|Year : 2019 | Volume
| Issue : 4 | Page : 743-750
Pembrolizumab for the treatment of nonsmall cell lung cancer: Current status and future directions
Qin Qin1, Baosheng Li2
1 Department of Oncology, The Second Clinical Medical College, Jingzhou Central Hospital, Yangtze University, Jingzhou, Hubei 434020, China
2 Department of Radiation Oncology (Chest Section), Shandong Cancer Hospital and Institute, Shandong University, Jinan, Shandong 250117, China
|Date of Web Publication||14-Aug-2019|
Department of Radiation Oncology (Chest Section), Shandong Cancer Hospital and Institute, Shandong University, Jinan, Shandong 250117
Source of Support: None, Conflict of Interest: None
The development of inhibitors of immune checkpoints has revolutionized the treatment for a subset of patients with advanced nonsmall cell lung cancer (NSCLC), resulting in promising clinical outcomes and durable responses. Pembrolizumab, a humanized anti-programmed cell death-1 (PD-1) antibody, has been approved as a first-line treatment for patients with advanced NSCLC with PD-L1 expression of ≥50% and as a second-line treatment for PD-L1 expression of ≥1%. Pembrolizumab in combination with standard chemotherapy has shown better clinical outcomes than chemotherapy as a first-line therapy in patients with advanced NSCLC without targetable mutations, regardless of PD-L1 expression. In this review, we summarized the current indications of pembrolizumab for NSCLC, briefly described immune-relevant pneumonitis and discussed potential biomarkers to predict clinical efficacy.
Keywords: Immune checkpoint inhibitor, nonsmall cell lung cancer, pembrolizumab, programmed cell death-1
|How to cite this article:|
Qin Q, Li B. Pembrolizumab for the treatment of nonsmall cell lung cancer: Current status and future directions. J Can Res Ther 2019;15:743-50
| > Introduction|| |
Lung cancer is the leading cause of cancer-related deaths in China and worldwide. According to American Surveillance, Epidemiology, and End Results analysis, only 18.6% of patients with lung cancer survive 5 years or more after diagnosis; for patients with distant metastases, the estimated 5-year overall survival (OS) was only 4.7%. Despite this unpromising outlook, a subset of patients with lung cancer, especially nonsmall cell lung cancer (NSCLC), do benefit from recent advances in targeted therapy and immunotherapy. Although targeted therapy, which has been used for many years, is a powerful treatment for patients with NSCLC with the corresponding driving mutations, immunotherapy, which aims to overcome immune evasion, is a new paradigm for treatment and has shown promising outcomes in a proportion of patients with NSCLC.
Immune evasion is a characteristic of cancer in which the immune system does not recognize tumor cells and no effective antitumor response is produced. The expression of immune inhibitory molecules, including immune checkpoint ligands, has a pivotal role in immune evasion in NSCLC. Programmed cell death-1 ligand 1 (PD-L1) is the most studied immune checkpoint ligand in NSCLC, in which the upregulation of PD-L1 expression has been widely demonstrated., PD-1 is an inhibitory costimulatory receptor expressed primarily on the surface of activated T lymphocytes. The binding of PD-1 to PD-L1 inhibits the antitumor cytotoxic T-lymphocyte response, resulting in immune escape; conversely, blockade of the PD-1/PD-L1 pathway, either by anti-PD-1 or anti-PD-L1 antibodies, exhibited promising antitumor effects in NSCLC.
Pembrolizumab (Keytruda, MK3475) is a high-affinity, humanized, IgG4 monoclonal antibody selectively for PD-1, which blocks the PD-1/PD-L1 pathway. Pembrolizumab, either as monotherapy or in combination with chemotherapy, showed remarkable activity against NSCLC and acceptable toxicity in the KEYNOTE series of clinical trials.,,,,,,, In this review, we have summarized the results of published clinical trials on pembrolizumab for the treatment of NSCLC to determine the current indications of pembrolizumab in the treatment of NSCLC. Immune-relevant pneumonitis, which may be lethal, and biomarkers predictive of pembrolizumab's benefits are discussed.
| > Efficacy of Pembrolizumab in the Treatment of Nonsmall Cell Lung Cancer|| |
KEYNOTE-001 was a phase 1 trial that investigated the efficacy and safety of pembrolizumab in patients with advanced or metastatic carcinoma, melanoma, or NSCLC. In this trial, 495 patients with advanced NSCLC were assigned to receive pembrolizumab at three different dose schedules: 2 mg or 10 mg/kg of body weight every 3 weeks, or 10 mg/kg every 2 weeks. The overall response rate (ORR) was 18.0% (95% confidence interval [CI]: 14.4–22.2) in 394 previously treated patients and 26.7% (95% CI: 18.4–36.5) in 101 previously untreated patients. The median duration of response was 10.4 months (range: 1.0–10.4) in previously treated patients and 23.3 months (range: 1.0–23.3) in previously untreated patients. The median progression-free survival (PFS) was 3.0 months (95% CI: 2.2–4.0) for previously treated patients and 6.0 months (95% CI: 4.1–8.6) for previously untreated patients. The median OS was 9.3 months (95% CI: 8.4–12.4) for previously treated patients and 22.1 months (95% CI: 17.1–27.2) for previously untreated patients [Table 1].
|Table 1: Main results of clinical trials with pembrolizumab as monotherapy in advanced nonsmall cell lung cancer and their clinical implication|
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Along with the demonstration of the favorable outcomes of pembrolizumab in previously treated and untreated patients with NSCLC, KEYNOTE-001 determined that PD-L1 expression in at least 50% of tumor cells was the cutoff correlated with improved efficacy. PFS and OS were longer among patients with a PD-L1 expression proportion score of at least 50% than among those with a score of <50%. The median PFS among patients with a proportion score of at least 50% was 6.1 months (95% CI: 2.1–12.5) for previously treated patients and 12.5 months (95% CI: 2.4–12.5) for previously untreated patients. The median OS among patients with a proportion score of at least 50% was not reached in previously treated patients (95% CI: 9.3 to not reached) or in previously untreated patients (95% CI: 22.1 to not reached) [Table 1].
Based on the results of KEYNOTE-001, three phase 3 clinical trials (KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042) were conducted for further assessment of the efficacy of pembrolizumab monotherapy in advanced NSCLC compared with standard chemotherapy. KEYNOTE-010 enrolled 1034 patients with previously treated, PD-L1-positive, advanced NSCLC: these patients were randomly assigned, in a 1:1:1 ratio, to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. In the total population, OS was significantly longer for pembrolizumab 2 mg/kg (10.4 months, 95% CI: 9.4–11.9) than for docetaxel (8.5 months, 95% CI: 7.5–9.8) (hazard ratio [HR] 0.71, 95% CI: 0.58–0.88; P = 0.0008) and for pembrolizumab 10 mg/kg (12.7 months, 95% CI: 10.0–17.3) than for docetaxel (HR 0.61, 95% CI: 0.49–0.75; P < 0.0001). No significant difference in PFS was observed among these three groups. In the analysis of patients with at least 50% of tumor cells expressing PD-L1, OS and PFS were significantly longer for pembrolizumab (2 mg/kg or 10 mg/kg) than for docetaxel [Table 1], further demonstrating the positive correlation between PD-L1 expression and pembrolizumab efficacy. This study also showed no significant difference in efficacy or safety between the pembrolizumab 2 mg/kg and 10 mg/kg group. Therefore, based on this study, pembrolizumab 2 mg/kg was approved as a second-line treatment for previously treated, PD-L1-positive, and advanced NSCLC.
Given the profound survival benefit of pembrolizumab in patients with PD-L1 expression on at least 50% of tumor cells, KEYNOTE-024 selectively enrolled this subset of patients (305 patients) with treatment-naïve NSCLC, to compare pembrolizumab with standard chemotherapy as the first-line therapy [Table 1]. The median PFS was 10.3 months (95% CI: 6.7 to not reached) in the pembrolizumab group compared with 6.0 months (95% CI: 4.2–6.2) in the chemotherapy group (HR 0.50; 95% CI: 0.37–0.68; P < 0.001). The estimated rate of OS at 6 months was 80.2% in the pembrolizumab group compared with 72.4% in the chemotherapy group (HR 0.60; 95% CI: 0.41–0.89; P = 0.005). The ORR was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), and the median duration of response was longer (not reached [range, >1.9 >14.5 months] vs. 6.3 months [range, >2.1– > 12.6]). Updated data from this study revealed a median OS of 30.0 months (18.3 to not reached) in the pembrolizumab group versus 14.2 months (9.8–19.0) in the chemotherapy group (HR 0.63; 95% CI: 0.47–0.86; P = 0.002); 12-month OS was 70.3% in the pembrolizumab group versus 54.8% in the chemotherapy group., Based on this study, pembrolizumab was approved as a first-line treatment for patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells.
To further explore the potential benefit of pembrolizumab as the first-line treatment for advanced NSCLC, KEYNOTE-042 enrolled patients with PD-L1 expression on at least 1% of tumor cells, to assess whether pembrolizumab will improve survival in patients with PD-L1 expression of at least 50% or 1%–49%. Totally, 1274 patients were randomized, at a 1:1 ratio, to ≤35 cycles of pembrolizumab 200 mg every 3 weeks or ≤6 cycles of standard chemotherapy; pembrolizumab significantly improved OS in patients with TPS ≥50% (HR 0.69), TPS ≥20% (HR 0.77), and TPS ≥1% (HR 0.81). However, according to ASCO data, there was no significant difference in OS between pembrolizumab treatment and chemotherapy for patients with TPS 1%–49%. Although the full data are unavailable, this study reestablished the role of pembrolizumab monotherapy in treatment-naïve patients with advanced NSCLC with PD-L1 expression of at least 50%; for patients with PD-L1 expression below 50%, pembrolizumab in combination with chemotherapy may be a better choice, as shown below.
Pembrolizumab in combination with chemotherapy
For decades, platinum-doublet chemotherapy was the standard first-line therapy for patients with advanced NSCLC without targetable mutations. However, given the evidence that pembrolizumab exhibited favorable efficacy and a nonoverlapping toxicity profile with chemotherapy in clinical trials, the combination of pembrolizumab with the standard chemotherapy as the first-line therapy appears quite reasonable. Chemotherapy eradicates tumor cells, not only through cytotoxic effects but also through immunological regulation., Chemotherapy has been shown to reduce T-regulatory cell activity,, enhance the cross-presentation of tumor antigens, and induce PD-L1 expression on tumor cells,, suggesting that the combination of pembrolizumab with chemotherapy may have synergistical antitumor effects.
KEYNOTE-021 was a phase 2 clinical trial to assess whether the combination of pembrolizumab with chemotherapy would show better outcomes than chemotherapy alone in patients with advanced nonsquamous NSCLC. In total, 123 patients were randomly assigned 1:1 to treatment with pembrolizumab plus carboplatin and pemetrexed or to carboplatin and pemetrexed alone. The ORR was 55% (95% CI: 42–68) in the pembrolizumab plus chemotherapy group and 29% (95% CI: 18–41) in the chemotherapy group. Median PFS was 13.0 months (95% CI: 8.3 to not reached) in the pembrolizumab plus chemotherapy group and 8.9 months (95% CI: 4.4–10.3) in the chemotherapy alone group. With a median follow-up of 10.6 months, median OS was not reached in both groups, and no difference in OS was observed. However, the updated data, with a median follow-up of 23.9 months, showed significant improvements in both PFS and OS with pembrolizumab plus chemotherapy; the HR for OS was 0.56, which confirmed the benefits of combining pembrolizumab with chemotherapy. Given these results, the benefits of pembrolizumab combined with chemotherapy were further explored in the phase 3 clinical trials, KEYNOTE-189, and KEYNOTE-407 [Table 2].
|Table 2: Main results of clinical trials with pembrolizumab in combination with chemotherapy in advanced nonsmall cell lung cancer and their clinical implication|
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KEYNOTE-189 was a phase 3 clinical trial conducted to assess whether the addition of pembrolizumab to first-line standard chemotherapy improved efficacy compared with chemotherapy alone in patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations. In total, 616 patients were randomly assigned, in a 2:1 ratio, to the combination group (200 mg pembrolizumab plus pemetrexed and a platinum-based drug every 3 weeks for four cycles, followed by pembrolizumab for a maximum of 35 cycles plus pemetrexed maintenance therapy) or the chemotherapy group (placebo plus pemetrexed and a platinum-based drug every 3 weeks for four cycles, followed by placebo and pemetrexed maintenance therapy). Crossover to pembrolizumab monotherapy was permitted when patients in the chemotherapy group had verified disease progression. The median PFS was 8.8 months (95% CI: 7.6–9.2) in the combination group and 4.9 months (95% CI: 4.7–5.5) in the chemotherapy group (HR 0.52; 95% CI: 0.43–0.64; P < 0.001); the estimated 12-month OS was 69.2% (95% CI: 64.1–73.8) in the combination group versus 49.4% (95% CI: 42.1–56.2) in the chemotherapy group (HR 0.49; 95% CI: 0.38–0.64; P < 0.001). Importantly, improved OS was seen for all PD-L1 expression categories evaluated, which indicated that no matter the PD-L1 expression on tumor cells, patients with nonsquamous NSCLC suitable for standard first-line chemotherapy could benefit from the addition of pembrolizumab; the benefit was greatest in patients with PD-L1 expression of at least 50% on tumor cells.
Similar to KEYNOTE-189, KEYNOTE-407 was a phase 3 clinical trial conducted to compare pembrolizumab combined with standard chemotherapy with chemotherapy alone, but in untreated metastatic squamous NSCLC; 559 patients were randomly assigned, at a 1:1 ratio, to the combination (200 mg pembrolizumab for a maximum of 35 cycles plus carboplatin and either paclitaxel or nanoparticle albumin-bound paclitaxel for the first four cycles) or chemotherapy (placebo plus chemotherapy) group. The results of this study were similar to those of KEYNOTE-189; both OS and PFS were improved in the combination group. The OS benefit was shown for all PD-L1 expression levels. The median OS was 15.9 months (95% CI: 13.2 to not reached) in the combination group and 11.3 months (95% CI: 9.5–14.8) in the chemotherapy group (HR 0.64; 95% CI: 0.49–0.85; P < 0.001). The median PFS was 6.4 months (95% CI: 6.2–8.3) in the combination group and 4.8 months (95% CI: 4.3–5.7) in the chemotherapy group (HR, 0.56; 95% CI: 0.45–0.70; P < 0.001).
Thus, pembrolizumab in combination with standard chemotherapy was the preferable choice for first-line therapy in patients with metastatic NSCLC with PD-L1 expression on <50% of tumor cells. For patients with PD-L1 expression on at least 50% of tumor cells, combination therapy and pembrolizumab monotherapy are better than chemotherapy; however, no evidence exists to indicate whether pembrolizumab as monotherapy or in combination with chemotherapy is better. Therefore, without direct comparisons, treatment decisions should be personalized after balancing potential risks and benefits.
Pembrolizumab for nonsmall cell lung cancer with brain metastases
Approximately 25%–40% of all patients with NSCLC will develop brain metastases during their illness. Treatment approaches include radiotherapy (stereotactic radiosurgery or whole brain radiotherapy), targeted therapies, or surgery in selected patients. These patients are usually excluded from most clinical trials, such as the KEYNOTE trials, owing to concerns about potential neurologic sequelae and uncontrolled brain disease. Therefore, information can rarely be obtained from the KEYNOTE trials regarding pembrolizumab for the treatment of NSCLC with brain metastases. A single institution phase 2 trial investigated the role of pembrolizumab in patients with brain metastases from melanoma or NSCLC: 18 NSCLC patients with PD-L1 expression and without neurologic symptoms or the need for corticosteroids were included and received pembrolizumab 10 mg/kg every 2 weeks until progression. For brain metastatic lesions, four patients achieved complete response, and two achieved partial response, which were durable. Given the scarcity of evidence, the role of pembrolizumab in the treatment of NSCLC brain metastases is still unknown, and more clinical trials are needed.
Safety of pembrolizumab in the treatment of nonsmall cell lung cancer
The most common adverse events (AEs) related to pembrolizumab included fatigue (10.4%–19.4%), decreased appetite (10%–14%), rash (9%–13%), diarrhea (6%–14.3%), and nausea (7.5%–11%), which were mainly of low grade.,, AEs of grade 3 or higher were reported in 9.5%–26.6% of patients administered pembrolizumab monotherapy, which was much lower than with chemotherapy (35%–53.3%)., In general, the AEs were manageable; however, the immune-related AEs (irAEs) of pembrolizumab are of the most concern.
By blocking the PD-1/PD-L1 interaction, pembrolizumab, similar to other immune checkpoint inhibitors, reactivates the antitumor immune response and leads to the emergence of unusual autoimmune toxicities called irAEs., The most common irAEs were hypothyroidism (6.7%–9.1%), pneumonitis (3.6%–6.5%), and hyperthyroidism (4%–7.8%). Other irAEs include infusion-related reactions, colitis, severe skin reactions, and pancreatitis., The incidence of irAEs of grade 3 or higher was below 2%, and death related to pembrolizumab treatment was rare (<1%) and mostly due to pneumonitis.,,, With the increased use of pembrolizumab in a variety of cancers, including NSCLC, the number of patients who suffer from potentially fatal pneumonitis will undoubtedly increase; therefore, understanding the clinical and radiologic features of pneumonitis will facilitate early detection, optimized treatment, and improved outcomes.
Pneumonitis is defined as focal or diffuse inflammation of the lung parenchyma without the presence of an infection. According to the analysis of a large number of studies on pneumonitis associated with anti-PD-1/PD-L1 antibodies, the most common symptoms are dyspnea and cough; one-third of patients were asymptomatic and diagnosed incidentally by imaging. The timing of onset varied widely, between 9 days and 19.2 months. Radiologic features of pneumonitis are classified into five subtypes: cryptogenic organizing pneumonia-like, ground glass opacities, interstitial, hypersensitivity, and pneumonitis not otherwise specified. Treatment is based on the severity of pneumonitis. Grade 1 pneumonitis can be treated with drug holding alone, with close clinical and radiologic follow-up. Grade 2 and higher pneumonitis should be treated with corticosteroids in addition to drug holding, with continued close clinical and radiologic follow-up. If symptoms worsen or radiologic findings suggest deterioration during corticosteroid treatment, new drugs, such as infliximab, may be considered.
| > Biomarkers For Pembrolizumab|| |
In the previous clinical trials, pembrolizumab showed improved clinical outcomes, durable responses, and acceptable toxicities, which make it a current important paradigm for treatment in patients with advanced NSCLC. Unfortunately, not all patients benefit from pembrolizumab; <1 quarter of unselected patients with advanced NSCLC achieved objective responses with pembrolizumab monotherapy. Therefore, it is imperative to develop reliable biomarkers that identify patients that are more likely to benefit from pembrolizumab.
The rationale of PD-1 blockade immunotherapy is to unleash preexisting tumor-specific T-cells to mount antitumor effects. The success of PD-1 blockade relies on two aspects: tumor immunogenicity, which implies the existence of tumor-derived neoantigens  and an immunosuppressive tumor microenvironment (TME), in which tumor-specific T-cells cannot function because of PD-1/PD-L1 interaction. Therefore, the predictive biomarkers for pembrolizumab can be broadly divided into two categories: those related to tumor immunogenicity and those indicative of a T cell-inflamed TME.
Biomarkers related to tumor immunogenicity
Tumor immunogenicity depends on the existence of tumor-derived neoantigens, which are formed by peptides that are not present in the normal human genome. For NSCLC, tumor-specific DNA mutations that form novel protein sequences are responsible for the existence of neoantigens. Theoretically, increased tumor mutation burden (TMB) suggests potential increases in tumor neoantigens and subsequently increased responses from PD-1 blockade immunotherapy. Many investigators have proposed and validated biomarkers related to TMB to predict the benefits of pembrolizumab.,, Rizvi et al. performed whole-exome sequencing of patients with NSCLC treated with pembrolizumab in two independent cohorts (n = 16 and 18, respectively) and demonstrated that higher nonsynonymous TMB was associated with improved ORR, durable clinical benefit, and PFS. Moreover, the molecular signature of smoking, higher neoantigen burden, and mutations of the DNA repair pathway, which were associated with higher TMB, were also predictive of the benefits of pembrolizumab. Mismatch repair deficiency, which results in exceptionally high numbers of somatic mutations and increased TMB, has been demonstrated as a useful biomarker across many different tumor types., However, as mismatch repair deficiency occurred in <1% of NSCLCs, it is not a proper biomarker in NSCLC.
Biomarkers indicative of T cell-inflamed tumor microenvironment
The most widely studied biomarker in this category is PD-L1 expression on tumor and immune cells. In most cases, PD-L1 is upregulated in response to interferon-γ (IFN-γ), which is a key cytokine produced by activated T cells in TME. The upregulation of PD-L1 results in adaptive immune resistance and is the cornerstone of PD-1/PD-L1 blockade therapy; thus, PD-L1 expression is the most reasonable biomarker for pembrolizumab. As demonstrated by KEYNOTE-001, 010, and 042, PD-L1 expression on at least 50% of tumor cells correlated positively with clinical benefits and was recognized as a valid biomarker to select patients who benefit the most from pembrolizumab.,, However, not all patients in this subgroup achieve benefits, and a proportion of patients beyond this subgroup do experience benefits. Therefore, more reliable biomarkers are needed.
Tumor-infiltrating lymphocytes (TILs) have an important role in killing tumor cells after PD-1/PD-L1 blockade, and insufficient TILs within TME may be a reason why tumors with PD-L1 upregulation fail to show benefits following pembrolizumab treatment. A more comprehensive biomarker that reflected the tumor-immune interaction within the TME, proposed by Ayers et al., was T cell-inflamed gene expression profiles (GEPs), which contain IFN-γ–responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance. Their data suggested that the high expression of T cell-inflamed GEPs is necessary, but not sufficient for the clinical response to pembrolizumab. Further investigation is required to determine whether it is a more effective biomarker than PD-L1 expression.
A recent study combined both TMB and T cell-inflamed GEPs to identify patients with different responses to pembrolizumab in 22 tumor types. TMB and T cell-inflamed GEPs were both predictive of clinical response: patients with high levels of TMB or T cell-inflamed GEPs showed greater response rates, whereas patients with low levels of TMB or T cell-inflamed GEPs had lower response rates. Importantly, TMB and T cell-inflamed GEPs led to poor correlation with predictions, as patients with high levels of both TMB and T cell-inflamed GEPs had the greatest response rates, whereas patients with low levels of both biomarkers had the lowest rates. Although combining biomarkers of both TMB and T cell-inflamed GEPs or PD-L1 expression may yield greater predictive values across many tumor types, the cutoff values of TMB and T cell-inflamed GEPs remain challenging. As different tumors have different levels of TMB and T cell-inflamed GEPs, tumor-specific cutoff values may be more appropriate for the prediction of response.
PD-L1 expression is the only validated predictive biomarker of pembrolizumab in NSCLC, and whether TMB or T cell-inflamed GEPs or TMB in combination with PD-L1 expression or TMB joint with T cell-inflamed GEPs may be better biomarkers need further investigation.
| > Conclusions and Future Directions|| |
In conclusion, pembrolizumab has been shown to have an important role in the treatment of advanced NSCLC without targetable mutations. For first-line treatment, pembrolizumab is recommended either as monotherapy in patients with PD-L1 expression of no <50% or in combination with standard chemotherapy regardless of PD-L1 expression. For subsequent treatment, pembrolizumab monotherapy is recommended in patients with PD-L1 expression no <1%. PD-L1 expression is the only validated biomarker to predict the benefits of pembrolizumab. However, integrating biomarkers indicative of both tumor immunogenicity and immunosuppressive TME, such as PD-L1 with TMB, may yield better predictive value and should be investigated further.
Since the rationale of pembrolizumab is to reactivate the presumably suppressed immune system to kill tumor cells, its role in NSCLC should not be confined to advanced or metastatic disease. For patients with Stage III NSCLC who have not progressed after definitive concurrent chemoradiation, pembrolizumab deserves further investigation as consolidation therapy. For patients with Stage I–III NSCLC who are candidates for radical surgery, the role of pembrolizumab as neoadjuvant or adjuvant therapy should also be explored. Moreover, pembrolizumab in combination with radiotherapy such as stereotactic body radiotherapy for early-stage NSCLC, given the synergistic effects of immune therapy and radiotherapy, has attracted much attention and awaits further investigation.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]