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Monotherapy Or Chemotherapy Adjunct: Pembrolizumab In Advanced NSCLC
To assess the effectiveness and safety of pembrolizumab monotherapy and in combination with chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).
Historically, patients with advanced NSCLC have a poor prognosis despite the use of platinum-based chemotherapy drugs. The 5-year relative survival rate of patients with distant metastases is low globally, being only 6.9% in the United States between 2010 and 2016. Recently, the use of immune checkpoint inhibitors (ICIs) such as nivolumab has greatly altered the treatment paradigm for NSCLC patients. Apart from blocking specific signaling pathways, they stimulate immune responses through antibody-dependent cell-mediated cytotoxicity (ADCC). Lately, Pembrolizumab, an IgG4 monoclonal antibody against programmed cell death protein 1 (PD-1), has become a powerful treatment option for advanced NSCLC.
The KEYNOTE-024 study compared pembrolizumab monotherapy versus chemotherapy in treatment-naive advanced NSCLC patients with high PD-L1 ≥ 50%. Pembrolizumab achieved a remarkable improvement in progression-free survival (PFS) and overall survival (OS). A 2019 study found that pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy in terms of PFS and OS in patients with PD-L1 ≥ 50%.
Several meta-analyses compared the efficacy of pembrolizumab plus chemotherapy and pembrolizumab monotherapy indirectly but presented paradoxical results. In this context, the present study aimed to compare the efficacy and safety of monotherapy and combination therapy in NSCLC patients with high PD-L1 levels.
Materials and Methods
Patients who were diagnosed with advanced NSCLC between January 2016 and August 2019, and treated at multiple centers in Japan, were enrolled in this retrospective study. Ninety-six patients met the following eligibility criteria: i) unresectable or recurrent NSCLC ii) pembrolizumab monotherapy or combined with chemotherapy as first-line treatment and iii) adjuvant chemotherapy before first-line treatment. Patient characteristics, pathological type, PD-L1 TPS, PFS, OS, and adverse events were collected. Patients who discontinued treatment during the first-line treatment or who had incomplete records were excluded. This study was approved by the Institutional Review Board and carried out per the declaration of Helsinki.
Patients were divided into monotherapy alone and combination therapy groups. Patients in the combination therapy groups had received either of the platinum-doublet chemotherapy regimens: carboplatin/cisplatin with pemetrexed or carboplatin with nanoparticle albumin-bound [nab]-paclitaxel/paclitaxel.
The progression-free survival (PFS), overall survival (OS), and response rate (RR) after treatment initiation were analyzed and compared between the groups. Clinical profiles of patients were analyzed to assess their possible relationship with treatment outcomes. Adverse events due to chemotherapy were also graded.
All statistical analyses were performed using JMP Pro 15 software (SAS Institute Inc.). Hazard ratios (HRs) and associated confidence intervals were calculated using the Cox proportional hazards model. A P value of <0.05 was considered statistically significant.
Among the 96 patients, 47 received monotherapy, and 49 received combination therapy. The median follow-up time was 379 days and 271 days in the monotherapy and combination therapy groups, respectively (p=0.0018). The median age was 71 years (range 36–87 years) and 68 years (range 52-81 years) in the monotherapy and combination therapy groups, respectively (p=0.0113).
The monotherapy group had 22 patients with non-squamous cell carcinoma and 12 with squamous cell carcinoma. In the combination therapy group, 35 had non-squamous cell carcinoma and 12 had squamous cell carcinoma.
On comparing patient characteristics it was revealed that the number of patients with a high PD-L1 expression (TPS ≥ 50%) was significantly greater in the monotherapy group than in the combination therapy group (p< 0.0001). However, there was no significant difference in sex, Eastern Cooperative Oncology Group performance status (ECOG) driver mutation status, clinical stage, or smoking history between the two groups.
Progression-free survival (PFS) and overall survival (OS)
The median PFS was 343 days in the monotherapy group and 328 days in the combination therapy group (HR 1.003, 95% confidence interval [CI] 0.54 – 1.85). However, no significant differences were observed when a subgroup analysis of PFS by age, ECOG PS, PD-L1 TPS, histological type, smoking history, brain metastasis, and neutrophil-to-lymphocyte ratio (NLR) was done. The median PFS was 343 days in the thermotherapy group (n = 46) that had the patients with a high PD-L1 expression (TPS ≥ 50%); the median PFS was not reached in the combination therapy group (n = 20).
As with PFS, there was no significant difference in the OS between monotherapy and combination therapy groups. Similarly, there was no statistical difference in OS even in the thermotherapy group.
In the monotherapy group, partial response, stable response, and progressive disease were observed in 24, 10, and 1 patient, respectively; in the combination therapy group the number of patients who showed partial response, stable response, and progressive disease were 30, 10, and 7, respectively. Though the objective response was 55.3% in the monotherapy group and 65.3% in the combination therapy group, the difference was statistically insignificant (p=0.3172).
Effect of metastasis on treatment outcomes
The hazard ratio for progression-free survival by subgroup analysis showed that PFS was longer with monotherapy than with combination therapy in the presence of liver, lung, bone, adrenal gland, and lymph node metastases. Subgroup analysis revealed a longer PFS in the patients of the monotherapy group with liver, lung, bone, adrenal gland, and lymph node metastases (p = 0.048, HR 0.41). Contrarily, for patients without any metastasis, the PFS of the combination therapy group was longer than that of the monotherapy group (p = 0034, HR 2.68).
Since metastasis to at least one of the five sites was a prognostic factor, the authors compared the PFS of patients in the monotherapy group and patients without metastases. PFS was significantly longer in the presence of metastases among patients who received monotherapy (p = 0.036, HR 0.43). Patients who received combination therapy showed no significant differences.
In the monotherapy group, the objective response rate was significantly higher in patients with metastases in comparison to the ones without metastases (82% vs. 29%, p = 0.0002). There were no significant differences in patient characteristics between both groups, except for the male/female ratio.
Treatment-related adverse events were more frequent in the combination therapy group than the monotherapy group (95.9% vs 63.8). 8 patients from the monotherapy group and 5 from the combination group discontinued treatment due to adverse events. The most common adverse events in the monotherapy groups were pneumonitis and skin rash. Neutropenia, nausea, vomiting, increase in alanine aminotransferase and aspartate aminotransferase levels, diarrhea, pneumonitis, and skin rash were common in the combination therapy group.
The effectiveness and safety of pembrolizumab alone and in combination with chemotherapy in patients with advanced NSCLC were retrospectively investigated in the present study.
Current treatment choice in the first-line setting in patients with advanced NSCLC without targetable gene alterations depends on the PD-L1 expression levels. In this study, the majority of patients in the monotherapy group had higher PD-L1 expression than the combination therapy group. However, there were no significant differences in PFS between both groups. Previous studies, KEYNOTE-189 and KEYNOTE-407, reported the median PFS as 11.1 and 8.00 months in patients with PD-L1 ≥ 50%, respectively. Recently, Wu et al. showed that Chinese patients from the KEYNOTE-042 global and China extension (NCT03850444) study could also obtain significant OS benefit from pembrolizumab monotherapy compared with standard chemotherapy.
Several meta-analyses focused on the comparison of combination therapy and pembrolizumab monotherapy but presented paradoxical results. Liu et al. showed that in patients with PD-L1 TPS ≥ 50%, pembrolizumab combined with chemotherapy superior to pembrolizumab monotherapy in terms of OS (HR =0.74, 95% CI: 0.56–0.98) but there was no difference on PFS (HR =0.83, 95% CI: 0.53–1.3. Gandhi et al. reported a result that was almost opposite to Liu’s. Combination therapy showed better results than monotherapy in terms of ORR (OR 1.60, 95% CI 1.20–2.20), PFS (HR 0.52, 95% CI 0.37–0.71) but not for OS (HR 0.75, 95% CI 0.51–1.10) in patients with PD-L1 high expression.
This study demonstrated that clinical outcomes, including PFS, OS, and RR were not significantly different between patients treated with pembrolizumab alone and with pembrolizumab in combination with chemotherapy. However, further randomized trials are needed to validate this benefit. The authors also reported that metastasis to the liver, lung, adrenal glands, bone, or lymph nodes is likely to be a predictive marker of longer PFS in patients treated with pembrolizumab monotherapy. This could be due to the differences in the tumor microenvironment.
This study is limited by its retrospective nature. First, the sample size was relatively small. Second, selection bias existed inevitably as the data were from multiple institutions. Third, the age of patients and the number of patients with a high PD-L1 expression were substantially different in both groups. Fourth, some metastasis-specific prognostic factors such as Royal Marsden Hospital (RMH) score, Gustave Roussy Immune Score (GRIm-Score), and activity of Tim-4+ cavity-resident macrophages were not analyzed.
Thus, prospective trials with an adequate sample size of patients are indispensable for validating both the efficacy and adverse events of these two treatments
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