the conclusion, following a balancing of advantages and risks, that the advantages in terms of overall survival, disease-related symptoms, health-related quality of life and severe adverse events outweigh the disadvantages in terms of serious side effects and therapy discontinuations. There is a significant improvement in treatment-related benefit that has not been achieved previously.

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

• Overall, there is an indication of considerable additional benefit.
• Consequently, the G-BA has determined that nivolumab in combination with ipilimumab offers considerable additional benefit for the first-line treatment of advanced renal cell carcinoma in adults with an unfavourable risk profile (IMDC score ≥ 3).
• Consequently, the certainty of the evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • overall survival
  • Nivolumab in combination with ipilimumab results in a statistically significant advantage in overall survival compared with treatment with sunitinib (HR: 0.58, 95% CI [0.41; 0.83]; p-value: 0.003). Median survival was significantly prolonged by 11.73 months with treatment using nivolumab + ipilimumab (21.45 months) compared with sunitinib (9.72 months).
  • The combination therapy consisting of nivolumab and ipilimumab thus leads to a significant improvement in overall survival compared with sunitinib.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival (PFS)
  • The PFS endpoint is defined as the period between the date of randomisation and the date of the first documented progression according to the Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) or the date of death from any cause, whichever occurs first. The results underlying this benefit assessment, taken from the second planned interim analysis of 6 August 2018, are based on data provided by the investigator.
  • For PFS, there is a statistically significant difference in favour of nivolumab + ipilimumab (HR: 0.599, 95% CI [0.433; 0.829]; p-value: 0.0018). Compared with sunitinib, the median time to event was prolonged by 1.99 months (6.26 months vs. 4.27 months). The proportion of patients experiencing an event was also higher in the sunitinib arm (94.4%) than in the intervention arm (80.2%).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. In this study, the mortality component of the endpoint was assessed via the overall survival endpoint as a standalone endpoint. The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (in accordance with RECIST v1.1). Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms (FKSI-DRS)
  • Symptoms (FKSI-DRS)
  • Disease-related symptoms were assessed using the FKSI-DRS questionnaire (Functional Assessment of Cancer Therapy – Kidney Symptom Index – Disease-Related Symptoms). The FKSI-DRS is a subscale of the FKSI-15 assessment tool and comprises 9 questions on specific symptoms in patients with advanced kidney cancer.
  • There was no statistically significant difference in the mean difference between the intervention and control arms.
• Morbidity – Health status (EQ-5D VAS)
  • Health status (EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • No statistically significant difference was observed between the treatment arms.
  • There are no statistically significant differences between the treatment arms in either case.
• morbidity
  • In summary, in the morbidity endpoint category, the combination therapy of nivolumab + ipilimumab showed neither advantages nor disadvantages compared with sunitinib.
• Quality of life – FACT-G
  • FACT-G
  • Health-related quality of life was assessed using the generic FACT-G questionnaire.
  • There was no statistically significant difference between the treatment arms in the FACT-G total score.
• quality of life
  • In summary, the combination therapy of nivolumab + ipilimumab showed neither advantages nor disadvantages compared with sunitinib in the health-related quality of life endpoint category.
• Side effects – serious AEs (SAEs)
  • Serious AEs (SAEs), therapy discontinuation due to AEs
  • For the endpoints of SAE and therapy discontinuation due to AEs, there was no statistically significant difference between the treatment arms in either case.
• Side effects – Severe AEs (CTCAE Grade 3–4)
  • Severe AEs (CTCAE Grade 3–4)
  • There was a statistically significant advantage in favour of nivolumab + ipilimumab compared with sunitinib (HR: 0.57, 95% CI [0.41; 0.81]; p-value: 0.001). The median time to the onset of a severe AE (CTCAE Grade 3–4) was 1.41 months longer with nivolumab + ipilimumab (2.76 months) compared with sunitinib (1.35 months).
• Overall assessment
  • For the assessment of the additional benefit of nivolumab in combination with ipilimumab for first-line treatment of advanced renal cell carcinoma in adults with an unfavourable risk profile (IMDC score ≥ 3), results are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • Treatment with nivolumab in combination with ipilimumab results in a statistically significant prolongation of overall survival compared with sunitinib. The median prolongation of 11.73 months is assessed as a significant improvement not previously achieved.
  • With regard to the other endpoint categories – morbidity and quality of life – neither an advantage nor a disadvantage can be identified for treatment with nivolumab in combination with ipilimumab compared with sunitinib.
  • In terms of side effects, the combination therapy shows an advantage over the appropriate comparator therapy due to positive effects regarding severe adverse events (CTCAE Grade 3–4). For specific adverse events, both advantages and disadvantages can be identified for nivolumab in combination with ipilimumab compared with sunitinib.
  • Taking the available results on patient-relevant endpoints as a whole, the significant prolongation of overall survival and the advantage in terms of side effects compared with sunitinib are not offset by any disadvantages in terms of morbidity and health-related quality of life.

Courtesy translation only, please refer to the German original.