Necitumumab (1) – Portrazza®

• Clinical trials
  • The SQUIRE trial is a randomised, open-label, controlled trial directly comparing necitumumab in combination with gemcitabine and cisplatin against gemcitabine and cisplatin alone.

Patients with locally advanced or metastatic, epidermal growth factor receptor (EGFR)-expressing, squamous cell non-small cell lung cancer (NSCLC), provided they have not previously received chemotherapy for this stage of the disease

• An additional benefit is not proven for necitumumab in combination with gemcitabine and cisplatin for the treatment of locally advanced or metastatic, EGFR-expressing, squamous cell NSCLC.
• The overall assessment concludes that the positive effect on overall survival is not supported by further positive effects on patient-relevant endpoints.
• In a balancing decision, the G-BA concludes that, for necitumumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone, no additional benefit has been demonstrated for patients receiving first-line treatment for locally advanced or metastatic, EGFR-expressing, In the case of squamous cell NSCLC, the additional benefit is not proven.
• mortality
  • The median overall survival with the combination of necitumumab, cisplatin and gemcitabine was 11.7 months versus 10.0 months with cisplatin and gemcitabine (HR = 0.79; 95% CI [0.69; 0.92]; p = 0.002).
  • Treatment with necitumumab thus resulted in a statistically significant but minor prolongation of median overall survival by 1.7 months.
  • As part of a follow-up assessment commissioned by the G-BA and carried out by the IQWIG to examine prolonged long-term survival with necitumumab compared with the control treatment, it was found that the number of patients at risk is very low, particularly in the period from 2 years onwards.
  • These minor patient numbers do not currently allow conclusions to be drawn regarding a survival benefit in the group of patients treated with necitumumab based on the survival risk estimates for the treatment groups.
• Morbidity – Progression-free survival
  • The median progression-free survival was 5.7 months with the combination of necitumumab, cisplatin and gemcitabine, compared with 5.5 months in the control arm receiving cisplatin and gemcitabine (hazard ratio: 0.84 [0.72; 0.97], p-value < 0.018).
  • The endpoint ‘progression-free survival’ is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The ‘mortality’ component of this endpoint was assessed as a standalone endpoint in the SQUIRE study via the ‘overall survival’ endpoint.
  • Furthermore, the morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the ‘progression-free survival’ endpoint.
  • However, as this does not affect the overall conclusion regarding additional benefit, it was not taken into account in the present assessment of additional benefit.
• Health-related quality of life
  • The LCSS total score correlates well only with questions on physical well-being and not with functional aspects or emotional and social well-being.
  • Overall, the LCSS is unsuitable for comprehensively capturing the complex construct of quality of life and is used in this assessment only in the form of the ASBI to assess symptoms, but not health-related quality of life.
• Side effects
  • An adverse event was documented in almost all patients during the course of the study.
  • It is not possible to draw any conclusions regarding a greater or minor risk in terms of the overall rate of adverse events.
  • Serious adverse events (SAEs) occurred with similar frequency in both treatment groups, with no statistically significant difference.
  • Patients treated with necitumumab plus gemcitabine and cisplatin were statistically significantly more likely to experience severe adverse events (SAEs) of CTCAE grades 3 and 4 than patients treated with gemcitabine and cisplatin alone.
  • With regard to the analyses of the most common adverse events, ‘venous thromboembolic events’ (9.2% vs. 5.3%; RR = 1.72; 95% CI [1.07; 2.78]; p < 0.024), “skin reactions” (79.2% vs. 11.5%; RR = 6.86; 95% CI [5.32; 8.86]; p < 0.001) and “conjunctivitis” (5.9% vs. 2.6%; RR = 2.31; 95% CI [1.18; 4.50]; p = 0.011).
  • Skin reactions represent a distressing event for patients.
  • Skin reactions are a class effect associated with EGFR antibodies.
  • Contrary to standard practice in everyday healthcare situations, the SQUIRE trial—due to a specific requirement from the US Food and Drug Administration (FDA)—did not permit the use of preventive treatments for the expected skin rashes during the first treatment cycle in the necitumumab arm.
  • In the overall analysis of the endpoints relating to side effects, no advantages were observed; however, negative effects were noted in terms of an increase in severe AEs (CTCAE grade ≥ 3) and the occurrence of specific AEs with treatment using necitumumab plus gemcitabine and cisplatin compared with treatment using the appropriate comparator therapy of gemcitabine and cisplatin.
• Overall assessment
  • A positive effect is a statistically significant prolongation of overall survival (median 11.7 versus 10.0 months), which, taking into account the current stage of the disease, is regarded as a minor effect on overall survival.
  • In the endpoint category of morbidity, there is no overall additional benefit.
  • In particular, no advantages were observed with regard to the effects on disease-specific symptoms.
  • Symptoms in advanced NSCLC are pronounced and distressing for patients.
  • Effects on symptoms are significant for patients.
  • Assessments of quality of life are considered particularly important in palliative care settings.
  • With regard to side effects, no advantages were observed; however, severe adverse events of CTCAE grades 3 and 4 occurred with statistically significant greater frequency.
  • In addition, skin reactions, conjunctivitis and venous thromboembolic events occurred at a statistically significantly higher rate.
  • The overall assessment concludes that the positive effect on overall survival is not supported by further positive effects on patient-relevant endpoints.
  • Taking into account only a minor positive effect on overall survival, the fact that there is no advantage in terms of symptoms that are burdensome for the patient is a severe disadvantage in the overall assessment; furthermore, no conclusions can be drawn regarding quality of life, whilst the disadvantages associated with side effects must also be taken into account.

Courtesy translation only, please refer to the German original.