Pembrolizumab (10) – Keytruda®

• Clinical trials
  • KEYNOTE 407 is a randomised, double-blind, controlled, parallel-group trial, which has been ongoing since August 2016, in which pembrolizumab in combination with carboplatin and (nab-) paclitaxel is compared with carboplatin in combination with (nab-) paclitaxel.
  • KEYNOTE 042 is a randomised, open-label, controlled trial that began in November 2014 and is currently still ongoing.

a) Adult patients receiving first-line treatment for metastatic squamous cell NSCLC with PD-L1 expression of < 50 % (TPS)

• Hint of considerable additional benefit.
• Overall, the G-BA concludes that there is considerable additional benefit for pembrolizumab in combination with carboplatin and (nab-)paclitaxel compared with carboplatin and (nab-)paclitaxel, based primarily on the advantage observed for the overall survival endpoint.
• However, the data are limited, particularly due to uncertainties regarding inappropriate analyses for some endpoints in the ‘side effects’ category. Consequently, in terms of the certainty of the findings, only a hint of additional benefit can be derived.
• mortality
  • In the KEYNOTE 407 trial, overall survival was defined as the time from randomisation to death from any cause.
  • There is a statistically significant difference in favour of pembrolizumab in combination with carboplatin-based chemotherapy compared with carboplatin-based chemotherapy alone (hazard ratio (HR): 0.56; [95% confidence interval (CI): 0.38; 0.82]; p-value = 0.003).
  • At the data cut-off date of 3 April 2018, the median survival time for the TPC patient population relevant for evaluation, with PD-L1 expression < 50 % (TPS) was 14.4 months in the intervention arm and 11.1 months in the control arm at the data cut-off date of 3 April 2018, representing an absolute difference of 3.3 months between the study arms in favour of the intervention.
  • With regard to the overall survival endpoint, the results of the KEYNOTE 407 trial thus demonstrate a significant improvement for pembrolizumab in combination with carboplatin-based chemotherapy compared with carboplatin-based chemotherapy alone.
• Morbidity – Symptoms – Dysphagia
  • The symptom scales from the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires were used to assess symptoms. In both cases, the time to the first clinically relevant deterioration is defined as an increase in the score of at least 10 points compared with the baseline value.
  • For the endpoint of dysphagia, as assessed by the EORTC QLQ-LC13, there was a statistically significant difference in favour of pembrolizumab in combination with carboplatin and (nab-)paclitaxel (HR: 0.52; 95% CI [0.31; 0.86]; p = 0.011).
• Morbidity – Health status
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • For the benefit assessment, the pharmaceutical manufacturer submitted responder analyses for the time to the first clinically relevant deterioration, in which a change in a patient’s VAS score of at least 7 or 10 points compared with baseline was defined as a response.
  • The responder analyses show no significant difference between the treatment arms, whether based on a MID of 7 or 10 points.
• Quality of life – physical functioning
  • To assess health-related quality of life, the global health status and the functional scales of the EORTC QLQ-C30 were used. In each case, the time to the first clinically relevant deterioration – defined as a decrease in the score of at least 10 points from baseline – was analysed.
  • For the physical functioning endpoint, there was a statistically significant difference in favour of pembrolizumab in combination with carboplatin and (nab-)paclitaxel (HR: 0.71; 95% CI [0.52; 0.96]; p = 0.028).
• Side effects
  • Adverse events (AEs) occurred at least once in almost every patient in both treatment arms.
  • No valid conclusions can be drawn for the endpoints ‘serious adverse events (SAEs)’ and ‘immune-mediated SAEs’.
  • For the endpoint ‘severe AEs’ (CTCAE grade ≥ 3), there was a statistically significant advantage in favour of pembrolizumab in combination with carboplatin and (nab-) paclitaxel (HR: 0.69; 95% CI [0.53; 0.90]; p = 0.006).
  • For the endpoint of immune-mediated AEs, there is a statistically significant difference in favor of pembrolizumab in combination with carboplatin and (nab-)paclitaxel (HR: 3.09; 95% CI [1.66; 5.77]; p < 0.001).
  • For the endpoint ‘therapy discontinuations due to adverse events’, no statistically significant difference was observed between the treatment arms.
• Overall assessment
  • For the benefit assessment of pembrolizumab in combination with carboplatin and (nab-) paclitaxel as first-line treatment for adult patients with metastatic squamous cell NSCLC and PD-L1 expression of < 50% (TPS), the KEXNOTE 407 study provides results on overall survival, morbidity, health-related quality of life and side effects.
  • In the mortality endpoint category, there is a statistically significant difference in overall survival between the study arms, with median overall survival in the intervention arm extended by 3.3 months. Pembrolizumab, in combination with carboplatin and (nab-)paclitaxel, leads to a significant improvement in overall survival compared with carboplatin and (nab-)paclitaxel alone.
  • Advantages of pembrolizumab in combination with carboplatin and (nab-) paclitaxel can also be observed in terms of morbidity. Here, a positive effect on symptoms is evident due to a reduction in dysphagia.
  • With regard to health-related quality of life, pembrolizumab in combination with carboplatin and (nab-)paclitaxel shows a beneficial effect on the physical functioning subscale.
  • In the endpoint category of side effects, no meaningful findings are available for serious adverse events (SAEs) or for the specific adverse event of immune-mediated SAEs. In addition, pembrolizumab in combination with carboplatin and (nab-) paclitaxel was associated with a reduction in severe AEs (CTCAE grade ≥ 3) and, in terms of specific AEs, an increase in immune-mediated AEs.

b) Adult patients receiving first-line treatment for metastatic squamous cell NSCLC with PD-L1 expression of ≥ 50 % (TPS)

• The additional benefit is not proven.
• In the absence of a direct comparative study to demonstrate additional benefit for patient group b), the pharmaceutical manufacturer has submitted an adjusted indirect comparison in the dossier.
• When assessing the indirect comparison submitted, it must be borne in mind, firstly, that no usable analyses from the indirect comparison are available for all patient-relevant endpoints. In particular, analyses in the endpoint categories of morbidity and health-related quality of life are completely absent, as endpoints in these categories were not collected in the KEYNOTE 042 study. Furthermore, in the ‘side effects’ endpoint category, analyses relating specifically to serious adverse events and specific adverse events are notably absent.
• Furthermore, taking into account the fact that results from adjusted, indirect comparisons are, by their very nature, associated with minor certainty of results, the G-BA therefore concludes, on balance, that in the present case it is not possible to make a definitive assessment of the positive and negative effects based on the indirect comparison provided. An additional benefit of pembrolizumab in combination with carboplatin and (nab-)paclitaxel compared with pembrolizumab alone is not proven.

Courtesy translation only, please refer to the German original.