Machine prescription for chronic migraine

Responsive to treatment individually, chronic migraine remains strikingly resistant collectively, incurring the second-highest population burden of disability worldwide. A heterogeneity of responsiveness, requiring prolonged-currently heuristic-individual evaluation of available treatments, may reflect a diversity of causal mechanisms, or the failure to identify the most important, single causal factor. Distinguishing between these possibilities, now possible through the application of complex modelling to large-scale data, is critical to determining the optimal approach to identifying new interventions in migraine and making the best use of existing ones. Examining a richly phenotyped cohort of 1446 consecutive unselected patients with chronic migraine, here we use causal multitask Gaussian process models to estimate individual treatment effects across ten classes of preventatives. Such modelling enables us to quantify the accessibility of heterogeneous responsiveness to high-dimensional modelling, to infer the likely scale of the underlying causal diversity. We calculate the treatment effects in the overall population, and the conditional treatment effects among those modelled to respond and compare the true response rates between these two groups. Identifying a difference in response rates between the groups supports a diversity of causal mechanisms. Moreover, we propose a data-driven machine prescription policy, estimating the time-to-response when sequentially trialing preventatives by individualized treatment effects and compare it to expert guideline sequences. All model performances are quantified out-of-sample. We identify significantly higher true response rates among individuals modelled to respond, compared to the overall population (mean difference of 0.034; 95% CI 0.003 to 0.065; p=0.033), supporting significant heterogeneity of responsiveness and diverse causal mechanisms. The machine prescription policy yields an estimated 35% reduction in time-to-response (3.750 months; 95% CI 3.507 to 3.993; p<0.0001) compared with expert guidelines, with no substantive increase in expense per patient. We conclude that the highly distributed mode of causation in chronic migraine necessitates high-dimensional modelling for optimal management. Machine prescription should be considered an essential clinical decision-support tool in the future management of chronic migraine.

Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium

PURPOSE 131I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate. PATIENTS AND METHODS Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m2/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected. RESULTS One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%. CONCLUSION Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.

Phase II study of binimetinib with imatinib in patients with unresectable KIT-mutant melanoma.

TPS9594 Background: Immune checkpoint inhibitors (ICI) have transformed treatment for patients (pts) with advanced melanoma, as have BRAF/MEK inhibitors for pts with BRAF V600-mutant melanoma. However, pts with acral or mucosal melanomas are in particular need of more options given a lower objective response rate (ORR) to ICI, and lower incidence of BRAF V600 driver mutation. Such BRAF mutations are found in only 5-10% of acral/mucosal melanomas, while KIT mutations/amplifications are found in 10-20%. Even when present, a KIT alteration does not guarantee response to KIT inhibition, with only about one-third responding as previously shown in 3 phase II studies. A significant number of KIT-mutant melanomas have been shown to demonstrate NF1 or SPRED1 loss, with recent preclinical work showing that such alterations are associated with the loss of negative suppression of RAS, resulting in RAS activation and MEK dependence. We hypothesize that NF1 or SPRED1 loss cooperates with KIT mutations to drive melanomagenesis and resistance to KIT inhibition, and propose to target this vulnerability with a combination approach to targeted therapy. This phase II study will be the first to evaluate the efficacy and safety of binimetinib plus imatinib in pts with KIT-mutant melanoma. Methods: This is an investigator-initiated phase II study of binimetinib in combination with imatinib in pts with BRAF V600 WT, KIT-mutant unresectable melanoma who have progressed on or who are ineligible for ICI (NCT04598009). Pts will be ≥18 yo with performance status ECOG 0-2, and have unresectable Stage IIIB/C/D or Stage IV melanoma that is BRAF V600 WT and KIT-mutant by CLIA-certified testing platform. Pts will have progressed on prior ICI or other standard-of-care (SOC) therapies, or be ineligible for or unable to tolerate SOC therapies. Pts with brain metastasis will be eligible if clinically stable and determination made that no CNS-specific treatment is required prior to study start. Pts previously treated with a MEK inhibitor will be excluded. A Simon 2-stage Minimax design will be used; the null hypothesis that the true response rate is 0.1 will be tested against a one-sided alternative. 15 pts will be accrued in the first stage. If there are £1 responses, the study will be stopped. Otherwise, 10 additional pts will be accrued for a total of 25. The null hypothesis that the true response rate is 0.1 will be rejected if ≥6 responses are observed. This yields a type I error rate of 0.05 and power of 0.8017 when the true response rate is 0.3.Primary endpoint: ORR (RECIST). Secondary endpoints: duration of response, progression-free survival, overall survival, clinical benefit rate (CR, PR, or SD ≥16 weeks), safety profile (CTCAE). Exploratory objectives to include investigations of association between clinical response and baseline NF1 and SPRED1 status, and of pathologic correlates of acquired resistance. Study began enrolling pts in December 2020 and is ongoing. Clinical trial information: NCT04598009.

Randomized phase II trial of avelumab alone or with cetuximab for unresectable, locally advanced or metastatic squamous cell anal carcinoma progressed to at least one line of treatment: The CARACAS study.

4051 Background: Advanced squamous cell anal carcinoma (advSCAC) is a rare disease with poor prognosis. No standard therapies beyond first line are currently available, yet a promising activity was documented for the anti-EGFR cetuximab (CET) and for anti-PD-1 agents in previous retrospective case series and phase I-II studies, respectively. In experimental models combination of EGFR and PD-L1 blockade was synergistic as PD-L1 blockade led to NK cells activation enhancing cetuximab ADCC. In this trial we aimed to evaluate safety and activity of the anti-PD-L1 avelumab (AVE) alone or in combination with CET in pretreated advSCAC. Methods: This was an open-label, prospective, multicenter randomized phase 2 trial (NCT03944252). Patients (pts) with advSCAC progressed after at least 1 line of treatment were randomized 1:1 to receive either AVE 10 mg/kg (arm A) or AVE + CET 500 mg/sqm (arm B) as bi-weekly regimens. A Simon’s two-stage Mini-Max design was used. The null hypothesis of a true response rate 5% was tested against the one-sided alternative of a true response rate 20% in each arm. Setting type I error at 0.05 and power at 80%, 30 pts per arm had to be randomized. No formal comparison between the two arms was planned. Primary endpoint was overall response rate (ORR); secondary endpoints were Progression-Free Survival (PFS), Overall Survival (OS) and safety. Results: Sixty pts were enrolled, 30 in each arm. All baseline characteristics were well balanced between the two arms. Median age was 63 years; M/F was 19/41; 12 out of 30 pts in each arm had distant metastases; 7 in arm A and 10 in arm B received > 1 previous lines of treatment. At a median follow up of 8.7 months, 3 out of 30 pts in each arm obtained PR (ORR 10%); SD was observed in 12 pts in arm A (40%) and 14 in arm B (47%). Disease control rate was thus 50% in arm A and 57% in arm B. Duration of disease control was 6.1 (95%CI 3.7–11.0) and 6.1 (95%CI 4.1–9.6) months in arm A and B, respectively. Median PFS was 2.1 (95%CI 1.8–4.0) in arm A and 3.9 months (95%CI 2.1–5.6) in arm B. Grade 3-4 adverse events were 13.3% in arm A and 33.3% in arm B: anemia 10% vs 13.3%, fatigue 0 vs 6.7%, skin toxicity 0 vs 6.7%. Treatment interruption due to AE occurred in 3 pts, 1 in arm A and 2 in arm B. Translational analyses will be performed on tissue and blood samples for exploratory purpose. Conclusions: The CARACAS trial was the first clinical study to test dual EGFR and PD-L1 blockade in advSCAC. Both AVE monotherapy and AVE-CET showed promising activity with manageable safety profile. Clinical trial information: NCT03944252 .

Nimbus: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer.

TPS1115 Background: A previous study from our group showed that approximately 9% of metastatic breast cancer (MBC) is hypermutated, defined as a tumor mutational burden (TMB) ≥10 Mutations/Megabase (Mut/Mb). The aim of this study is to evaluate if patients with hypermutated HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/Kg intravenously (IV) every 14 days plus Ipilimumab 1 mg/Kg IV every 6 weeks in subjects with hypermutated metastatic HER2-negative breast cancer. Patients with measurable HER2-negative MBC, TMB ≥10 Mut/Mb assessed by a cancer-gene panel evaluating > 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting are eligible. The primary objective is overall response rate according to RECIST 1.1. Secondary objectives include the safety and tolerability of the combination, progression-free survival, and overall survival. The study will follow a two-stage design. In the first stage 14 patients will be enrolled. If there is at least one patient with objective response, accrual will continue to the second stage where an additional 16 patients will be enrolled. If there are at least 4 patients with an objective response among the 30 patients, the regimen will be considered worthy of further study. If the true response rate is 5%, the chance the regimen is declared worthy of further study is less than 5%. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is > 90%. Tumor biopsies, peripheral blood, and stool collection are mandatory and will be obtained at baseline, on treatment (end of cycle 1), and at disease progression and will be assessed for potential biomarkers of treatment response. The trial was activated in February 2019, and accrual should be completed in 18 months. Clinical trial information: NCT03789110.

A phase II, noncomparative, open label, multicentre, study of AZD9291 in patients with locally advanced or metastatic EGFR mutated “T790M undetectable or unknown” non-small cell lung cancer (stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).

TPS9107 Background: Osimertinib (OSI), is an oral, potent, irreversible inhibitor of both epidermal growth factor receptor (EGFR) sensitizing and resistance mutations (T790M) indicated for the treatment of pts with advanced EGFR T790M mutation-positive NSCLC. In the AURA study, OSI was associated with an ORR of 21% (13/61) among all patients with T790M negative mutation. Response rate broken down by immediate versus no immediate prior EGFR TKI was 11% (4/36 pts) versus 36% (9/25) respectively. This better activity with deferred OSI, drug able to inhibit also the EGFR sensitizing mutations, could be explained by a selection of sensitive tumor cells during chemotherapy (re-challenge strategy). Aim of the current study is prospective evaluate the efficacy of OSI in EGFR mutated, T790M “undetectable or unknown” patients as third-line therapy after a first-line EGFR TKI and a subsequent chemotherapy. Methods: OSIRIS study is a prospective single-arm, phase 2, open label, italian multicenter study. T790M “undetectable or unknown" is defined by the following conditions: inconclusive/negative tumor test result for T790M at the time of disease progression or medical inaccessible/contraindications/declined tumor biopsy or insufficient tumor tissue for testing. Pts are treated with OSI 80 mg once daily until disease progression or unacceptable toxicity. The single-arm design is appropriate, as there is no accepted standard therapy for these pts after chemotherapy. The primary endpoint is ORR according to RECIST version 1.1. The null hypothesis that the true response rate is 9% will be tested against a one-sided alternative. In the first stage, 32 pts will be accrued. If there are 3 or fewer responses in these 32 pts, the study will be stopped. Otherwise, 49 additional pts will be accrued for a total of 81. This design yields a type I error rate of 0.05 and power of 80% when the true response rate is 19%. Secondary endpoints are PFS, OS and safety. Exploratory: mutational analysis of a panel of genes involved in resistance to EGFR-TKIs is planned. Clinical trial information: 2016-002555-17.

Using Expert Opinion to Quantify Uncertainty in and Cost of Using Nondestructive Evaluation on Bridges

A previous literature review indicated that there is little published experimental data that can be used to determine quantities such as bias, accuracy, reliability, and cost of common Nondestructive Evaluation (NDE) methods as far as their use on bridges is concerned. This study attempts to quantify these parameters for common bridge NDE methods through a four-round Delphi method survey with experts in the NDE bridge field. The survey results indicate that most commonly used bridge NDE methods tend to be underbiased and relatively reliable. Furthermore, the accuracy of commonly used bridge NDE methods tends to be relatively variable with the average test measuring a true response between 80% and 85% of the time. In general, it was shown by the participant responses that the more expensive the method was, the better the bias, accuracy, and reliability the method had, and vice versa. The information presented in this paper can serve as a starting point for characterizing different NDE methods for use in bridge management and inspection planning and identifies the type of information that is still needed. As such, this research has the potential to promote further research on this subject.