Objective:
The objective is to compare the approved indications for programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) inhibitors that are restricted by PD-L1 expression as determined by companion diagnostics in the US prescribing information (USPI) and summary of product characteristics (SmPC).

Methods:
Comparison of PD-1/PD-L1 inhibitors was made based on materials from the FDA and EMA website. Drugs included in the analysis were currently marketed PD-1/PD-L1 inhibitors in the US and EU approved between 09/2014 to 09/2020: nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab and durvalumab. 

Results:
Pembrolizumab’s US restricted indications include non-small cell lung cancer (NSCLC)/metastatic NSCLC (mNSCLC) with PD-L1 tumor proportion score (TPS) ≥ 1%, metastatic, unresectable or recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 combined positive score (CPS) ≥ 1%, metastatic urothelial carcinoma (UC) and esophageal squamous cell carcinoma (SCC) with CPS ≥10, and recurrent, metastatic gastric and cervical cancers with CPS ≥ 1%. All restricted indications required PD-L1 testing through the FDA-approved immunohistochemistry (IHC) 22C3 pharmDxTM kit. In the EU, pembrolizumab’s restricted indications include NSCLC, HNSCC, and UC; however, the indications for NSCLC and HNSCC were restricted further to limit treatment to patients with TPS ≥ 50% or CPS ≥ 1%. 

Atezolizumab’s US restricted indications include the treatment of locally advanced or metastatic UC with TPS ≥ 5%, mNSCLC with high tumor PD-L1 expression, and mTNBC in combination with paclitaxel with TPS ≥ 1%. All restricted indications required PD-L1 testing through the Ventana PD-L1 (SP142) assay. The EU restricted indications for atezolizumab were the same except there was no restriction for a separate second line indication for NSCLC. 

Durvalumab has no PD-L1-restricted indications in the US, but the EU has restricted the indication for NSCLC, limiting therapy to patients whose tumors express PD-L1 TPS ≥ 1% as determined by VENTANA PD-L1 (SP263) Assay, an FDA-approved companion diagnostic. Though this IHC assay is not approved in the EU, it is included in the clinical trials section of the SmPC.

Lastly, nivolumab only has a US-restricted indication for mNSCLC in combination with ipilimumab for PD-L1 (≥1%) as determined by the PD-L1 IHC 28-8 pharmDx assay companion diagnostic. In the EU, nivolumab does not have any restricted indications out of its six indications, which does not include the specific NSCLC indication which is restricted in the US.

Conclusions:
Overall, it was found that the European Medicines Agency (EMA) was more restrictive for indications of various PD-L1 inhibitors that are currently marketed. Indications were generally restricted for PD-L1 expression if their corresponding clinical studies were inclusive of only patients who met minimum PD-L1 expression cutoffs or evaluated primary endpoints in subgroups with PD-L1-positive tumors, as was most commonly observed with pembrolizumab across the board. The EMA was more restrictive than the Food and Drug Administration (FDA) for pembrolizumab, using higher cutoffs for PD-L1 expression to further escalate indication restrictions or adding new cutoffs to indications not restricted by the FDA in NSCLC and HNSCC indications.

The FDA may restrict indications that were not restricted by the EMA if that specific indication was either not approved in the EU, currently under review in the EU (due to different health authority review timelines), or a trial restricting use in the US was not approved by the EMA. This was the case for nivolumab’s NSCLC indication and atezolizumab’s NSCLC indication. 

Although various clinical trials included subgroup analyses in patients with different PD-L1 expressions, most analyses were exploratory and thus not statistically powered to detect a difference in patient response. Therefore, indications were rarely restricted on the basis of exploratory analyses, except in the case of durvalumab. Durvalumab’s restricted NSCLC indication is only present in the SmPC, although the same study was used for both FDA and EMA approvals. An exploratory post-hoc analysis requested by the EMA revealed that overall survival benefit was observed across all subgroups but TPS < 1%, which is likely why the EMA restricted the indication to tumors expressing PD-L1 TPS ≥ 1%. This information indicates that the EMA may be willing to accept post-hoc analyses in order to restrict indications, even though their statistical significance is questionable.

A Comparative Analysis of FDA and EMA Approvals for PD-1/PD-L1 Inhibitors Linked to Specific PD-L1 Thresholds

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