Risk Factors for Immune Checkpoint Inhibitor Immunotherapy Toxicity Among Older Adults with Cancer.

OBJECTIVES: Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults. MATERIALS AND METHODS: This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians. For patients aged ≥70 years, frequency, type, and grade of irAEs and their association with baseline patient demographics, comorbidities, mobility, and functional status were characterized using bivariate analysis. Based on those results, multivariable logistic regressions were constructed to model the association between these characteristics with any grade and grade 3 or higher irAEs. RESULTS: Data were analyzed for 238 patients aged ≥70 years who received IO for mostly (≥90%) advanced cancer between 2011 and 2018. Thirty-nine percent of older adults experienced an irAE and 13% experienced one that was grade 3 or higher. In the multivariable analysis, depression was associated with an increased incidence of any grade irAE, while decreased life-space mobility was associated with an increased incidence of grade ≥3 irAEs. CONCLUSION: Most characteristics of special interest among older adults, include fall risk, weight loss, cognitive limitations, and hearing loss, were not associated with irAEs in our study. However, decreased life-space mobility and depression are potential risk factors for IO toxicity among older adults with advanced cancer. Interventions designed to evaluate and mitigate modifiable risk factors for treatment-related toxicity are needed, and the results of this study may be useful for guiding those efforts.

Association of Allostatic Load With Overall Mortality Among Patients With Metastatic Non-Small Cell Lung Cancer.

Importance: Adverse social determinants of health (SDHs) (eg, poverty) are associated with poor oncologic outcomes among patients with lung cancer. However, no studies have evaluated biological correlates of adverse SDHs, operationalized as allostatic load (AL), with mortality due to lung cancer. Objective: To examine the association among AL, SDHs, and mortality among patients with metastatic non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This cross-sectional study of an observational cohort was performed at a National Cancer Institute-designated comprehensive cancer center with data accrued from June 1, 2017, to August 31, 2019. Patients with metastatic (stage IV) NSCLC enrolled at diagnosis into a prospective observational cohort study were included in the present analysis if they had all the biomarkers to calculate an AL score (N = 143). Follow-up was completed on August 31, 2021, and data were analyzed from July 1 to September 30, 2021. Exposures: Social determinants of health. Main Outcomes and Measures: Overall mortality and AL. Results: A total of 143 patients met the study criteria with a median age of 63 (IQR, 55-71) years (89 men [62.2%] and 54 women [37.8%]). In terms of race and ethnicity, 1 patient (0.7%) was Asian, 7 (4.9%) were Black, 117 (81.8%) were White, 17 (11.9%) were of multiple races, and 1 (0.7%) was of other race or ethnicity. The mean (SD) AL was 2.90 (1.37). Elevated AL covaried with lower educational level (r = -0.26; P = .002), male sex (r = 0.19; P = .02), limited mobility (r = 0.19; P = .04), worsening self-care (r = 0.30; P < .001), problems engaging in usual activities (r = 0.21; P = .01), depressive symptoms (r = 0.23; P = .005), and a high number of stressful life events (r = 0.30; P < .001). Multivariable analysis found only increasing difficulty with mobility (r = 0.37 [95% CI, 0.13-0.60]; P = .002) and male sex (r = 0.63 [95% CI, 0.19-1.08]; P = .005) associated with higher AL. On adjusted analysis, elevated AL (hazard ratio, 1.43 [95% CI, 1.16-1.79]; P = .001) and low educational level (hazard ratio, 2.11 [95% CI, 1.03-4.34]; P = .04) were associated with worse overall mortality. Conclusions and Relevance: The findings of this cross-sectional study suggest that higher AL was associated with adverse SDHs and worse overall mortality among patients with advanced NSCLC. These results provide a framework for replication and further studies of AL as a biological correlate for SDH and future prognostic marker.

Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma.

Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

A double-blind randomized discontinuation phase-II study of sorafenib (BAY 43-9006) in previously treated non-small-cell lung cancer patients: eastern cooperative oncology group study E2501.

INTRODUCTION: Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase-II study in heavily pretreated non-small-cell lung cancer (NSCLC) patients (≥ 2 prior therapies) used a randomized discontinuation design. METHODS: Patients received 400 mg of sorafenib orally twice daily for two cycles (2 months) (step 1). Responding patients on step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease 2 months after randomization. RESULTS: There were 299 patients evaluated for step 1; of these, 81 eligible patients were randomized on step 2 and received sorafenib (n = 50) or placebo (n = 31). The 2-month disease control rates after randomization were 54% and 23% for patients initially receiving sorafenib and placebo, respectively, p = 0.005. The hazard ratio for progression on step 2 was 0.51 (95% [confidence interval] CI 0.30, 0.87, p = 0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), hazard ratio 0.67 (95% CI 0.40-1.11), p = 0.117. A dispensing error occurred, which resulted in the unblinding of some patients, but not before completion of the 8-week initial step 2 therapy. Toxicities were manageable and as expected. CONCLUSIONS: The results of this randomized discontinuation trial suggest that sorafenib has single-agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC.

Delivering affordable cancer care in high-income countries.

The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.

Genetic blockade of the insulin-like growth factor-I receptor: a promising strategy for human pancreatic cancer.

Pancreatic cancer is one of the most lethal malignant tumors. Insulin-like growth factor (IGF)-I receptor (IGF-Ir) signaling is required for maintenance of growth and tumorigenicity of many tumors, but this pathway has not been well studied in pancreatic cancer. We have shown previously successful therapy in colorectal and lung cancer xenograft models using recombinant adenoviruses expressing dominant negative IGF-I receptors. In this study, we sought to better dissect the mechanism of action of this virus and determine whether IGF-Ir targeted adenoviruses represent potentially effective therapeutics for human pancreatic cancer cells. Truncated IGF-I receptors (IGF-Ir/dn; 482 and 950 amino acids long, respectively, IGF-Ir/482st and IGF-Ir/950st) that function as dominant negative inhibitor were cloned into recombinant adenoviruses and used to treat human pancreatic cancer cells. We assessed the effect of IGF-Ir/dn on signaling blockade, growth, stress response, chemotherapy, radiation-induced apoptosis, and in vivo therapeutic efficacy in xenografts. IGF-Ir/dn expression suppressed tumorigenicity both in vitro and in vivo and up-regulated stressor-induced apoptosis. It effectively blocked both IGF-I and IGF-II-induced activation of Akt-1. IGF-Ir/dn expression increased radiation and chemotherapy-induced apoptosis, and the combination therapy of IGF-Ir/dn with chemotherapy was very effective against tumors in mice. In an i.p. model, IGF-Ir/dn therapy reduced dissemination and prolonged survival times. Moreover, IGF-Ir/482st was more effective than IGF-Ir/950st because of its bystander effect. The antitumor activity of IGF-Ir/dn is mediated through inhibition of Akt-1 and enhances the efficacy of chemotherapy. Adenovirus-IGF-Ir/482st may be a useful anticancer therapeutic for pancreatic cancer.

Improving the evaluation of new cancer treatments: challenges and opportunities.

There are, at present, ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. Many of the new classes of agents, however, are predicted to work in only small subpopulations of patients, target unconventional aspects of tumour development and interact with other agents in an unpredictable manner. How can clinical trials be re-designed to accommodate the new features of targeted anticancer drugs?