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Overall survival (OS) as well as progression-free survival (PFS) were superior when immune checkpoint inhibitors of the programmed cell death 1 (PD-1) apoptosis factor were used in cancer patients compared with programmed cell death ligand 1 (PD-L1) inhibitors, a systematic review and meta-analysis of the literature indicated.

In data from 19 randomized clinical trials involving 11,379 patients, anti-PD-1 agents produced a significant OS benefit compared with anti-PD-L1 inhibitors (HR 0.75, 95% CI 0.65-0.86; P<0.001), Jie Wang, MD, PhD, of Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, and colleagues .

The same class of agents produced a similar and significant PFS benefit as well (HR 0.73 95% CI 0.56-0.96; P=0.02) compared with PD-L1 inhibitors.

In contrast, no significant differences in adverse events (AEs) were observed between PD-1 and PD-L1 inhibitors. "To our knowledge, this is the first systematic review and meta-analysis that compared treatment outcomes and safety profiles between anti-PD-1 and anti-PD-L1 in patients with solid tumors," investigators stated.

"Our meta-analysis suggests that anti-PD-1 exhibited better survival outcomes than anti-PD-L1 in patients with solid tumors in either overall, monotherapy, or combination therapy settings, with comparable safety profiles," they concluded.

For the meta-analysis, studies of anti-PD-1 and anti-PD-L1 drugs were screened and paired with so-called "mirrored" trial characteristics including tumor types, treatment lines, intervention regimens, control groups, and biomarker status for further mirrored comparisons. Wang and colleagues said the mirror principle allows indirect comparative analysis of different studies with a minimal risk of bias across multiple interventions.

"All randomized clinical trials that had compared the efficacy of anti-PD-1 or anti-PD-L1 as monotherapy or in combination with standard treatment in patients with solid tumors were selected," they wrote. The studies reviewed explored the efficacy of PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda), as well as avelumab (Bavencio) and atezolizumab (Tecentriq), both PD-L1 inhibitors. Patients had a range of solid tumors including non-small cell lung cancer (NSCLC); gastric or gastroesophageal junction cancer; renal cell carcinoma; and urothelial (bladder) cancer.

Stratified by the type of intervention used, PD-1 inhibitors had better OS benefit compared with PD-L1 inhibitors when used alone as monotherapy (HR 0.78, 95% CI 0.63-0.95; P=0.01), Wang and colleagues reported.

This was also true when PD-1 inhibitors were used in combination with other agents where the combination resulted in a substantial improvement in OS compared with anti-PD-L1 agents (HR 0.68, 95% CI 0.55-0.83; P<0.001).

Depending on the type of analyses performed, OS rates were significantly prolonged for patients with NSCLC treated with a PD-1 inhibitor compared with a PD-L1 inhibitor (HR 0.77, 95% CI 0.65-0.92; P<0.001) as well as for patients with gastric or gastroesophageal junction cancer (HR 0.57, 95% CI 0.42-0.78; P<0.001) relative to OS rates achieved with a PD-L1 inhibitor. It was recently reported that first-line treatment with nivolumab plus ipilimumab (Yervoy) led to a longer duration of OS versus chemotherapy in patients with advanced NSCLC independent of the PD-L1 expression level.

In contrast, PD-1 inhibitors did not significantly improve OS compared with PD-L1 inhibitors for patients with either urothelial or renal cell carcinoma, as researchers noted. This is in apparent contradiction to previous reports where both PD-1 and PD-L1 inhibitors have proven to be so effective that they have become standard treatment for patients with metastatic urothelial cancer.

"Consistent with the results for OS, patients receiving anti-PD-1 appeared to exhibit better PFS than those receiving anti-PD-L1," researchers continued, where there was significant improvement in PFS for PD-1 inhibitors compared to PD-L1 inhibitors (HR 0.73, 95% CI 0.56-0.96; P=0.02).

In terms of safety, rates for adverse events (AEs) at grade 3 and above as well as immune-related AEs were comparable between the two classes of agents. Similarly, the incidence of AEs causing death or discontinuation from treatment were also comparable between PD-1 and PD-L1 inhibitors. The authors suggested that the superior efficacy of PD-1 inhibitors compared with PD-L1 inhibitors might be due to the fact that PD-1 antibodies can bind to PD-1, further blocking the binding of PD-1 to its ligands (PD-L1 and PD-L2) at the same time.

"The magnitude of possible survival benefit of anti-PD-1 compared with anti-PD-L1 is clinically relevant which may provide important clues for treatment selection for clinicians in clinical practice," Wang and colleagues summarized. "[But] further head-to-head studies are warranted for direct comparison across alternative interventions," they suggested.

However, previously reported studies support the efficacy of PD-L1 inhibitors in various tumor types. For example, the PD-L1 checkpoint inhibitor durvalumab (Imfinzi) improved the pathologic complete response (pCR) rate in early triple-negative breast cancer when added to an anthracycline, taxane-based neoadjuvant therapy regimen.

And while pembrolizumab is a PD-1 inhibitor, results from the KEYNOTE-059 trial showed that patients with PD-L1-positive advanced gastric and gastroesophageal cancer had a higher overall response rate than those who tested negative for PD-L1, suggesting that PD-L1 positive status does matter when treating patients with an immune checkpoint inhibitor.

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