PD-L1 Inhibition Boosts Response in Various Cancers

A phase I study shows that an antibody targeting programmed death-ligand 1 is effective against a range of solid tumours

medwireNews: Immunotherapy with MPDL3280A, an antibody that blocks programmed death-ligand 1 (PD-L1), improves treatment response in patients with solid tumours of various types and is especially effective against tumours with PD-L1-positive tumour-infiltrating immune cells, research suggests.

The inhibition of PD-L1, a protein that can aid cancer cells to evade detection and eradication by the immune system, is the focus of two studies published in Nature.

In the PCD4989g phase I expansion trial, which had an adaptive design that allowed for studying Biomarker-enriched cohorts, tumours responded to treatment in 18% of 175 patients with various solid cancers who received MPDL3280A intravenously every 3 weeks, report Roy Herbst, from Yale School of Medicine in New Haven, Connecticut, USA, and colleagues.

When stratified by tumour type, confirmed responses, as assessed by RECIST 1.1, were observed in 21%, 26%, 13% and 13% of patients with non-small-cell lung cancer (n=53), melanoma (n=43), renal cell carcinoma (n=56) and other tumours (such as colorectal and gastric cancer), respectively.

Response to the MPDL3280A regimen varied with the expression of PD-L1 expression in pre-treatment tumour samples. Patients with an immunohistochemistry (IHC) score of 2 or 3 in tumour-infiltrating immune cells had an objective response rate (ORR) of 34% compared with 16% in those with IHC 0 or 1.

The response was particularly pronounced when PD-L1 was expressed by tumour-infiltrating immune cells, rather than by tumour cells, a finding that was "unexpected", remark the authors.

However, they add that “larger studies will be needed to study the relationship between PD-L1 expression and patient survival.”

In the other study, the team led by Thomas Powles, from Queen Mary University of London, UK, also found that response rates were "particularly high" in patients enrolled in the metastatic urothelial bladder cancer cohort of the PCD4989g study who hadPD-L1-positive tumour-infiltrating immune cells.

At the first assessment at 6 weeks, participants with a PD-L1 IHC score of 2 or 3 in tumour-infiltrating immune cells (n=30) had an ORR of 43% versus 11% in those with IHC 0 or 1 (n=35). The ORR in patients with IHC 2 or 3 tumours increased marginally to 52% after 12 weeks of follow-up. This highlights a rapid response to treatment with MPDL3280A for many of the patients, say the researchers.

Treatment-related adverse events of any grade were observed in 57% of patients. Grade 3 events were reported by 4% of patients, and there were no grade 4 or 5 adverse events. Additionally, MPDL3280A immunotherapy did not result in renal toxicity.

"There is an urgent need for efficacious and well-tolerated therapies in metastatic [urothelial bladder cancer], as even first-line chemotherapy is poorly tolerated in a large proportion of individuals", say the researchers.

They conclude that “[t]his study provides striking preliminary efficacy and safety results with MPDL3280A for the treatment of [urothelial bladder cancer]”, which has led the US Food and Drug Administration to grant the drug breakthrough status for this condition.

References

Herbst RS, Soria J-C, Marcin Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515: 563–567. doi:10.1038/nature14011

Powles T, Eder JP, Gregg D. Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014; 515: 558–562. doi:10.1038/nature13904

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