Checkpoint Inhibitors Associated With Prolonged Survival in NSCLC

Jaime Rosenberg

Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related death globally. While docetaxal has been the standard of care for advanced NSCLC, the emergence of immune checkpoint inhibitor therapies has recently created a new standard for a second or later line of treatment. New study findings published in JAMA Oncology have found that these checkpoint inhibitors are associated with prolonged survival in second-line therapy in NSCLC.

“Identifying clinical or molecular factors that predict benefit of checkpoint inhibitors in advanced NSCLC remains crucial for the selection of appropriate patients for this class of therapy,” wrote the authors of the study.

Using the potential predictive value of routinely collected data on patient, disease, and molecular characteristics as guidance, the authors selected patients with advanced NSCLC for checkpoint inhibitors in second and later lines of therapy.

The authors assessed 5 randomized clinical trials that compared nivolumab, pembrolizumab, or atezolizumab with docetaxel. Of the 3025 patients, 427 received nivolumab, 691 received pembrolizumab, 569 received atezolizumab, and 1338 received docetaxel. Data collection took place from February 1, 2017, to March 31, 2017, and for each trial, the trial name, year of publication or conference presentation, patients’ clinicopathological characteristics, type of chemotherapy, and type of checkpoint inhibitor were obtained.

The hazard ratio (HR) and 95% Cl for overall survival (OS) of the intention-to-treat population were also extracted, as well as the following predefined subgroups: epidermal growth factor receptor (EGFR) status; Kirsten RAS (KRAS) status; smoking status; age; sex; performance status; tumor histology; and central nervous system metastasis.

The fixed-effects inverse-variance-weighted method was used to pull results to estimate the size of the treatment benefit, and tests of interaction were used to determine the differences in treatment effect across subgroups. Results showed that treatment with a checkpoint inhibitor was associated with a 31% reduction in risk of death when compared with chemotherapy (HR, 0.69; 95% CI, 0.63-0.75; P  < .001).

When analyzed by EGFR and KRAS mutation status, prolonged survival was observed in the EGFR wild-type subgroup (HR, 0.67; 95% CI, 0.60-0.75; P  < .001), but not in the EGFR mutant subgroup (HR, 1.11; 95% CI, 0.80-1.53; P  = .54; interaction,  = .005). Conversely, prolonged OS was observed in the KRAS mutant subgroup (HR, 0.65; 95% CI, 0.44-0.97; P = .03) but not in the KRAS wild-type subgroup (HR, 0.86; 95% CI, 0.67-1.11; P = .24; interaction, P = .24).

Treatment benefits were similar according to smoking status (never smokers [HR, 0.79] vs ever smokers [HR, 0.69]; interaction, P = .40), performance status (0 [HR, 0.69] vs 1 [HR, 0.68]; interaction, P = .85), age (<65 years [HR, 0.71] vs ≥65 years [HR, 0.69]; interaction, P = .74), histology (squamous [HR, 0.67] vs nonsquamous [HR, 0.70]; interaction, P = .71), and sex (male [HR, 0.69] vs female [HR, 0.70]; interaction, P = .82).

“Checkpoint inhibitors, compared with docetaxel, significantly prolonged OS in second and later lines of treatment for advanced NSCLC,” concluded the authors. “Our findings of no OS benefit for EGFR mutant tumors suggest that checkpoint inhibitors should be considered only for this group after exhaustion of other effective therapies.”

The authors also noted that with the absence of a significant interaction KRAS status and treatment effect, they could not recommend KRAS as a predictive biomarker and larger studies are warranted.

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