IMpower210: A phase III study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer.

Objective: IMpower210 (NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs. docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC) in East Asian patients. Methods: Key eligibility criteria for this phase III, open-label, randomized study included age ≥18 years; histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system (7th edition); Eastern Cooperative Oncology Group performance status of 0 or 1; and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab (1,200 mg) or docetaxel (75 mg/m2). The primary study endpoint was overall survival (OS) in the intention-to-treat (ITT) population with wild-type epidermal growth factor receptor expression (ITT EGFR-WT) and in the overall ITT population. Results: Median OS in the ITT EGFR-WT population (n=467) was 12.3 [95% confidence interval (95% CI), 10.3-13.8] months in the atezolizumab arm (n=312) and 9.9 (95% CI, 7.8-13.9) months in the docetaxel arm [n=155; stratified hazard ratio (HR), 0.82; 95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5 (95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1 (95% CI, 8.4-14.2) months (n=377) with docetaxel treatment (n=188; stratified HR, 0.87; 95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm. Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade 3/4 TRAEs.

Efficiency and toxicity of nab-paclitaxel and camrelizumab in the second or above line treatment of advanced non-small cell lung cancer: a retrospective cohort study.

Background: Paclitaxel-based chemotherapy represented by nanoparticle albumin-bound paclitaxel (nab-ptx) combined with programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has become the standard model for the 1st treatment of advanced non-small cell lung cancer (NSCLC) with negative driver genes (such as EGFR, ALK, etc.), indicating that nab-ptx and PD-1/PD-L1 inhibitors are synergistic. Considering PD-1/PD-L1 inhibitors alone or chemotherapy single has limited efficiency in the 2nd line or above of NSCLC, so it is of great significance to explore the combination of PD-1/PD-L1 inhibitors and nab-ptx to further improve the therapeutic efficiency in such field. Methods: We retrospectively collected the date of these advanced NSCLC patients who accept the combination treatment of PD-1/PD-L1 inhibitor and nab-ptx in the 2nd or above line. We further analysed baseline clinical characteristics, therapeutic efficacy, treatment-related adverse events (AEs) and followed up survival. The main parameters of the study were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs. Results: A total of 53 patients were enrolled in this study. The preliminary results indicated that the ORR of the combination of camrelizumab and nab-ptx was about 36% in the 2nd or above line of NSCLC, with 19 cases of partial response (PR), 16 of stable disease (SD), and 18 cases of progressive disease (PD); the mean PFS and OS were 5 months and 10 months, respectively. Further subgroup analysis demonstrated that the expression of PD-L1 level and the decrease of regulatory T cell (Treg) correlated with the efficiency. the main adverse reactions were neuropathy, bone marrow suppression, fatigue, and hypothyroidism, most of which were mild and tolerable, indicating such regimen was higher efficiency and lower cytotoxicity for NSCLC. Conclusions: The combination of nab-ptx and camrelizumab shows promising efficiency and lower toxicities for advanced NSCLC in the 2nd or above line treatment. The mechanism of action may be related to depleting Treg ratio; such a regimen may have the potential to become an effective treatment approach for NSCLC. However, due to the limitation of sample size, the real value of this regimen needs to be further confirmed in the future.

A Prospective Trial Evaluating the Safety and Systemic Response From the Concurrent Use of Radiation Therapy with Checkpoint Inhibitor Immunotherapy in Metastatic Non-Small Cell Lung Cancer.

INTRODUCTION/BACKGROUND: This study assessed the safety and systemic (abscopal) response from the addition of local stereotactic body radiation therapy (SBRT) to checkpoint inhibitor (CPI) immunotherapy in patients with metastatic non-small cell lung cancer. PATIENTS/METHODS: Thirty-five patients with at least 2 sites of measurable disease on PET/CT received standard-of-care CPI immunotherapy alone (n = 19), or in combination with 4 cycles doublet carboplatin/pemetrexed chemotherapy (n = 16), and 3 to 5 fractions SBRT to a single extracranial target lesion between cycles 1 to 2 of the systemic therapy. Adverse events were assessed using CTCAE version 5.0. Best systemic objective response rate (ORR) was assessed using iRECIST criteria, excluding any irradiated lesion(s). Additional SBRT to a different target lesion was offered to patients who continued on immunotherapy with unconfirmed progressive disease or mixed response. RESULTS: Fifteen patients (44%) experienced 22 grade 1 to 2 toxicities potentially attributable to radiation, most commonly pneumonitis (n = 9) and fatigue (n = 6), and no grade 3 to 5 radiation-induced toxicities. Patients undergoing combined CPI-chemotherapy received a lower median biologically effective dose of SBRT than those undergoing CPI monotherapy (43.2 vs. 60Gy), but had a higher rate of radiation-induced toxicity (56% vs. 32%, P < .01). The best systemic ORR was 53%, with 20.5% stable disease and 26.5% progressive disease. Fifteen patients underwent a subsequent course of SBRT based on their response, among which 3 (20%) had progression-free intervals of 12, 16, and 10 months thereafter. CONCLUSIONS: Addition of SBRT to CPI immunotherapy (with/without chemotherapy) is safe. The favorable systemic response observed warrants further assessment with a randomized trial.

Predictive Role of Computed Tomography Texture Analysis in Patients with Metastatic Urothelial Cancer Treated with Programmed Death-1 and Programmed Death-ligand 1 Inhibitors.

BACKGROUND: Reliable biomarkers to predict the response of metastatic urothelial cancer (mUC) to programmed death-1 and programmed death-ligand 1 (PD-1/PD-L1) inhibitors are being investigated. Texture analysis represents tumor heterogeneity and may serve as a predictor of response in mUC. OBJECTIVE: To assess the predictive ability of computed tomography (CT) texture analysis for progression-free survival (PFS) in patients with mUC treated with PD-1/PD-L1 inhibitors. DESIGN, SETTING, AND PARTICIPANTS: Forty-two postplatinum patients with mUC treated with PD-1/PD-L1 inhibitors from 2013 to 2018, including those with measurable disease per RECIST 1.1 who had contrast-enhanced baseline or first follow-up CT within 3mo after starting treatment, were included. PFS was calculated based on serial follow-up CT scans. Eleven patients with follow-up of <12mo without progression were excluded. Texture features of measurable lesions on baseline and first follow-up CT were extracted using commercially available software (TexRAD; Feedback Plc, Cambridge, UK) using different spatial scaling factors (0, 2-6). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Stepwise logistic regression analysis was conducted to identify patients with PFS <12mo, and performance was assessed using receiver operator characteristic curves. RESULTS AND LIMITATIONS: Of 31 included patients, 18 had PFS <12mo. Twenty-five baseline CT and 29 first follow-up CT scans met the inclusion criteria. In patients with PFS <12mo, entropy and mean were higher on first follow-up CT (p=0.02 and p=0.005, respectively). A predictive model including mean and entropy on first follow-up CT yielded 95% sensitivity, 80% specificity, 90% positive predictive value, 89% negative predictive value, and 90% accuracy (area under the curve=0.963) to identify patients with PFS <12mo. Limitations include retrospective nature and small sample size. CONCLUSIONS: CT texture analysis can help predict early progression with high accuracy soon after starting PD-1/PD-L1 inhibitors. Studies investigating the correlation of texture analysis with survival endpoints may help validate texture analysis as a biomarker of PD-1/PD-L1 inhibitors' treatment response. PATIENT SUMMARY: Computed tomography texture analysis can help predict durability of response in patients with metastatic urothelial cancer early during treatment with programmed death-1 and programmed death-ligand 1 (PD-1/PD-L1) inhibitors.

Desensitizing Effect of Cancer Cachexia on Immune Checkpoint Inhibitors in Patients With Advanced NSCLC.

INTRODUCTION: Programmed cell death 1 (PD-1) inhibitors have become standard treatment for patients with advanced NSCLC. However, few studies have focused on the impact of cancer cachexia on the efficacy of PD-1 or programmed death-ligand 1 (PD-L1) inhibitors among patients with NSCLC. METHODS: We retrospectively reviewed medical records of patients with advanced NSCLC who received PD-1 or PD-L1 inhibitor monotherapy from May 2016 to December 2018. We defined cancer cachexia as unintentional weight loss greater than 5% over 6 months and high PD-L1 as greater than 50% expression on tumor cells. We evaluated the objective response rates (ORRs) and progression-free survival (PFS). RESULTS: Among 108 patients, 52 had cancer cachexia. Patients with cachexia had a lower ORR (15% versus 57%, p < 0.001) and shorter PFS (2.3 mo versus 12.0 mo, p < 0.001) than those without cachexia. Patients with low PD-L1 expression had a lower ORR (14% versus 53%, p < 0.001) and shorter PFS (2.8 mo versus 10.8 mo, p = 0.002) than those with high PD-L1 expression. Multivariate analysis revealed cancer cachexia and low PD-L1 expression as independent negative predictors of PFS. Among patients with cachexia, there was no significant difference in the ORR (p = 0.514) or PFS (p = 0.992) on the basis of PD-L1 expression. CONCLUSIONS: Our findings indicate that cancer cachexia might be a negative predictor of the efficacy of PD-1 or PD-L1 inhibitors and reduce the impact of PD-L1 expression on the effect of PD-1 or PD-L1 inhibitors in patients with advanced NSCLC. Further clinical and basic studies are needed.

[First-line Combination Immunotherapy in Advanced Non-small Cell Lung Cancer].

Programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor has become one of the important treatment options for patients with advanced non-small cell lung cancer (NSCLC). However, only a small subset of patients with NSCLC can currently receive single-agent PD-1 inhibitors as first-line therapy, for the limitations of population selection exclude most patients from immuno-oncology (IO) monotherapy. In order to expand the candidate population for IO first-line treatment and make more newly diagnosed patients benefit from IO treatment, a series of studies are focusing on the combination of IO and other drugs in NSCLC. We reviewed the latest clinical data of IO first-line combination therapy in recent years, suggesting that on the basis of PD-1/PD-L1 inhibitors, combined with other IO, chemotherapy, anti-angiogenic drugs, targeted therapy or radiotherapy may produce synergistic anti-tumor effects. It is expected to benefit more newly diagnosed patients.
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