Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer

Several clinical factors including smoking, previous treatment, and antibiotic usage are reported to be involved in affecting the efficacy of ICI therapy.

“Several clinical factors are reported to be involved in affecting the efficacy of ICI therapy, including smoking, previous treatment, and ATB usage.15,32,39”

Inhibitors of programmed death 1 (PD-1) and its ligand PD-L1 are effective therapies for metastatic NSCLC lacking sensitising EGFR or ALK mutations.

“Inhibitors of programmed death 1 (PD-1) and its ligand PD-L1 are effective therapies for metastatic NSCLC lacking sensitising EGFR or ALK mutations.2–6”

Patients more likely to benefit from checkpoint immunotherapy include those with high somatic mutation density, elevated PD-L1 expression, and/or IFNγ transcriptional profiles.

“Patients more likely to benefit from checkpoint immunotherapy include those with tumors demonstrating a high density of somatic mutations, elevated PD-L1 expression and/or are enriched with IFNγ transcriptional profiles (8–13).”

The degree of tumor inflammation, assessed by type I/II IFN signaling and infiltrating effector T cells, is associated with improved response to checkpoint immunotherapy.

“The degree of tumor inflammation, as assessed by the presence of type I/II IFN signaling and infiltrating effector T cells, is associated with an improved response to checkpoint immunotherapy (8–11,13).”

Only 4% of patients had squamous cell carcinoma, compared with 15-20% in the overall lung cancer population.

“Only 4% of patients had a diagnosis of squamous cell carcinoma (SqCC) as compared to 15–20% in the overall lung cancer population (4, 34), likely due to the anticipated low frequency of actionable molecular abnormalities in SqCC, and also a competing SqCC trial at our institution at the time of this study.”

Resistance to ICIs limits the number of patients who achieve durable responses.

“However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses”

Most patients and cancers do not respond to ICIs.

“Despite the fact that many patients experience dramatic tumor regression in response to ICIs, most patients and cancers do not respond to these therapies.”

PD-L1 expression intensity on tumor cells is a commonly used biomarker positively correlated with ICI response in several cancers.

“One of the most commonly used biomarkers for predicting response to ICIs is the intensity of PD-L1 expression on tumor cells, which is positively correlated with response to ICIs in several cancer settings (74,75,80).”

Among melanoma patients, 60-70% do not have an objective response to anti-PD-1 therapy; of responders, 20-30% eventually relapse.

“Even among patients with melanoma, which has one of the highest rates of response to ICI, 60-70% of patients do not experience an objective response to anti-PD-1 therapy; of those that do, 20-30% demonstrate eventual tumor relapse and progression (74,75).”

Tumors with absent or low PD-L1 expression are more likely to be resistant to anti-PD-1/PD-L1, supported by response rates up to 10% in PD-L1-low melanoma and NSCLC versus 40-50% in high PD-L1.

“Thus, it stands to reason that tumors with absent or low expression of PD-L1 are more likely to exhibit resistance to anti-PD-1 and anti-PD-L1 therapies, and this assertion is supported by response rates of only up to 10% in patients with PD-L1-low melanoma and patients with NSCLC treated with anti-PD-1 compared with 40-50% in patients with high PD-L1 expression (74,80).”

The cause of high mutational burden does not determine ICI response; melanoma and NSCLC with UV/carcinogen mutations respond as well as tumors with genomic instability or deficient mismatch repair.

“The underlying cause of the high mutational burden is not important for determining whether a tumor will respond to ICIs, as melanoma and NSCLC, which acquire mutations through UV-and carcinogen-induced DNA damage, respectively, respond just as well to ICIs as do tumors that acquire mutations through genomic instability or deficient mismatch repair (74,80,87).”