Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.

Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

Osorio JC ，Ni A ，Chaft JE ，Pollina R ，Kasler MK ，Stephens D ，Rodriguez C ，Cambridge L ，Rizvi H ，Wolchok JD ，Merghoub T ，Rudin CM ，Fish S ，Hellmann MD ... -  《-》

Thyroid function abnormality induced by PD-1 inhibitors have a positive impact on survival in patients with non-small cell lung cancer.

Thyroid function abnormality (TFA) is a common immune-related adverse event (irAEs), but the association between it and the efficacy of programmed cell death protein 1 (PD-1) inhibitor in advanced non-small cell lung cancer (NSCLC) is finitely understood. We conducted a single center, retrospective study of advanced NSCLC patients who were treated with PD-1 inhibitors between 10 October 2016 and 1 April 2020. TFA was characterized as new onset subclinical hypothyroidism, overt hypothyroidism, subclinical hyperthyroidism and overt hyperthyroidism. Frequency of development of TFA-irAEs, and its relationship with overall survival (OS) and progression free survival (PFS) were evaluated. In our study, 191 patients were treated with PD-1 inhibitors. Among them, forty patients (20.9%) developed TFA, of whom 10 (5.2%) presented with subclinical hypothyroidism, 15 (7.9%) with overt hypothyroidism, 6 (3.1%) with subclinical hyperthyroidism and 9 (4.7%) with overt hyperthyroidism. Survival analysis showed that the OS (16.8 months vs. 11.1 months, p < 0.001) and PFS (10.4 months vs. 5.5 months, p < 0.001) were significantly longer in patients with TFA-irAEs than in those without TFA-irAEs. In subgroup analysis of hypothyroidism and hyperthyroidism groups, similar trends were also obtained for both OS and PFS. After adjusting for potential confounding variables, patients with TFA-irAEs had a lower mortality risk (HR 0.334, 95%CI 0.196-0.571) than those without TFA-irAEs. TFA-irAEs is associated with enhanced PD-1 inhibitor efficacy in advanced NSCLC patients and it may be a biomarker for antitumor immune response.

Zhou Y ，Xia R ，Xiao H ，Pu D ，Long Y ，Ding Z ，Liu J ，Ma X ... -  《-》

Profiling Preexisting Antibodies in Patients Treated With Anti-PD-1 Therapy for Advanced Non-Small Cell Lung Cancer.

Toi Y ，Sugawara S ，Sugisaka J ，Ono H ，Kawashima Y ，Aiba T ，Kawana S ，Saito R ，Aso M ，Tsurumi K ，Suzuki K ，Shimizu H ，Domeki Y ，Terayama K ，Nakamura A ，Yamanda S ，Kimura Y ，Honda Y ... -  《-》

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.

In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology. Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses. No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC. NCT01295827.

Chatterjee M ，Turner DC ，Felip E ，Lena H ，Cappuzzo F ，Horn L ，Garon EB ，Hui R ，Arkenau HT ，Gubens MA ，Hellmann MD ，Dong D ，Li C ，Mayawala K ，Freshwater T ，Ahamadi M ，Stone J ，Lubiniecki GM ，Zhang J ，Im E ，De Alwis DP ，Kondic AG ，Fløtten Ø ... -  《-》

Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis.

Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy. PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single-agent U.S. Food and Drug Administration-approved PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all-grade (1-4) or high-grade (3-4) adverse events (AEs), all- or high-grade treatment-related symptoms, hematologic toxicities and immune-related AEs, treatment discontinuation due to toxicities, or treatment-related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated. A total of 3,450 patients from 7 RCTs were included in the meta-analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non-small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD-1/PD-L1 inhibitors had a significantly lower risk of all- and high-grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all-grade anorexia, nausea, and constipation, any all- and high-grade AEs, and treatment discontinuation. There was an increased risk of all-grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all- and high-grade pneumonitis with PD1/PD-L1 inhibitors. PD-1/PD-L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD-1/PD-L1 inhibitors. The Oncologist 2017;22:470-479 IMPLICATIONS FOR PRACTICE: We conducted a systematic review and meta-analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy. PD1/PD-L1 inhibitors were associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune-related adverse events (AEs). Summary toxicity endpoints favor PD1/PD-L1 inhibitors (any all- and high-grade AEs and treatment discontinuation). PD1/PD-L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well-balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer.

Nishijima TF ，Shachar SS ，Nyrop KA ，Muss HB ... -  《-》