Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50.

BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%. RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis. CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

Predictive ability of a drug-based score in patients with advanced non-small-cell lung cancer receiving first-line immunotherapy.

BACKGROUND: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This 'drug score' was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1-2 and poor risk with score 3-4. METHODS: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non-small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy). RESULTS: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts. CONCLUSION: Our 'drug score' showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients.

Post-progression outcomes of NSCLC patients with PD-L1 expression ≥ 50% receiving first-line single-agent pembrolizumab in a large multicentre real-world study.

BACKGROUND: Treatment sequencing with first-line immunotherapy, followed by second-line chemotherapy, is still a viable option for NSCLC patients with PD-L1 expression ≥50%. METHODS: We evaluated post-progression treatment pathways in a large real-world cohort of metastatic NSCLC patients with PD-L1 expression ≥ 50% treated with first-line pembrolizumab monotherapy. RESULTS: Overall, 974 patients were included. With a median follow-up of 22.7 months (95%CI: 21.6-38.2), the median overall survival (OS) of the entire population was 15.8 months (95%CI: 13.5-17.5; 548 events). At the data cutoff, among the 678 patients who experienced disease progression, 379 (55.9%) had not received any further treatment, and 359 patients (52.9%) had died. Patients who did not receive post-progression therapies were older (p = 0.0011), with a worse ECOG-PS (p < 0.0001) and were on corticosteroids prior to pembrolizumab (p = 0.0024). At disease progression, 198 patients (29.2%) received a switched approach and 101 (14.9%) received pembrolizumab ByPD either alone (64 [9.4%]) or in combination with local ablative treatments (37 [5.5%]) (LATs). After a random-case control matching according to ECOG-PS, CNS metastases, bone metastases, and (previous) best response to pembrolizumab, patients receiving pembrolizumab ByPD plus LATs were confirmed to have a significantly longer post-progression OS compared to patients receiving pembrolizumab ByPD alone 13.9 months versus 7.8 months (p = 0.0179) 241 patients (35.5%) among the 678 who had experienced PD, received a second-line systemic treatment (regardless of previous treatment beyond PD). As compared to first-line treatment commencement, patients' features at the moment of second-line initiation showed a significantly higher proportion of patients aged under 70 years (p = 0.0244), with a poorer ECOG-PS (p < 0.0001) and having CNS (p = 0.0001), bone (p = 0.0266) and liver metastases (p = 0.0148). CONCLUSIONS: In the real-world scenario NSCLC patients with PD-L1 expression ≥50% treated with first-line single-agent pembrolizumab achieve worse outcomes as compared to the Keynote-024 trial. Poor post-progression outcomes are major determinants of the global results that should be considered when counselling patients for first-line treatment choices.

Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy.

BACKGROUND: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate. METHODS: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses. RESULTS: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, ß-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate. CONCLUSION: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression ≥ 50%: a multicenter study with external validation.

BACKGROUND: The association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression. METHODS: We present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group. RESULTS: 962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI: 1.04-2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI: 0.37-0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.61 (95% CI: 0.45-0.82)) in the pembrolizumab cohort. Conversely, they had a significantly shorter PFS in the chemotherapy cohort (HR=1.27 (95% CI: 1.01-1.60)). Obese patients had a significantly longer overall survival (OS) within the pembrolizumab cohort (HR=0.70 (95% CI: 0.49-0.99)), while no significant differences according to baseline BMI were found in the chemotherapy cohort. BMI variation significantly affected ORR, PFS and OS in both the pembrolizumab and the chemotherapy cohorts. CONCLUSIONS: Baseline obesity is associated to significantly improved ORR, PFS and OS in metastatic NSCLC patients with a PD-L1 expression of ≥50%, receiving first line pembrolizumab, but not among patients treated with chemotherapy. BMI variation is also significantly related to clinical outcomes.

Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes.

BACKGROUND: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%. PATIENTS AND METHODS: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes. RESULTS: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival. CONCLUSIONS: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting.