Assessing Pathologic Response in Resected Lung Cancers: Current Standards, Proposal for a Novel Pathologic Response Calculator Tool, and Challenges in Practice.

The efficacy of neoadjuvant treatment for NSCLC can be pathologically assessed in resected tissue. Major pathologic response (MPR) and pathologic complete response (pCR), defined as less than or equal to 10% and 0% viable tumor cells, respectively, are increasingly being used in NSCLC clinical trials to establish them as surrogate end points for efficacy to shorten time to outcome. Nevertheless, sampling and MPR calculation methods vary between studies. The International Association for the Study of Lung Cancer recently published detailed recommendations for pathologic assessment of NSCLC after neoadjuvant treatment, with methodology being critical. To increase methodological rigor further, we developed a novel MPR calculator tool (MPRCT) for standardized, comprehensive collection of percentages of viable tumor, necrosis, and stroma in the tumor bed. In addition, tumor width and length in the tumor bed are measured and unweighted and weighted MPR averages are calculated, the latter to account for the varying proportions of tumor beds on slides. We propose sampling the entire visible tumor bed for tumors having pCR regardless of size, 100% of tumors less than or equal to 3 cm in diameter, and at least 50% of tumors more than 3 cm. We describe the uses of this tool, including potential formal analyses of MPRCT data to determine the optimum sampling strategy that balances sensitivity against excessive use of resources. Solutions to challenging scenarios in pathologic assessment are proposed. This MPRCT will facilitate standardized, systematic, comprehensive collection of pathologic response data with a standardized methodology to validate studies designed to establish MPR and pCR as surrogate end points of neoadjuvant treatment efficacy.

Important Surgical and Clinical End Points in Neoadjuvant Immunotherapy Trials in Resectable NSCLC.

Neoadjuvant immunotherapy may improve outcomes in patients with resectable NSCLC and is being evaluated in phase 2 and 3 studies. Nevertheless, preoperative treatment postpones resection; the potential for increased surgical complexity and greater intra- and postoperative morbidity and mortality is an additional consideration. In studies primarily designed to evaluate efficacy, the impact of neoadjuvant immunotherapy on surgery is based on parameters that are poorly defined and reported differently between studies. Defining and reporting common end points among trials would improve understanding and facilitate cross-comparison of different immunotherapy regimens and may facilitate wider adoption of induction therapies by surgeons and oncologists. We propose several surgical end points and related metrics for neoadjuvant immunotherapy in resectable NSCLC. These include the periods from screening to treatment initiation and from last neoadjuvant dose to surgery; reporting of the allowable window for surgery to preclude masking delays caused by induction treatment-related toxicity; complete resection (R0) rate; preoperative downstaging; a standardized list of immune-related adverse events and associated delay to surgery; preoperative attrition; postoperative attrition before adjuvant therapy; and postoperative 30- and 90-day mortality and morbidity rates. Intraoperative end points (blood loss, duration, and type of surgery) and our proposed system of grading complexity based on lymphadenopathy and fibrosis would allow quantitation of technical difficulty and quality of oncologic resection. In conclusion, the standardization, reporting, and prospective inclusion of these end points in study protocols would provide a comparative overview of the impact of different neoadjuvant immunotherapy regimens on surgery and ultimately clinical oncologic outcomes in resectable NSCLC.

Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial.

INTRODUCTION: Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC. METHODS: A total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported. RESULTS: PFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60-0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73-1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1-high subgroup (HR = 0.48, 95% CI: 0.29-0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively. CONCLUSIONS: Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms.

Activation of neuronal gene expression by the JMJD3 demethylase is required for postnatal and adult brain neurogenesis.

The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here, we show that JMJD3, a histone H3 lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life.