Neratinib (1) – Nerlynx®

• Clinical trials
  • The benefit assessment of neratinib is based on the results of the pivotal, randomised, double-blind Phase III ExteNET trial.

Adult patients with early-stage hormone receptor-positive, HER2-overexpressed/amplified breast cancer who have completed trastuzumab-based adjuvant therapy less than one year ago, for extended adjuvant treatment

• mortality
  • overall survival
  • In the ExteNET study, overall survival is defined as the time from randomisation to death from any cause.
  • As this number had not been reached by the relevant data cut-off date, nor by any subsequent data cut-off date, no analyses are available for the overall survival endpoint in the relevant patient population.
  • At the time of the first data cut-off, nine deaths had occurred in the intervention arm and 14 in the control arm within the patient population of hormone receptor-positive patients (regardless of the time elapsed between completion of trastuzumab therapy and randomisation).
• Morbidity – Recurrences
  • Patients in this therapeutic indication are treated with a curative approach as part of extended adjuvant treatment for breast cancer following complete resection, (neo)adjuvant chemotherapy and trastuzumab therapy.
  • Nevertheless, tumour cells may remain and cause a recurrence at a later stage.
  • A recurrence means that the attempt at a cure through the curative therapeutic approach was unsuccessful.
  • The occurrence of a recurrence is relevant to the patient.
  • The endpoint ‘recurrences’, operationalised as recurrence rate and recurrence-free survival, comprises the following individual components: ductal carcinoma in situ, invasive ipsilateral breast recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant metastases (including death due to breast cancer), death from any cause.
  • Recurrence rate (event rate)
  • A statistically significant advantage was observed in the recurrence rate, favouring neratinib compared with placebo (relative risk [RR]: 0.43 [95% CI: 0.27; 0.67]; p < 0.001).
  • At the time of the data cut-off, recurrence occurred in 3.9% of patients in the neratinib arm and in 9.0% of patients in the placebo arm.
  • Recurrence-free survival (time-to-event analysis)
  • With regard to recurrence-free survival, there was a statistically significant advantage in favour of neratinib compared with placebo (hazard ratio [HR]: 0.45 [95% CI: 0.28; 0.71]; p < 0.001).
  • Overall, therefore, with regard to the endpoint of recurrence – operationalised as the recurrence rate and recurrence-free survival – there is a clear, clinically relevant advantage of neratinib compared with a watch-and-wait approach.
• quality of life
  • Health-related quality of life is assessed in the study using the disease-specific FACT-B questionnaire.
  • For the benefit assessment, the pharmaceutical manufacturer provided analyses of the mean difference from baseline for this questionnaire, based on an MMRM analysis.
  • There is no statistically significant difference between the treatment groups in the overall FACT-B score for the mean change at month 12.
• Side effects
  • Total AEs
  • By the time of the first data cut-off, an adverse event had occurred in 98.0% of patients in the neratinib arm and in 86.3% of patients in the control arm.
  • Serious adverse events (SAEs)
  • With regard to serious adverse events, there is a statistically significant disadvantage for neratinib compared with placebo.
  • Severe adverse events (CTCAE grade ≥ 3)
  • With regard to severe adverse events (CTCAE grade ≥ 3), there was a statistically significant disadvantage for neratinib compared with placebo.
  • Therapy discontinuations due to adverse events
  • With regard to therapy discontinuations due to adverse events, there is a statistically significant disadvantage for neratinib compared with placebo.
  • Specific adverse events
  • In detail, statistically significant disadvantages compared with placebo were observed for specific adverse events relating to gastrointestinal disorders (SOC, CTCAE grade ≥ 3), including diarrhoea (PT, CTCAE grade ≥ 3); fatigue (PT, CTCAE grade ≥ 3); metabolic and nutritional disorders; nervous system disorders; laboratory tests (all SOC, CTCAE grade ≥ 3); skin and subcutaneous tissue disorders (SOC, AE) and muscle spasms (PT, AE).
  • When the results on side effects are considered as a whole, neratinib shows a moderate disadvantage compared with a ‘watch-and-wait’ approach due to an increase in serious side effects, as well as significant disadvantages due to an increase in severe side effects (CTCAE grade ≥ 3) and therapy discontinuations due to adverse events, resulting in a significant overall disadvantage.
• Overall assessment
  • For the assessment of the additional benefit of neratinib for extended adjuvant treatment of adult patients with hormone receptor-positive, HER2-overexpressed/amplified early-stage breast cancer who completed trastuzumab-based adjuvant therapy less than one year ago, results are available for the endpoint categories of morbidity, quality of life and side effects.
  • An analysis of the overall survival endpoint was not planned for the data cut-off point used; consequently, based on the available results, it is not possible to assess the impact of extended adjuvant treatment with neratinib on overall survival.
  • In the morbidity category, with regard to disease recurrences observed in the study—based on the endpoint of recurrence, operationalised as recurrence rate and recurrence-free survival—there is a clear, clinically relevant advantage of neratinib compared with a ‘watch-and-wait’ approach.
  • With regard to health status, as measured by the EQ-5D VAS, and health-related quality of life, as measured by the FACT-B questionnaire, there are no statistically significant differences between the treatment groups.
  • With regard to side effects, there are disadvantages in the form of an increase in serious adverse events, as well as significant disadvantages due to an increase in severe adverse events (CTCAE grade ≥ 3) and therapy discontinuations due to adverse events.
  • In the overall assessment of the results for patient-relevant endpoints, a clear advantage in terms of preventing recurrence is offset by significant disadvantages regarding side effects.
  • The disadvantages in the ‘side effects’ category are weighed against the aim of curative treatment and do not entirely call into question the advantages in terms of preventing recurrence.

Courtesy translation only, please refer to the German original.