Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score-Matched Survival Outcome Comparisons.

PURPOSE: Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) to reduce risk of relapse after completion of immunotherapy was investigated previously in a single-arm, phase II study (NMTRC003B; ClinicalTrials.gov identifier: NCT02395666) that suggested improved event-free survival (EFS) and overall survival (OS) compared with historical rates in a phase III trial (Children Oncology Group ANBL0032; ClinicalTrials.gov identifier: NCT00026312). Using patient-level data from ANBL0032 as an external control, we present new analyses to further evaluate DFMO as HRNB postimmunotherapy maintenance. PATIENTS AND METHODS: NMTRC003B (2012-2016) enrolled patients with HRNB (N = 141) after standard up-front or refractory/relapse treatment who received up to 2 years of continuous treatment with oral DFMO (750 ± 250 mg/m2 twice a day). ANBL0032 (2001-2015) enrolled patients with HRNB postconsolidation, 1,328 of whom were assigned to dinutuximab (ch.14.18) treatment. Selection rules identified 92 NMTRC003B patients who participated in (n = 87) or received up-front treatment consistent with (n = 5) ANBL0032 (the DFMO/treated group) and 852 patients from ANBL0032 who could have been eligible for NMTRC003B after immunotherapy, but did not enroll (the NO-DFMO/control group). The median follow-up time for DFMO/treated patients was 6.1 years (IQR, 5.2-7.2) versus 5.0 years (IQR, 3.5-7.0) for NO-DFMO/control patients. Kaplan-Meier and Cox regression compared EFS and OS for overall groups, 3:1 (NO-DFMO:DFMO) propensity score-matched cohorts balanced on 11 baseline demographic and disease characteristics with exact matching on MYCN, and additional sensitivity analyses. RESULTS: DFMO after completion of immunotherapy was associated with improved EFS (hazard ratio [HR], 0.50 [95% CI, 0.29 to 0.84]; P = .008) and OS (HR, 0.38 [95% CI, 0.19 to 0.76]; P = .007). The results were confirmed with propensity score-matched cohorts and sensitivity analyses. CONCLUSION: The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with postimmunotherapy DFMO.

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.

Mechanism of action biomarkers predicting response to AKT inhibition in the I-SPY 2 breast cancer trial.

The AKT inhibitor MK2206 (M) was evaluated in I-SPY 2 and graduated in the HER2+, HR-, and HR- HER2+ signatures. We hypothesized that AKT signaling axis proteins/genes may specifically predict response to M and tested 26 phospho-proteins and 10 genes involved in AKT-mTOR-HER signaling; in addition, we tested 9 genes from a previous study in the metastatic setting. One hundred and fifty patients had gene expression data from pretreatment biopsies available for analysis (M: 94, control: 56) and 138 had protein data (M: 87, control: 51). Logistic modeling was used to assess biomarker performance in pre-specified analysis. In general, phospho-protein biomarkers of activity in the AKT-mTOR-HER pathway appeared more predictive of response to M than gene expression or total protein biomarkers in the same pathway; however, the nature of the predictive biomarkers differed in the HER2+ and TN groups. In the HER2+ subset, patients achieving a pCR in M had higher levels of multiple AKT kinase substrate phospho-proteins (e.g., pmTOR, pTSC2). In contrast, in the TN subset responding patients had lower levels of AKT pathway phospho-proteins, such as pAKT, pmTOR, and pTSC2. Pathway mutations did not appear to account for these associations. Additional exploratory whole-transcriptome analysis revealed immune signaling as strongly associated with response to M in the HER2+ subset. While our sample size is small, these results suggest that the measurement of particular AKT kinase substrate phospho-proteins could be predictive of MK2206 efficacy in both HER2+ and TN tumors and that immune signaling may play a role in response in HER2+ patients.

DNA repair deficiency biomarkers and the 70-gene ultra-high risk signature as predictors of veliparib/carboplatin response in the I-SPY 2 breast cancer trial.

Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2- patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2- patients (VC: 72 and concurrent controls: 44). We also evaluated the 70-gene ultra-high risk signature (MP1/2), one of the biomarkers used to define subtype in the trial. We used logistic modeling to assess biomarker performance. Successful biomarkers were combined using a simple voting scheme to refine the 'predicted sensitive' group and Bayesian modeling used to estimate the pathologic complete response rates. BRCA1/2 germline mutation status associated with VC response, but its low prevalence precluded further evaluation. PARPi-7, BRCA1ness, and MP1/2 specifically associated with response in the VC arm but not the control arm. Neither CIN70 nor PARP1 protein specifically predicted VC response. When we combined the PARPi-7 and MP1/2 classifications, the 42% of triple negative patients who were PARPi7-high and MP2 had an estimated pCR rate of 75% in the VC arm. Only 11% of HR+/HER2- patients were PARPi7-high and MP2; but these patients were also more responsive to VC with estimated pathologic complete response rates of 41%. PARPi-7, BRCA1ness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care.

Application of adaptive design methodology in development of a long-acting glucagon-like peptide-1 analog (dulaglutide): statistical design and simulations.

BACKGROUND: Dulaglutide (dula, LY2189265), a long-acting glucagon-like peptide-1 analog, is being developed to treat type 2 diabetes mellitus. METHODS: To foster the development of dula, we designed a two-stage adaptive, dose-finding, inferentially seamless phase 2/3 study. The Bayesian theoretical framework is used to adaptively randomize patients in stage 1 to 7 dula doses and, at the decision point, to either stop for futility or to select up to 2 dula doses for stage 2. After dose selection, patients continue to be randomized to the selected dula doses or comparator arms. Data from patients assigned the selected doses will be pooled across both stages and analyzed with an analysis of covariance model, using baseline hemoglobin A1c and country as covariates. The operating characteristics of the trial were assessed by extensive simulation studies. RESULTS: Simulations demonstrated that the adaptive design would identify the correct doses 88% of the time, compared to as low as 6% for a fixed-dose design (the latter value based on frequentist decision rules analogous to the Bayesian decision rules for adaptive design). CONCLUSIONS: This article discusses the decision rules used to select the dula dose(s); the mathematical details of the adaptive algorithm-including a description of the clinical utility index used to mathematically quantify the desirability of a dose based on safety and efficacy measurements; and a description of the simulation process and results that quantify the operating characteristics of the design.

Subcutaneously administered recombinant human interleukin-2 and interferon alfa-2a for advanced breast cancer: a phase II study of the Cancer and Leukemia Group B (CALGB 9041).

New and more effective treatments are needed for metastatic breast cancer. This study aimed to determine the effectiveness of a combination of subcutaneously administered recombinant human interleukin-2 (rIL-2), 1.5 MU/m(2) for 5 consecutive days repeated for 3 weeks, and interferon alpha-2a (IFN), 7.5 MU/m(2), administered subcutaneously three times per week. Women who had previously received 1-2 prior chemotherapy regimens for measurable inoperable, recurrent, or metastatic breast cancer were eligible. Of 40 patients accrued to the study, 32 were evaluable for response assessment. Toxicities were frequent but manageable. The most common grade 3 and 4 toxicities were lymphopenia (17%) and malaise/fatigue (24%). There were no complete responses, one partial response (3%), and six patients with stable disease (19%). Of the seven patients with partial response or stable disease, all had tumors that expressed hormone receptors. The median survival was 8.9 months and all patients have died. Good performance status was the most important predictor of survival. In this group of women with metastatic breast cancer, the overall prognosis was poor. This combination of rIL-2 and IFN was ineffective.