Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?

The development of immune checkpoint inhibitors (ICI) represents a major milestone in immune-oncology. Over the years these agents have demonstrated efficacy in an increasing array of malignancies. Despite this success however, significant challenges remain. Novel approaches to both drug development and trial design are required to incorporate the unique pharmacokinetic and pharmacodynamic properties of ICIs. Further, it has also been established that the benefit of ICIs is limited to only a subset of patients. The molecular interactions between native immune cells and tumorigenesis and progression represent an active area of biomarker research, and elucidating the mechanisms of response and resistance is crucial to develop rational trial designs for the next wave of immune-oncology (IO) clinical trials, particularly in patients with primary and/or acquired resistance. Efforts are now being made to integrate both biological and clinical information using novel multi-omic approaches which are now being developed to further elucidate the molecular signatures associated with IO treatment response and resistance and enable rational drug development and trial design processes. As such, precision IO and the ability to deliver patient-specific choices for ICI monotherapies or combination therapies has become an increasingly tangible goal. We herein describe the current landscape in ICI drug development and discuss the challenges and future directions in this exciting and evolving era in immune-oncology.

Mitosis trumps T stage and proposed international association for the study of lung cancer/american thoracic society/european respiratory society classification for prognostic value in resected stage 1 lung adenocarcinoma.

INTRODUCTION: We investigated whether a group of pathologists could reproducibly apply the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification for lung adenocarcinoma to a cohort of stage 1 tumors and whether this architectural classification and/or other parameters could demonstrate survival advantage. METHODS: A total of 145 cases of 7 edition of tumor, node, metastasis stage 1 adenocarcinoma were retrospectively reviewed for predominant architectural pattern, including cribriform pattern, nuclear grade, mitotic index, and necrosis. The parameters were assessed for reproducibility and survival and using multivariate analysis, compared with stage, age, and sex. RESULTS: The majority of tumors had a mixed architecture with the acinar pattern being the most common predominant architecture. Micropapillary and cribriform architecture were the least frequent patterns. This study demonstrated that a group of five pathologists could reproducibly apply the IASLC/ATS/ERS classification. Although there were insufficient cribriform-predominant adenocarcinomas for assessment, when the percentage of all cribriform was combined with other architectures, it was associated with a worse prognosis. The majority of the parameters assessed demonstrated significance with univariate analysis but only mitotic index, as assessed by the highest count/10 high-power fields remained significant with multivariate analysis. CONCLUSION: In this study of resected stage 1 primary lung adenocarcinoma, we found mitotic index to be the only independent prognostic marker. It was more closely associated with outcome than either pathologic T stage or IASLC/ATS/ERS architecture-based classification. Further validation of concordance and reproducibility in reporting mitotic index, as well as validation of prognostic significance, needs to be undertaken in independent data sets.