A Phase II Study of Nivolumab in Patients With Advanced Non–small-cell Lung Cancer who Responded to Prior PD-1/L1 Inhibitors: West Japan Oncology Group 9616L (WJOG9616L)

Immune-checkpoint inhibitors (ICIs) play an important role in treatment for advanced non–small-cell lung cancer. Over one-half of patients, however, have relapse. Although rechallenge treatment of anti-cancer drugs that showed efficacy in prior lines of therapy has been broadly accepted in lung cancer, evidence of efficacy of rechallenge of ICIs has been limited to anecdotal case series. We therefore plan a phase II study. The primary endpoint is to assess the overall response rate of nivolumab in patients with advanced non–small-cell lung cancer who responded to prior ICIs. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Sixty patients will be enrolled in this trial. Programmed death-ligand 1 expression level in circulating tumor cells will be evaluated as a surrogate biomarker for the prediction of the efficacy.     

Relationship Between Prior Radiotherapy and Checkpoint-Inhibitor Pneumonitis in Patients With Advanced Non–Small-Cell Lung Cancer

PurposeTo investigate the relationship between radiotherapy (RT), in particular chest RT, and development of immune-related (IR) pneumonitis in non–small-cell lung cancer (NSCLC) patients treated with anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1).Patients and MethodsBetween June 2011 and July 2017, NSCLC patients treated with anti–PD-1/PD-L1 at a tertiary-care academic cancer center were identified. Patient, treatment, prior RT (intent, technique, timing, courses), and IR pneumonitis details were collected. Treating investigators diagnosed IR pneumonitis clinically. Diagnostic IR pneumonitis scans were overlaid with available chest RT plans to describe IR pneumonitis in relation to prior chest RT. We evaluated associations between patient, treatment, RT details, and development of IR pneumonitis by Fisher exact and Wilcoxon rank-sum tests.ResultsOf the 188 NSCLC patients we identified, median follow-up was 6.78 (range, 0.30-79.3) months and median age 66 (range, 39-91) years; 54% (n = 102) were male; and 42% (n = 79) had stage I-III NSCLC at initial diagnosis. Patients received anti–PD-1/PD-L1 monotherapy (n = 127, 68%) or PD-1/PD-L1-based combinations (n = 61, 32%). In the entire cohort, 70% (132/188) received any RT, 53% (100/188) chest RT, and 37% (70/188) curative-intent chest RT. Any grade IR pneumonitis occurred in 19% (36/188; 95% confidence interval, 13.8-25.6). Of those who developed IR pneumonitis and received chest RT (n = 19), patients were more likely to have received curative-intent versus palliative-intent chest RT (17/19, 89%, vs. 2/19, 11%; P = .051). Predominant IR pneumonitis appearances were ground-glass opacities outside high-dose chest RT regions.ConclusionNo RT parameter was significantly associated with IR pneumonitis. On subset analysis of patients who developed IR pneumonitis and who had received prior chest RT, IR pneumonitis was more common in patients who received curative-intent chest RT. Attention should be paid to NSCLC patients receiving curative-intent RT followed by anti–PD-1/PD-L1 agents.     

Health-related quality of life in cancer patients treated with PD-(L)1 inhibitors: a systematic review

Introduction: A systematic review was performed to explore the health-related quality of life (HRQoL) outcomes among cancer patients receiving PD-(L)1 inhibitors compared to those receiving traditional cytotoxic therapy.

Areas covered: Citations from PubMed and the American Society of Clinical Oncology meeting library were examined. Cross-references from original studies and review articles were also reviewed. Eligible trials included randomized controlled trials of cancer patients treated with one of the PD-(L)1 inhibitors and reporting HRQoL outcomes. A total of 11 studies were included in the current review. PD-(L)1 inhibitors were associated with a consistent prolongation of the time to symptomatic deterioration. This was shown with the three agents (nivolumab, pembrolizumab, and atezolizumab) as well as across a variety of solid tumors (lung cancer, melanoma, head and neck cancer and urothelial cancer). Moreover, PD-(L)1 inhibitor therapy was associated with better symptomatic control at different follow-up points. This was observed regardless of the agent used of the solid tumor treated.

Expert commentary: Across a variety of solid tumor indications as well as a variety of PD-(L)1 inhibitors, the use of PD-(L)1 inhibitors is associated with an improvement in the quality of life. The utility of patient-reported outcomes in predicting clinical benefit from these agents needs to be explored further.     

PD-1 checkpoint inhibition: Toxicities and management

Purpose

With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others.

肝癌肝移植术后复发转移的免疫治疗

原发性肝癌（肝癌）是我国肝移植的主要适应证之一,但肝癌肝移植受者术后5年生存率不足50%,术后复发转移是影响受者长期生存的主要原因。目前,以程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡蛋白配体1（PD-L1）免疫检查点抑制剂为代表的免疫治疗在中晚期肝癌治疗中取得显著疗效,但其在肝癌肝移植术后肿瘤复发转移受者中能否应用尚有较多争议,主要原因在于其在发挥作用的同时可能会引起急性排斥反应。本文总结了免疫治疗在肝癌肝移植术后复发转移受者中的应用进展,以期通过免疫治疗改善肝癌肝移植受者的生存率。     

Comparative Efficacy of Second- and Subsequent-line Treatments for Metastatic NSCLC: A Fractional Polynomials Network Meta-analysis of Cancer Immunotherapies

BackgroundExtended onset of treatment effect and longer-term survival with anti–programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immunotherapies, atezolizumab, nivolumab, and pembrolizumab, have changed the landscape of second- or subsequent-line (2L+) treatments for adults with non–small-cell lung cancer (NSCLC). This systematic literature review included phase I to IV randomized, controlled trials of 2L+ NSCLC therapies from MEDLINE, Embase, and secondary sources.Materials and MethodsStudies of treatments approved in the European Union or United States had to be in English with ≥ 10 patients per arm. A fractional polynomials network meta-analysis (NMA) was conducted because traditional NMA of hazard ratios does not account for delayed onset of clinical effect or long-term survival observed in PD-L1/PD-1 inhibitor trials. Adjusted analyses accounted for treatment switching in the atezolizumab OAK trial. Expected survival time reflected area under the curve over the time horizon. Expected overall survival (OS) was ranked by median ranking with 95% credible intervals and by surface under the cumulative ranking curve. Of 25,115 screened records, 28 studies were included in the quantitative analyses of OS and progression-free survival.ResultsPD-L1/PD-1 inhibitors had comparable expected 5-year OS; all performed better than other treatment options. In unadjusted analyses, surface under the cumulative ranking curve ranked nivolumab first (87.9%), followed by atezolizumab (85.8%) and pembrolizumab (82.8%). Analyses adjusted for patients switching from docetaxel to immunotherapy ranked atezolizumab first (89.6%), followed by nivolumab (86.5%) and pembrolizumab (81.9%).ConclusionThis NMA applied an appropriate approach for indirect comparisons, including cancer immunotherapies, and supported robustness of PD-L1/PD-1 immunotherapies for 2L+ treatment of NSCLC.     

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with recurrent oral squamous cell carcinoma treated with nivolumab

The immune checkpoint inhibitor (ICI), nivolumab, has revolutionised the treatment of recurrent and metastatic oral cancer. However, the response rate to ICIs remains low, and identifying predictors of nivolumab response is critical. Although the neutrophil-to-lymphocyte ratio (NLR) has been suggested as a predictive marker of nivolumab response in patients with various types of cancer, its utility in oral squamous cell carcinoma (OSCC) has not been elucidated. In this retrospective multicentre cohort study, we evaluated the association between NLR and outcome of nivolumab treatment in 64 patients with OSCC treated between 2017 and 2020. The objective response and disease control rates were 25.1% and 32.9%, respectively. The rates for complete and partial responses were 15.7% (10/64) and 9.4% (6/64), respectively; stable and progressive disease rates were 7.8% (5/64) and 67.1% (43/64), respectively. Complete and partial responses were classified as responders, and stable and progressive diseases were classified as non-responders. The median (range) pre-treatment NLR among responders was 4.3 (2.8–8.0), which decreased to 4.0 (2.6–6.3) after nivolumab treatment, and the median (range) pre-treatment NLR among non-responders was 5.1 (2.7–7.9), which increased to 6.4 (4.0–14.0) with tumour growth. Moreover, overall survival was significantly worse in the group with a higher post-treatment NLR (≥5) than in the group with a lower NLR (<5). Patients with a post-treatment NLR of ≥6 had worse outcomes for salvage chemotherapy following nivolumab treatment. Thus, post-treatment NLR could be a useful marker for predicting the response to nivolumab treatment or salvage chemotherapy in patients with OSCC.     

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

IntroductionIn CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years’ minimum follow-up.MethodsTreatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only).ResultsOverall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months’ minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43–0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66–0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed.ConclusionsWith all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.