Alliance Foundation Trial 09: A randomized, multicenter, phase 2 trial evaluating two sequences of pembrolizumab and standard platinum-based chemotherapy in patients with metastatic NSCLC

INTRODUCTION: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. METHODS: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a pick a winner design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. RESULTS: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively ( CONCLUSIONS: Additional evaluation of either sequence in a phase 3 trial is not warranted

A Phase II Trial of Prexasertib (LY2606368) in Patients With Extensive-Stage Small-Cell Lung Cancer

Patients with extensive-stage small-cell lung cancer (ED-SCLC) need improved outcomes in the relapsed/refractory setting. This phase II study evaluated the safety and efficacy of prexasertib, a checkpoint kinase 1 inhibitor, in platinum-sensitive and platinum-refractory ED-SCLC. Prexasertib demonstrated response rates of 5.2% in platinum-sensitive and 0% in platinum-refractory ED-SCLC. Prexasertib did not show prespecified efficacy as monotherapy in ED-SCLC. Background: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage smallcell lung cancer (ED-SCLC).Patients and Methods: This was a parallel-cohort phase II study of 105 mg/m2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m2 days 1-3, 14-day cycle). Results: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ≥3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified. Conclusion: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC

Protein-altering germline mutations implicate novel genes related to lung cancer development

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk

Role of Neoadjuvant Immune Checkpoint Inhibitors in Resectable Non-Small Cell Lung Cancer

The neoadjuvant use of immune checkpoint inhibitors (ICI) in resectable non-small cell lung cancer (NSCLC) is being increasingly adopted, but questions about the most appropriate applications remain. Although patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy or targeted therapies +/− radiotherapy, they still have a high risk of recurrence and death. In recent years, immune checkpoint inhibitors (ICI) (anti-PD-1/PD-L1 and anti-CTLA-4) have provided a new and effective therapeutic strategy for the treatment of advanced NSCLC. Therefore, it is possible that ICIs for early-stage NSCLC may follow the pattern established in metastatic disease. Currently, there are several ongoing trials to determine the efficacy in the neoadjuvant setting for patients with local or regional disease. To date, only nivolumab in combination with chemotherapy has been approved by the U.S. FDA in the preoperative setting, but data continue to evolve rapidly, and treatment guidelines need to be determined. In this article, we review the current preclinical and clinical evidence on neoadjuvant ICIs alone and combination in the treatment of early-stage NSCLC

A randomized phase III study of abemaciclib versus erlotinib in patients with stage IV non-small cell lung cancer with a detectable KRAS mutation who failed prior platinum-based therapy: JUNIPER

Introduction: JUNIPER compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, with erlotinib in patients with non-small cell lung cancer (NSCLC) harboring a Kirsten rat sarcoma (KRAS) mutation. Methods: JUNIPER was a Phase III, multicenter, randomized, open-label trial of abemaciclib versus erlotinib in patients with stage IV NSCLC and a detectable mutation in codons 12 or 13 of the KRAS oncogene, who progressed after platinum-based chemotherapy and 1 additional therapy (could include immune checkpoint inhibitor therapy). Randomized patients (3:2) received either 200 mg abemaciclib twice daily or 150 mg erlotinib once daily with best supportive care until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety. Results: Between December 2014 and April 2017, 453 patients were randomly assigned to receive abemaciclib (N = 270) or erlotinib (N = 183). Median OS was 7.4 months (95% confidence interval [CI]: 6.5, 8.8) with abemaciclib and 7.8 months (95% CI: 6.4, 9.5) with erlotinib (hazard ratio [HR] = 0.968 [95% CI: 0.768, 1.219]; p = .77). Median PFS was 3.6 months (95% CI: 2.8, 3.8) with abemaciclib and 1.9 months (95% CI: 1.9, 2.0) with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p <.000001). ORR was 8.9% and 2.7% (p = .010), and the disease control rate was 54.4% and 31.7% (p <.001) with abemaciclib and erlotinib, respectively. Safety results reflected the known safety profiles of abemaciclib and erlotinib. Conclusions: In this study, the primary endpoint of OS was not met; PFS and ORR were improved with manageable toxicity in the abemaciclib arm. The increases in response rates and PFS support further investigation of abemaciclib in other NSCLC subpopulations or in combination with other agents. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT02152631

IN VIVO INDUCTION AND IN VITRO INHIBITION OF HEPATIC CYTOCHROME P450 ACTIVITY BY THE BENZODIAZEPINE ANTICONVULSANTS CLONAZEPAM AND DIAZEPAM

ABSTRACT: The ability of the benzodiazepines, as a chemical class, to cause the induction and/or inhibition of cytochromes P450 has not been well characterized. In the present study, the induction of the cytochrome P450 2B subfamily (CYP2B) in vivo and the inhibition of CYP2B activity in vitro by selected benzodiazepines was examined in hepatic tissues derived from male F344/NCr rats. Initial studies of the in vivo induction or in vitro inhibition of benzyloxyresorufin O-dealkylation activity revealed that both clonazepam and diazepam were relatively effective in vivo inducers of CYP2B when administered in the diet at 500 ppm for 5 days and also were fairly potent inhibitors of the activity of these hemoproteins in vitro. Oxazepam, in contrast, was ineffective as an inducer or an inhibitor of this activity. Further studies were performed to characterize the subfamily selectivity of the P450 induction and inhibition displayed by clonazepam. Specifically, microsomes from rats treated with clonazepam (1000 or 1800 ppm in the diet for 5 days) were found to be highly induced with respect to catalytic activities mediated by CYP2B, including benzyloxyresorufin and pentoxyresorufin O-dealkylation or testosterone 16␤-hydroxylation, but other CYP proteins were minimally induced. In addition to inducing the CYP2B subfamily, clonazepam also induced the RNA encoding other drug metabolizing enzymes (e.g., epoxide hydrolase and the glutathione S-transferase ␣-subfamily) that are typically induced by phenobarbital-type inducers. Finally, clonazepam proved to be a potent noncompetitive or &quot;mixed-type&quot; competitive inhibitor of catalytic activities mediated by CYP2B, but not by other CYP proteins (e.g. CYP2A, CYP3A) in microsomes derived from phenobarbital-pretreated rats. Clonazepam (CZP) 1 is a clinically important benzodiazepine anticonvulsant that is employed for the treatment of absence, akinetic, and myoclonic seizures in children (1). The benzodiazepines diazepam and oxazepam are used clinically as sedative-hypnotics and anxiolytics (1). Several of the chemical classes that possess sedative/anticonvulsant or anxiolytic activity (e.g. barbiturates, hydantoins and dialkylacetylureas) also induce hepatic cytochrome P450 subfamilies 2B and 3A (CYP2B and CYP3A) in the rat (2-6) and mouse A variety of structurally diverse compounds induce the CYP2B subfamily in the rat, including phenobarbital (PB), clotrimazole (CLOT), ␣-hexachlorocyclohexane, diallyl sulfide, and certain of the polychlorinated biphenyls (e.g., 2,2Ј,4,4Ј,5,5Ј-hexachlorobiphenyl) (18 -20). Interestingly, a significant number of the compounds that are inducers of the CYP2B subfamily are also striking inhibitors of CYP2B-mediated catalytic activity in vitro. Thus, animal pretreatment with many of the known in vitro CYP2B-inhibitors, including SKF 525-A (21), CLOT (20, This work has been presented in part in abstract form (reference 46). The work was supported in part by NIEHS Center grant ES05022 and RO1 grant GM 44982 (P.E.T.)