Sotorasib (2) – Lumykras®

b) Adults with advanced non-small cell lung cancer (NSCLC) harbouring a KRAS p.G12C mutation following first-line treatment with cytotoxic chemotherapy

• An additional benefit is not proven.
• For adults with advanced non-small cell lung cancer (NSCLC) with a KRAS p.G12C mutation following first-line treatment with cytotoxic chemotherapy, the pharmaceutical manufacturer has not provided any data for the assessment of additional benefit. Consequently, additional benefit is not proven.

c1) Adults with advanced non-small cell lung cancer (NSCLC) with a KRAS p.G12C mutation following first-line treatment with a PD-1/PD-L1 antibody in combination with platinum-based chemotherapy or following sequential therapy with a PD-1/PD-L1 antibody and platinum-based chemotherapy – c1) Adults for whom docetaxel represents the appropriate treatment on an individual patient basis

• Hint for a non-quantifiable additional benefit.
• In the overall assessment, sotorasib as monotherapy is therefore considered for the treatment of adults with advanced NSCLC harbouring a KRAS p.G12C mutation following first-line therapy with a PD-1/PD-L1 antibody in combination with platinum-based chemotherapy, or following sequential therapy with a PD-1/PD-L1 antibody and platinum-based chemotherapy – for whom docetaxel represents the treatment best suited to the individual patient – a non-quantifiable additional benefit compared with docetaxel is identified.
• Overall, a hint for the reliability of the findings regarding the established additional benefit is derived.
• mortality
  • The endpoint of overall survival was defined in the CodeBreak 200 study as the time from the date of randomisation to death from any cause. No statistically significant difference was observed between the treatment arms.
  • With regard to overall survival, therefore, the additional benefit of sotorasib compared with docetaxel is not proven.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival (PFS) is defined in the study as the time from the date of randomisation until disease progression or death from any cause, whichever occurred first.
  • For PFS, there is a statistically significant advantage in favour of sotorasib compared with docetaxel.
  • 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 is assessed via the overall survival endpoint as a separate endpoint. The morbidity component is assessed in accordance with RECIST criteria (version 1.1) and thus predominantly by means of imaging procedures. 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.
• Conclusion on the morbidity endpoints
  • Taking the results as a whole, an advantage for sotorasib can be identified with regard to morbidity, the extent of which cannot be quantified.
• Health-related quality of life
  • Health-related quality of life among patients in the CodeBreak 200 study is assessed using the functional scales of the EORTC QLQ-C30 questionnaire. Following the above assessment of the data, the high level of uncertainty prevails, arising from a balance between the differential proportion of patients included in the analysis across the treatment arms and the extent of the effects on the quality-of-life endpoints. It is therefore not possible to conclude with sufficient certainty that there is an effect on overall quality of life. Consequently, it is concluded that the data cannot be evaluated.
• Side effects – Total adverse events (AEs)
  • In the CodeBreak 200 study, AEs occurred in almost all participants in both treatment arms. The results are presented here for supplementary information only.
• Overview of the results on side effects
  • In the overall review of the results on side effects, neither an advantage nor a disadvantage can be identified for treatment with sotorasib compared with docetaxel.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of sotorasib in adults with advanced NSCLC harbouring a KRAS p.G12C mutation following first-line therapy with a PD-1/PD-L1 antibody in combination with platinum-based chemotherapy, or following sequential therapy with a PD-1/PD-L1 antibody and platinum-based chemotherapy, results are available on mortality, morbidity, health-related quality of life and side effects from the open-label, randomised, controlled Phase III CodeBreak 200 trial.
  • In the CodeBreak 200 trial, sotorasib was compared with docetaxel.
  • No statistically significant difference was observed between the treatment arms for the endpoint of overall survival.
  • With regard to the endpoints of symptoms and health status, which were assessed in the CodeBreak 200 study using the EORTC QLQ-C30, EORTC QLQ-LC13, BPI-SF, FACT-G GP5 and PGI-C, there are uncertainties arising from the difference of more than 15 percentage points in the proportion of patients included in the analysis between the treatment arms. With regard to the EQ-5D VAS analyses, a statistically significant advantage in favour of sotorasib over docetaxel is evident for the health status endpoint. In the overall assessment of the results, an advantage for sotorasib can be observed in terms of morbidity, the extent of which cannot be quantified.
  • No evaluable data are available for the ‘health-related quality of life’ endpoint category, as assessed using the functional scales of the EORTC QLQ-C30 questionnaire.
  • An overall review of the results on side effects reveals neither an advantage nor a disadvantage for treatment with sotorasib compared with docetaxel.
  • In the overall assessment, sotorasib as monotherapy is therefore recommended for the treatment of adults with advanced NSCLC harbouring the KRAS p.G12C mutation following first-line therapy with a PD-1/PD-L1 antibody in combination with platinum-based chemotherapy, or following sequential therapy with a PD-1/PD-L1 antibody and platinum-based chemotherapy – for whom docetaxel represents the appropriate treatment on an individual patient basis – a non-quantifiable additional benefit over docetaxel has been identified.

c2) Adults with advanced non-small cell lung cancer (NSCLC) with a KRAS p.G12C mutation following first-line treatment with a PD-1/PD-L1 antibody in combination with platinum-based chemotherapy or following sequential therapy with a PD-1/PD-L1 antibody and platinum-based chemotherapy – c2) Adults for whom a treatment other than docetaxel is the individually appropriate therapy

• The additional benefit is not proven.
• For the patient population of adults with advanced non-small cell lung cancer (NSCLC) with a KRAS p.G12C mutation following first-line treatment with a PD-1/PD-L1 antibody in combination with platinum-based chemotherapy or following sequential therapy with a PD-1/PD-L1 antibody and platinum-based chemotherapy, and for whom a treatment other than docetaxel is the appropriate treatment on an individual patient basis, no conclusions regarding additional benefit can be drawn on the basis of the CodeBreak 200 study. As only results comparing the treatment with docetaxel were submitted for the benefit assessment, no usable data are available overall. An additional benefit of sotorasib for patient population c2) is therefore not proven.

Courtesy translation only, please refer to the German original.