Background and Importance Cemiplimab, pembrolizumab, atezolizumab ± bevacizumab, nivolumab + ipilimumab and durvalumab + tremelimumab in combination with chemotherapy, and nivolumab + ipilimumab, are licensed for the treatment of 1L adult patients with metastatic NSCLC expressing PD-L1≥1%.

Aim and Objectives To know if the combinations of immunotherapy and chemotherapy (ct) can be declared equivalent therapeutic alternatives (ETA).

Material and Methods Phase III randomised clinical trials (CT) with similar characteristics were searched in MEDLINE-Pubmed. An adjusted indirect comparison (IC) was performed using Bucher’s method (ITC calculator). Overall survival outcomes in patients with PD-L1≥1% were taken as the primary endpoint. All the combinations were compared with cemiplimab-ct. Delta value (Δ), maximum clinically irrelevant difference, was taken as the value from the ESMO-MCBS Guidelines to consider substantial benefit, HR=0.70 and its inverse 1.43. To declare them as ETA, the GENESIS-GHEMA guidelines were applied.

Results Data from CT against a common comparator were included. The studies were similar, although the cemiplimab-chemotherapy CT included patients with stage IIIB, IIIC and IV, while the other CT included only stage IV; furthermore, some trials included only patients with squamous or non-squamous histology and others both. The following results were obtained: HR (cemiplimab-ct vs pembrolizumab-ct non-squamous histology) 0.82 [95% CI 0.55 – 1.22] p 0.34; HR (cemiplimab-ct vs pembrolizumab-ct squamous) 0.81 [95% CI 0.56 – 1.18] p 0.27; HR (cemiplimab-ct vs atezolizumab ±bevacizumab-ct non-squamous) 0.72 [95% CI 0.50 – 1.04] p 0.08; HR (cemiplimab-ct vs nivolumab-ipilimumab) 0.67 [95% CI 0.48 – 0.94] p 0.02; HR (cemiplimab-ct vs nivolumab-ipilimumab-ct ) 0.74 [95% CI 0.51 – 0.94] p 0.12; HR (cemiplimab-ct vs durvalumab-tremelimumab-ct) 0.68 [95% CI 0.47 – 0.98] p 0.04.

Conclusion and Relevance According to the ETA guidelines, combinations of atezolizumab±bevacizumab, nivolumab-ipilimumab and pembrolizumab in combination with chemotherapy showed type C positioning ‘probable clinical equivalence’. Nivolumab-ipilimumab and durvalumab-tremelimumab-chemotherapy showed type F positioning ‘probably relevant difference’.

There are no statistically significant differences between cemiplimab-chemotherapy and the other approved combinations with the exception of durvalumab-tremelimumab-chemotherapy and nivolumab-ipilimumab in favour of cemiplimab-chemotherapy. Combinations of immunotherapy and chemotherapy do not meet strict criteria for (ETA) as there is uncertainty as to whether there may be clinically relevant differences.

Conflict of Interest No conflict of interest.