Programmed Cell Death Ligand 1 Immunohistochemistry: A Concordance Study Between Surgical Specimen,Biopsy, and Tissue Microarray

BackgroundThe immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) expression in tumor tissue of non–small-cell lung cancer patients has now been integrated in the diagnostic workup. Analysis is commonly done on small tissue biopsy samples representing a minimal fraction of the whole tumor. The aim of the study was to evaluate the correlation of PD-L1 expression on biopsy specimens with corresponding resection specimens.Materials and MethodsIn total, 58 consecutive cases with preoperative biopsy and resected tumor specimens were selected. From each resection specimen 2 tumor cores were compiled into a tissue microarray (TMA). Immunohistochemical staining with the antibody SP263 was performed on biopsy specimens, resection specimens (whole sections), as well as on the TMA.ResultsThe proportion of PD–L1-positive stainings were comparable between the resection specimens (48% and 19%), the biopsies (43% and 17%), and the TMAs (47% and 14%), using cutoffs of 1% and 50%, respectively (P > .39 all comparisons). When the resection specimens were considered as reference, PD-L1 status differed in 16%/5% for biopsies and in 9%/9% for TMAs (1%/50% cutoff). The sensitivity of the biopsy analysis was 79%/82% and the specificity was 90%/98% at the 1%/50% cutoff. The Cohens κ value for the agreement between biopsy and tumor. was 0.70 at the 1% cutoff and 0.83 at the 50% cutoff.ConclusionThe results indicate a moderate concordance between the analysis of biopsy and whole tumor tissue, resulting in misclassification of samples in particular when the lower 1% cutoff was used. Clinicians should be aware of this uncertainty when interpreting PD-L1 reports for treatment decisions.     

Managing cardiotoxicity associated with immune checkpoint inhibitors

Immuno-oncology is a fast evolving field of cancer therapy and immune checkpoint inhibitors (ICIs) are clearly a breakthrough in this field. Cardiotoxicity with conventional anti-cancer therapies has been well studied in the past and clear guidelines for management of these side effects are available in the literature. However, cardiotoxicity with novel agents such as ICIs has been fairly under-reported and/or underestimated and we are yet to formulate clear guidelines for management of these rare side effects. In the last few years, there has been an overall increase in the number of cases of cardiotoxicity related to ICIs. In this literature review, we describe the mechanism of action of the most widely used ICIs and their related cardiotoxicities. The increase in number of case reports about the potential of cardiotoxicities with these novel agents clearly indicates the need for a new insight into the field of cardio-immuno-oncology.     

Association Between Early Immune-related Adverse Events and Clinical Outcomes in Patients With Non–Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

IntroductionPrevious studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non–small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes.Patients and MethodsWe prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS).ResultsIn the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts.ConclusionOur results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.     

Programmed Death 1 and Programmed Death Ligand 1 Inhibitors in Advanced and Recurrent Urothelial Carcinoma: Meta-analysis of Single-Agent Studies

We performed a systematic review and meta-analysis on the response rates of patients with treatment-refractory urothelial carcinoma treated with programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors. We reviewed the literature for prospective studies evaluating PD-1/PD-L1 inhibitors in refractory urothelial carcinoma patients, which formed the basis for US Food and Drug Administration approval of 5 different antagonistic antibodies targeting PD-1 or PD-L1 (atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab). We considered studies examining PD-1/PD-L1–treated patients, which we identified using the following key terms in the Pubmed, Scopus, Web of Science, ClinicalTrial.gov, and Cochrane Library databases. Eligible studies had ≥ 20 patients each and reported response rates, duration of response, and overall survival (OS). We performed fixed and random-effects meta-analyses to model the point estimates for objective response rate and complete response. The median progression-free survival (PFS) and OS for studies reporting these statistics were evaluated. We found 10 eligible studies that met our inclusion criteria, providing extractable numerators and denominators for response rates, PFS, and OS for 1934 patients with metastatic urothelial carcinoma. The objective response rate was 18% (95% confidence interval, 15-22) for second-line or later therapies. The random-effects estimate for complete response was 4% (95% confidence interval, 3-5), including all disease locations and all PD-1 and PD-L1 inhibitors. Median OS and PFS were < 13 months and 3 months, respectively, across all studies, irrespective of PD-L1 expression. We found that the estimated response rates of agents included in this meta-analysis seem to be more favorable than other salvage therapies.     

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

IntroductionNivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort.MethodsPatients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review.ResultsOverall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively.ConclusionsWhereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy.     

Central diabetes insipidus related to anti-programmed cell-death 1 protein active immunotherapy

Cancer immunotherapy is a breakthrough strategy entwined with toxicity. Immune-related hypophysitis is conventionally considered distinctive of cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. Immune-related central diabetes insipidus (CDI) is exceptional. CDI rarely manifests as hypernatremia, which is almost always euvolemic. We report a 71-years-old male patient with advanced lung cancer who experienced severe chronic hypernatremia presented as alterations in mental status five months after initiation of treatment with the anti-PD-1 checkpoint inhibitor nivolumab. Combination of persistent hypernatremia, polyuria, high plasma osmolality and hyposthenuria raised suspicion of diabetes insipidus, prompting measurement of serum concentration of arginine vasopressin (AVP). The inappropriately undetectable serum levels of AVP confirmed central diabetes insipidus (CDI). Nivolumab-related hypophysitis was recognized as possible cause of CDI. Further hormonal assessment excluded any endocrinopathy indicating disorder of posterior pituitary. Pituitary MRI was normal with persistence of hyperintensity of posterior pituitary on T1-weighted images (bright spot). The patient was scheduled to receive 1-deamino-8-D-arginine vasopressin (DDAVP), but he died suddenly due to cardiac arrest before initiation of treatment. Our report describes the first case of nivolumab related CDI, building on existing literature through: (I) underscoring hypovolemic hypernatremia as CDI manifestation; (ii) bringing into spotlight the rare anti-PD-1 treatment related hypophysitis; (iii) enriching the limited evidence on immune-related CDI. Increased awareness of nivolumab related CDI will enable prompt recognition and therapeutic intervention.