Retifanlimab (2) – Zynyz®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the completed, pivotal, randomised, double-blind Phase III trial POD1UM-303 for benefit assessment.
  • In this trial, retifanlimab in combination with carboplatin and paclitaxel was compared with carboplatin in combination with paclitaxel.

Adults with metastatic or inoperable locally recurrent squamous cell carcinoma of the anal canal (SCAC); first-line treatment

• Hint of a minor additional benefit.
• On balance, the advantage in terms of overall survival is thus offset by the disadvantage of therapy discontinuations due to AEs. This disadvantage does not call into question the extent of the improvement in overall survival. Overall, therefore, the extent of the additional benefit is assessed as minor.
• In particular, given the high potential for bias in the overall survival endpoint and the lack of suitable data on patient-reported symptoms and quality of life, there is a hint regarding the validity of the evidence for the observed extent of the additional benefit.
• mortality
  • In the POD1UM-303 study, overall survival was defined as the time from the date of randomisation to the date of death from any cause.
  • For this endpoint, a statistically significant advantage was observed in favour of retifanlimab in combination with carboplatin and paclitaxel; the extent of this advantage is assessed as a relevant improvement, but no more than a minor one. It should be noted that the effect estimate is based on a wide confidence interval; consequently, uncertainty regarding the precision of the effect estimate must be taken into account when interpreting the results [HR = 0.73; 95% confidence interval: 0.54; 0.99].
  • In the POD1UM-303 study, patients were able to switch from the placebo arm to monotherapy with retifanlimab following disease progression (treatment switch). At the data cut-off date of 26 September 2025, 77 individuals (50.0%) from the control arm were receiving retifanlimab monotherapy.
  • The RPFST and IPCW models are not statistical methods that allow the treatment effect to be assessed with sufficient certainty in terms of the overall survival endpoint in studies involving a treatment switch, particularly as the central assumptions of the models (common treatment effect and no unmeasured confounders) cannot be verified on the basis of empirical data.
  • Overall, the analysis of overall survival using the RPFST and IPCW models is not taken into account in the present benefit assessment.
• Morbidity – Progression-free survival (PFS)
  • PFS was the primary endpoint of the POD1UM-303 trial and was defined as the time from the date of randomisation to disease progression according to RECIST 1.1 (based on assessment by a review committee (BICR)) or death.
  • PFS was statistically significantly prolonged with retifanlimab in combination with carboplatin and paclitaxel.
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories. The mortality component of this endpoint is already assessed via the overall survival endpoint as a standalone endpoint. The morbidity component ‘disease progression’ was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically confirmed disease progression according to the RECIST 1.1 criteria).
  • Taking the above aspects into account, there are differing views within the GBA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Symptoms (EORTC QLQ-C30) and health status (EQ-5D-VAS)
  • Data on patient-reported symptoms and health status were collected in the POD1UM-303 study using the EORTC QLQ-C30 symptom scales and the EQ-5D visual analogue scale, respectively.
  • However, due to the minor response rates (proportion of missing values already at baseline (approx. 20 per cent) and in the early stages of the study (from cycle 2 onwards, mostly > 30 per cent)) the data are not suitable for drawing conclusions regarding the extent of the additional benefit.
• Quality of life – EORTC QLQ-C30 and EORTC QLQ-ANL27
  • In line with the above comments on symptoms, there are also no suitable data available on health-related quality of life that would allow conclusions to be drawn regarding the extent of the additional benefit.
• Side effects – Total adverse events (AEs)
  • AEs occurred in all patients in the POD1UM-303 study. The results are presented here only for supplementary information.
• Side effects – Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3)
  • For the endpoints ‘serious AEs’ (SAEs) and ‘severe AEs’ (CTCAE grade ≥ 3), no statistically significant differences were observed between the treatment arms.
• Side effects – therapy discontinuations due to AEs
  • For the endpoint ‘therapy discontinuations due to AEs’, a statistically significant disadvantage was observed for retifanlimab in combination with carboplatin and paclitaxel.
• Overall assessment
  • For the benefit assessment of retifanlimab in combination with carboplatin and paclitaxel for the first-line treatment of adults with metastatic or inoperable locally recurrent squamous cell carcinoma of the anal canal (SCAC), results are available from the randomised, controlled trial POD1UM-303, in which retifanlimab in combination with carboplatin and paclitaxel was compared with carboplatin and paclitaxel alone.
  • For the endpoint, there is a statistically significant advantage in favour of retifanlimab in combination with carboplatin and paclitaxel; the extent of this advantage is assessed as relevant, but no more than a minor improvement. It is noted that the effect estimate is based on a wide confidence interval; consequently, uncertainty regarding the precision of the effect estimate is taken into account when interpreting the results.
  • In the morbidity endpoint category, due to insufficient response rates, no suitable data are available for patient-reported symptoms and health status that would allow conclusions to be drawn regarding the extent of the additional benefit.
  • Similarly, with regard to health-related quality of life, there are no suitable data available due to insufficient response rates that would allow conclusions to be drawn about the extent of the additional benefit.
  • Based on the results regarding side effects, there is a disadvantage for retifanlimab in combination with carboplatin and paclitaxel due to a significantly higher rate of therapy discontinuations caused by AEs.
  • Overall, therefore, the advantage in terms of overall survival is offset by the disadvantage in terms of therapy discontinuations due to AEs. This disadvantage does not call into question the extent of the improvement in overall survival. Overall, therefore, the extent of the additional benefit is assessed as minor.

Courtesy translation only, please refer to the German original.