The role of checkpoint inhibitors immunotherapy in advanced non-small cell lung cancer in the elderly

Introduction: Immune checkpoint inhibition is a novel treatment modality that has brought a new hope to patients with advanced NSCLC. Several molecules targeting cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 receptor/programmed death ligand-1 (PD1/PD-L1) pathways are under evaluation in NSCLC and three of them are currently approved: nivolumab and atezolizumab for advanced NSCLC after prior chemotherapy and pembrolizumab for advanced NSCLC expressing PD-L1 ≥ 1% after at least one prior chemotherapy regimen and > 50% as a first-line response.

Areas covered: To date, the efficacy and toxicity of immune checkpoint inhibitors in the elderly is unclear because available studies involved mainly a low number of elderly patients. In this paper, the authors discuss the frailty of the elderly patient and the challenges of choosing the best therapeutic strategy, focusing on the role of immune checkpoint inhibitors.

Expert opinion: There are several outstanding goals that need to be met for the proper and safe use of immunotherapeutic drugs. In terms of the elderly, it is true that age-tailored clinical trials are needed to confirm the real impact of immunotherapy and harmonize the standard of care in this specific demographic.     

Early Reassessment of Total Metabolic Tumor Volume on FDG-PET/CT in Advanced Melanoma Patients Treated with Pembrolizumab Predicts Long-Term Outcome

PD-1 Immune checkpoint inhibitors, such as Pembrolizumab, can have a durable beneficial therapeutic effect in patients with advanced melanoma. However, not all patients will benefit equally from these therapies, and (potentially life-threatening) immune-related adverse events may occur. In this study, we investigate the value of early response assessment by FDG-PET/CT as a biomarker for predicting survival. We identified all patients with advanced melanoma who were treated with Pembrolizumab in our medical center and underwent a baseline and at least one follow-up FDG-PET/CT. The total metabolic tumor volume (TMTV) was calculated, and the evolution was compared to survival parameters. A total of 77 patients underwent a baseline and at least one follow-up FDG-PET/CT, 36 patients had follow-up imaging within 2–4 months, and 21 patients an FDG-PET/CT 5–6 months after baseline. When the TMTV evolution was categorized into two subgroups (stable/decrease versus increase), an association was found between stability or decrease in TMTV and better PFS and OS. A similar trend, however non-significant, was observed at 5–6 months. The evolution in TMTV as assessed by FDG-PET/CT 2–4 months after treatment initiation is associated with long-term outcomes in patients with advanced melanoma treated with Pembrolizumab.     

Steroid Use Independently Predicts for Poor Outcomes in Patients With Advanced NSCLC and High PD-L1 Expression Receiving First-Line Pembrolizumab Monotherapy

BackgroundReal-world data have suggested a detrimental effect of steroid use in patients with advanced non–small-cell lung cancer (NSCLC) receiving immunotherapy. However, previous studies included heterogeneous cohorts of patients receiving different lines of treatment with several immuno-oncology agents and various combinations of chemotherapy and immuno-oncology agents.Patients and MethodsA comprehensive clinicopathologic database of patients with NSCLC and programmed cell death ligand 1 >50% treated with frontline pembrolizumab monotherapy was constructed in 14 centers in Italy, Spain, Greece, and Switzerland. A multivariate analysis adjusting for the established prognostic factors was performed using a Cox regression model.ResultsFor the 265 eligible patients, the median age at diagnosis was 67 years, 66% were male, 90% were current or former smokers, 18% had had an Eastern Cooperative Oncology Group performance status of 2 or 3. Of the NSCLC subtypes, 64% were adenocarcinoma and 25% were squamous cell. Of the patients, 18% had had brain metastases at diagnosis and 24% had received steroids before or during pembrolizumab treatment. The median time to progression was 4.4 months with and 13.7 months without steroid use (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.69-3.85; log-rank P < .001). The median survival was 22.5 months for the whole cohort, 7.7 months for the steroid group, and not reached for the non-steroid group (HR, 3.64; 95% CI, 2.34-5.68; log-rank P < .001). On multivariate analysis accounting for all established prognostic variables, steroid use was still independently associated with a high risk of progression (HR, 1.864; 95% CI, 1.179-2.949; P = .008) and death (HR, 2.292; 95% CI, 1.441-3.644; P < .001)ConclusionsIn patients with advanced NSCLC and programmed cell death ligand 1 expression > 50% receiving frontline pembrolizumab monotherapy, any use of steroids before or during treatment was associated with an 86% increase in the risk of progression and a 2.3-fold increase in the risk of death, even accounting for palliative indication-related bias, including the presence of central nervous system metastasis. The use of steroids for palliative indications should be restricted to absolutely necessary for patients receiving immuno-oncology monotherapy.     

Differential Efficacy of Pembrolizumab According to Metastatic Sites in Patients With PD-L1 Strongly Positive (TPS ≥ 50%) NSCLC

BackgroundPembrolizumab has shown significantly better efficacy than platinum doublet chemotherapy in patients with programmed cell death ligand 1 (PD-L1) strongly positive (tumor proportion score ≥ 50%) non–small-cell lung cancer (NSCLC). However, the predictors of response to pembrolizumab have not yet been fully elucidated for patients with PD-L1 strongly positive NSCLC.Patients and MethodsWe retrospectively analyzed 145 patients who had been treated with pembrolizumab for PD-L1 strongly positive (TPS ≥ 50%) NSCLC without an EGFR (epidermal growth factor receptor) mutation or ALK rearrangement from February 2017 to March 2020. Various clinical characteristics, including Eastern Cooperative Oncology Group performance status, treatment line, PD-L1 expression, C-reactive protein level, neutrophil/lymphocyte ratio, and metastatic sites, and the clinical outcome of pembrolizumab treatment were examined.ResultsPatients with higher PD-L1 expression (≥ 75%; n = 90) had a higher objective response rate (ORR) and longer progression-free survival (PFS) compared with those with lower expression (50%-74%; n = 55; ORR, 51% vs. 33%; P = .0305; median PFS, 13.9 months vs. 5.2 months; P = .0111). In addition, 15 patients with liver metastasis (LM) had a significantly lower ORR and shorter PFS than the 130 patients without LM (ORR, 20% vs. 47%; P = .0468; median PFS, 3.4 months vs. 9.4 months; P = .0018). A multivariate analysis indicated that PD-L1 expression and LM were significant predictors of PFS after pembrolizumab treatment (higher PD-L1 expression: hazard ratio, 0.58; 95% confidence interval, 0.38-0.91; P = .0183; presence of LM: hazard ratio, 2.05; 95% confidence interval, 1.03-3.82; P = .0420).ConclusionPD-L1 expression and LM status were predictors of the efficacy of pembrolizumab in patients with PD-L1 strongly positive NSCLC.     

Development of destructive thyroiditis and diabetes mellitus after three injections of pembrolizumab for skin melanoma

The exponential rise in the use of immune checkpoint inhibitors (Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, and Avelumab) as the new standard for cancer treatment increase the incidence the immune-related adverse events due to immune activation. Endocrine immune-related adverse events are the third most commonly reported. Thyroid gland is most susceptible to autoimmune dysfunctions from immune checkpoint inhibitors and associated with the use of anti-PD-1 monoclonal antibodies. Hypophysitis develops more often during therapy with anti-CTLA-4 monoclonal antibodies. But such immune-related adverse events as diabetes mellitus, hypoparathyroidism are rare (about 1% of cases).We present a clinical case of the patient with skin melanoma who was prescribed therapy with immune checkpoints inhibitors (Pembrolizumab). Immune-related adverse events developed with damage to the endocrine organs after 3 Pembrolizumab injections. Of greatest interest is the development of two endocrine immune-related adverse events at once: destructive thyroiditis (with a short phase of thyrotoxicosis and subsequent persistent hypothyroidism) and diabetes mellitus. We tried to reflect the chronology of diseases and their features as fully as possible for endocrinologists, oncologists, therapists, family doctors and other medical doctors of related specialties.     

免疫检测点抑制剂治疗后"超进展"的晚期肺腺癌患者2例及文献复习

目的:免疫检测点抑制剂治疗在多种肿瘤中都表现出了很好的疗效。然而,约10%的患者在治疗中出现肿瘤加速生长的情况,临床上将其称为超进展。对于在接受免疫检测点抑制剂治疗中发生“超进展”的非小细胞肺癌患者来说,仍然需要对其临床病理特征进行更多的研究。方法:我们报导2例分别使用帕博利珠单抗和阿特珠单抗二线治疗的晚期肺腺癌患者。这两例患者均在治疗后出现肿瘤快速进展,根据目前的诊断标准评价为“超进展”。另外,我们通过复习相关文献,探讨“超进展”的定义、风险因素及患者预后。结果:本文中报导的2例“超进展”的患者具有相应的临床特点,但与既往研究中所报导的不完全一致。结论:在接受免疫检测点抑制剂治疗后发生的“超进展”现象具有复杂性,研究“超进展”相关的临床病理特征很有必要。     

Toxicity management with combination chemotherapy and programmed death 1/programmed death ligand 1 inhibitor therapy in advanced lung cancer

PurposeThe combination of an anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibody with platinum-based chemotherapy can improve outcomes for patients with advanced non-small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC) compared with chemotherapy alone. For patients receiving these new treatment regimens, it is important that toxicities be managed effectively. A particular challenge can be determining the etiology of an event, especially when there are overlapping symptoms that can be attributed to either immunotherapy or to platinum-based chemotherapy. Here, we evaluate adverse events (AEs) reported in clinical trials of combination therapy with an anti-PD-1 or anti-PD-L1 (anti-PD-[L]1) immunotherapy and chemotherapy to provide information on toxicity management.MethodsWe performed a systematic review of the literature focused on randomized controlled trials of anti-PD-(L)1 therapy combined with platinum-based chemotherapy for advanced/metastatic NSCLC and SCLC.ResultsEleven reports from 9 randomized studies evaluating pembrolizumab, nivolumab, and atezolizumab combined with platinum-based chemotherapy in patients with advanced lung cancer were identified. Immune-mediated AEs and infusion reactions occurred more commonly in patients who received anti-PD-(L)1 immunotherapy with platinum-based chemotherapy compared with chemotherapy alone; however, there was no evidence of unexpected or unanticipated toxicity with these combinations.ConclusionCombinations of anti-PD-(L)1 immunotherapy with platinum-based chemotherapy regimens improve outcomes for patients with NSCLC and SCLC, and toxicity is generally manageable. Strategies for appropriate workup of AEs to allow clinicians to make informed decisions regarding causality and treatment modifications when appropriate are an important element of management of patients receiving an anti-PD-(L)1 agent combined with platinum-based chemotherapy.     

Clinical Development of Immunotherapy for Deficient Mismatch Repair Colorectal Cancer

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. Despite excellent prognosis for early stage disease, 5-year survival rates in metastatic disease remain low. A small subset of CRC is defined by a deficiency in mismatch repair (dMMR) resulting in high levels of microsatellite instability and are responsive to immunotherapy. Immune checkpoint inhibitors (ICIs) targeting the programmed death 1 (PD-1)/programmed death ligand 1 axis and cytotoxic T-lymphocyte antigen 4 have been explored and show robust clinical outcomes with prolonged progression-free survivals in nonrandomized single-arm clinical trials. On the basis of these data, single-agent therapy with pembrolizumab and nivolumab and combination therapy with nivolumab/ipilimumab have been approved by the US Food and Drug Administration for metastatic CRC that has progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Ongoing clinical trials are exploring the use of these agents in earlier lines of therapy such as first-line metastatic therapy and adjuvant therapy for stage III CRC. However, resistance to ICIs does occur in a subset of patients and ongoing clinical trials are exploring novel approaches in these PD–1-refractory patients. The aim of this review is to outline the development and decision-making of ICIs in the treatment of dMMR CRC and to discuss ongoing clinical trials in this therapeutic space.