Afatinib (2) – Giotrif®

• Clinical trials
  • The Lux-Lung 3 trial was the pivotal registration trial for afatinib in this therapeutic indication, in which patients were treated with either afatinib or chemotherapy comprising cisplatin in combination with pemetrexed.
  • The Lux-Lung 6 trial was a randomised controlled trial in which patients were treated with either afatinib or chemotherapy comprising cisplatin in combination with gemcitabine.

1a) Untreated patients with an ECOG performance status of 0 or 1 – patient group with the EGFR Del19 mutation

• For previously untreated patients with an ECOG performance status of 0 or 1 and with the EGFR Del19 mutation, there is an indication of a major additional benefit.
• For this patient group, the G-BA classifies the extent of the additional benefit of afatinib as major, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a sustained and, to date, unprecedented major improvement in treatment-related benefit, as a major prolongation of survival is achieved.
• Level of certainty (probability of additional benefit): As the results of only one study form the basis of the benefit assessment, the maximum level of certainty that can be derived is an indication of additional benefit.
• mortality
  • For the patient population with the EGFR Del19 mutation, the results from the third data cut-off point show a statistically significant prolongation of overall survival for afatinib compared with cisplatin + pemetrexed (HR: 0.54, CI: 0.36; 0.79, p-value = 0.002).
  • The median survival time was 33.3 months in the afatinib group compared with 21.1 months in the cisplatin + pemetrexed group, representing a median survival benefit of 12.2 months.
• Morbidity – Progression-free survival
  • For patients with the EGFR Del19 mutation, subgroup analyses show a statistically significant advantage for afatinib compared with cisplatin + pemetrexed (HR: 0.26, CI: 0.17–0.42, p < 0.001).
• Morbidity – Symptoms
  • In the overall study population, a statistically significant advantage was observed for afatinib compared with cisplatin plus pemetrexed for the endpoints of dyspnoea, cough, pain (chest), fatigue, nausea and vomiting, and hair loss.
  • For the endpoint of dyspnoea, there is a relevant effect modification by EGFR mutation status: in the patient population with the EGFR Del19 mutation and the EGFR L858R mutation, there is a statistically significant advantage of afatinib compared with cisplatin + pemetrexed.
  • A statistically significant disadvantage of afatinib compared with cisplatin + pemetrexed was observed in the overall study population for the endpoints of diarrhoea, mouth pain and dysphagia.
  • Although symptoms such as dyspnoea, cough, pain or fatigue are relevant symptoms of the disease, the symptoms assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires were classified as non-serious in terms of their severity in the Lux-Lung 3 study.
• quality of life
  • For the endpoint of physical functioning, a statistically significant difference in favour of afatinib was observed.
  • For all other endpoints measuring quality of life in the EORTC QLQ-C30, no statistically significant differences were observed between the treatment groups: global health status, emotional functioning, cognitive functioning, role functioning and social functioning.
• Side effects
  • Adverse events occurred at least once in almost every patient in both treatment groups.
  • The proportion of patients with at least one serious adverse event (SAE) was 31.0% in the afatinib treatment group and 22.5% in the cisplatin + pemetrexed treatment group.
  • The proportion of patients with at least one severe adverse event (CTCAE grade ≥ 3) was 62.4% in the afatinib treatment group and 56.8% in the cisplatin + pemetrexed treatment group.
  • Treatment was discontinued due to adverse events in 16.2% of patients in the afatinib treatment group and 15.3% of patients in the cisplatin + pemetrexed treatment group.
  • Taking into account the significantly longer follow-up period for afatinib and the associated high potential for bias, there are no significant differences between the treatment groups based on the unadjusted proportions.
• Overall assessment
  • The endpoint of overall survival shows, for the patient population with the EGFR Del19 mutation, that treatment with afatinib results in a prolongation of survival compared with cisplatin + pemetrexed, the extent of which is assessed as a major prolongation of survival.
  • This assessment is based on the results of the final analysis of overall survival (3rd data cut-off).
  • Furthermore, for the patient group with the EGFR Del19 mutation, predominantly positive effects are observed with regard to individual endpoints reflecting symptoms and quality of life.
  • With regard to side effects, the available analyses of adverse events do not indicate either an advantage or a disadvantage of afatinib compared with cisplatin plus pemetrexed.
  • Particularly given the extent of the prolongation in survival and in view of the available results on other patient-relevant endpoints, which overall support the additional benefit, a major additional benefit of afatinib over the appropriate comparator therapy (cisplatin + pemetrexed) is identified for untreated patients with an ECOG performance status of 0 or 1 and with the EGFR Del19 mutation.

1b) Previously untreated patients with an ECOG performance status of 0 or 1 – patient group with the EGFR L858R mutation

• For previously untreated patients with an ECOG performance status of 0 or 1 and an EGFR L858R mutation, additional benefit is not proven.
• For this patient group, the overall assessment of the available results on mortality, morbidity, quality of life and side effects does not demonstrate any additional benefit of afatinib.
• Therefore, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, an additional benefit is not proven.
• mortality
  • For the patient population with the EGFR L858R mutation, the third data set shows no statistically significant difference between treatment with afatinib and treatment with cisplatin plus pemetrexed (HR: 1.30, CI: 0.80; 2.11, p-value = 0.292).
  • Median survival was 27.6 months with afatinib versus 40.3 months with cisplatin plus pemetrexed; the difference is not statistically significant (HR: 1.30, CI: 0.80; 2.11, p-value = 0.292).
• Morbidity – Progression-free survival
  • For the patient population of patients with the EGFR L858R mutation, as well as patients with other EGFR mutations, no statistically significant difference was observed between treatment with afatinib and treatment with cisplatin + pemetrexed.
• Morbidity – Symptoms
  • For the endpoint of dyspnoea, there is a relevant effect modification by EGFR mutation status: in the patient population with the EGFR Del19 mutation and the EGFR L858R mutation, there is a statistically significant advantage of afatinib over cisplatin + pemetrexed.
  • With regard to symptoms, as reflected by various endpoints from the cancer- and lung cancer-specific questionnaires used, afatinib exhibits both positive and negative effects, with the positive effects outweighing the negative ones.
  • The symptoms recorded in this study are classified as non-serious in terms of their severity.
• quality of life
  • With regard to quality of life, afatinib has a positive effect, which is reflected in one of the six endpoints used to assess the various aspects of quality of life.
  • However, the results for the other five quality-of-life endpoints assessed show no positive effect.
• Side effects
  • With regard to side effects, the available analyses of adverse events do not indicate either an advantage or a disadvantage of afatinib compared with cisplatin plus pemetrexed.
• Overall assessment
  • The overall survival endpoint shows no statistically significant difference between treatment with afatinib and treatment with cisplatin + pemetrexed in the patient population with the L858R EGFR mutation.
  • The final analysis of overall survival (3rd data cut-off) is decisive for this assessment.
  • The overall assessment takes particular account of the fact that there is no positive effect for the endpoint of overall survival.
  • With regard to the other endpoints assessed in the study, there is no clear overall advantage that would allow an additional benefit to be established in the overall assessment, despite the lack of effects on the overall survival endpoint.
  • In the overall assessment, therefore, additional benefit is not proven for afatinib compared with the appropriate comparator therapy (cisplatin + pemetrexed) in previously untreated patients with an ECOG performance status of 0 or 1 and with the L858R EGFR mutation.

1c) Previously untreated patients with an ECOG performance status of 0 or 1 – patient group with other EGFR mutations

• For previously untreated patients with an ECOG performance status of 0 or 1 and with other EGFR mutations, additional benefit is not proven.
• For this patient group, the overall assessment of the available results on mortality, morbidity, quality of life and side effects does not identify any additional benefit from afatinib.
• Therefore, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, an additional benefit is not proven.
• mortality
  • For the patient population with other EGFR mutations, the results of the third data cut-off show no statistically significant difference for the endpoint of overall survival (HR: 2.42, CI: 0.96; 6.11, p-value = 0.054).
• Morbidity – Progression-free survival
  • For the patient population of patients with the L858R EGFR mutation, as well as patients with other EGFR mutations, no statistically significant difference was observed between treatment with afatinib and cisplatin + pemetrexed.
• Overall assessment
  • The interim analysis of overall survival (2nd data cut-off) indicated a statistically significant negative effect of afatinib.
  • This result was not confirmed by the findings of the final analysis (3rd data cut-off), which are now primarily used to assess the overall survival endpoint.
  • For the endpoint of overall survival, therefore, neither a positive effect nor a clearly negative effect can be inferred from the available results for the patient population with other EGFR mutations.
  • For the overall assessment, it is taken into account that this is a small group of patients in the Lux-Lung 3 trial, which includes various other rare EGFR mutations and is therefore heterogeneous with regard to this characteristic.
  • In the overall assessment of the available results for all endpoints, it is concluded that, for the group of previously untreated patients with an ECOG performance status of 0 or 1 and with other EGFR mutations, there is no evidence of additional benefit for afatinib compared with the appropriate comparator therapy (cisplatin + pemetrexed) is not proven.

2) Previously untreated patients with an ECOG performance status of 2

• For previously untreated patients with an ECOG performance status of 2, additional benefit is not proven.
• No relevant data were submitted that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.
• The pharmaceutical manufacturer’s argument that the results from the treatment of previously untreated patients with an ECOG performance status of 0 or 1 are transferable to patients with an ECOG performance status of 2 is not accepted.

3) Patients following prior treatment with platinum-based chemotherapy

• An additional benefit is not proven for patients following prior treatment with platinum-based chemotherapy.
• No study was submitted that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.
• The Lux-Lung 2 study submitted by the pharmaceutical manufacturer is a single-arm study which is not suitable for assessing the benefit of afatinib compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.