Phase II study of pembrolizumab and lenvatinib in advanced well-differentiated neuroendocrine tumors.

BACKGROUND: Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fibroblast growth factor receptors and has demonstrated efficacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well-differentiated gastrointestinal (GI) and thoracic NETs. PATIENTS AND METHODS: A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment. RESULTS: Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression-free survival (PFS) was 8 months (95% confidence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or definitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment. CONCLUSIONS: The combination of pembrolizumab and lenvatinib did not show sufficient response in patients with NETs to warrant continued enrollment on trial.

A phase II study of axitinib in advanced neuroendocrine tumors.

Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29months, we observed a median PFS of 26.7months (95% CI, 11.4-35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4-45.3), and the median TTF was 9.6months (95% CI, 5.5-12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients.

A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors.

BACKGROUND: The liver is the predominant site of metastases among patients with advanced neuroendocrine tumors (NETs). Prior retrospective studies have reported high response rates in patients treated with transarterial embolization (TAE). NETs are highly vascular and are known to express vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR). We hypothesized that administration of sunitinib, a VEGFR inhibitor, following TAE would extend progression-free survival (PFS). PATIENTS AND METHODS: Patients with metastatic NETs to the liver underwent a series of selective TAEs followed by sunitinib (until disease progression or maximum of 12 months). Radiographic response (by RECIST), survival, and safety parameters were monitored. RESULTS: Thirty-nine patients were enrolled. The overall response rate was 72% [95% confidence interval (CI), 0.58-0.86]. Median PFS was 15.2 months. Rates of overall survival (OS) at 1 and 4 years were 95% (95% CI, 0.88-1.00) and 59% (95% CI, 0.38-0.80), respectively. A significant 34% rise in serum VEGF was observed following the initial TAE (P = 0.03). CONCLUSIONS: Hepatic TAE is a highly active treatment option for patients with metastatic NETs to the liver. Embolization stimulates release of VEGF into the circulation. Sunitinib, an oral VEGFR inhibitor, can be safely administered following embolization. The high rates of PFS and OS associated with this sequence of therapies are encouraging.

Reorganization of an arid ecosystem in response to recent climate change.

Natural ecosystems contain many individuals and species interacting with each other and with their abiotic environment. Such systems can be expected to exhibit complex dynamics in which small perturbations can be amplified to cause large changes. Here, we document the reorganization of an arid ecosystem that has occurred since the late 1970s. The density of woody shrubs increased 3-fold. Several previously common animal species went locally extinct, while other previously rare species increased. While these changes are symptomatic of desertification, they were not caused by livestock grazing or drought, the principal causes of historical desertification. The changes apparently were caused by a shift in regional climate: since 1977 winter precipitation throughout the region was substantially higher than average for this century. These changes illustrate the kinds of large, unexpected responses of complex natural ecosystems that can occur in response to both natural perturbations and human activities.

Effects of competition, colonization, and extinction on rodent species diversity.

Analyses of long-term experimental data from the Chihuahuan desert revealed that species diversity of other rodents was higher on plots from which kangaroo rats (Dipodomys spp.) had been removed. The difference was due to consistently higher colonization and lower extinction probabilities of small granivorous rodents in the absence of competitively dominant kangaroo rats. The results of this ecosystem experiment demonstrate the importance of both competitive exclusion and metapopulation dynamics for biological diversity in a natural community.

Carrying food items to cover for consumption: the behavior of ten bird species feeding under the risk of predation.

In earlier work (Lima et al. 1985; Lima 1985), we found that gray squirrels (Sciurus carolinensis) and black-capped chickadees (Parus atricapillus) when exploiting a patch of food in the open often carried individual food items to protective cover for consumption. Their tendency to carry (i) decreased as distance of the patch from cover increased, and (ii) increased as size of the available food items increased. A simple model indicated that this behavior was consistent with a trade-off between efficient foraging and predation risk. Maximal feeding efficiency was achieved by always eating at the patch, whereas minimal time exposure to predators was achieved by carrying all items to cover for consumption. Because predation-riskrelated trade-offs are likely to be of importance in the determination of feeding behavior, we surveyed the behavior of 10 bird species feeding under similar conditions to assess both the generality of the above results and the adequacy of some simple assumptions concerning the assessment and perception of predation risk.We observed considerable interspecific variability in behavior. Of the 10 species studied, 4 behaved in a manner similar to the squirrels and chickadees. Five other species showed an increased tendency to carry with larger items but no clear tendency to decrease carrying from longer distances. The one remaining species exhibited neither behavioral trend.The model that predicted squirrel and chickadee behavior failed to account for all observed behavior. The behavior of all species, however, was influenced by predation risk, and the discrepancy between theory and observation most likely reflects shortcomings of the model. These discrepancies indicate that other factors, in addition to exposure time, may be of significance in the perception of predation risk by several (or all) of the species studied. Of particular importance may be a distance-dependent probability of escaping attack. Other results indicate that predation risk may influence handling times via aspects of the digestive process.