Publications

Anti-programmed cell death protein 1 (PD1) antibodies, pembrolizumab and nivolumab, alone or in combination with ipilimumab, have become standard treatment for melanoma and multiple other malignancies. Neurological adverse effects are rare and have not been well characterized to date. Patients who developed neurological adverse effects while being treated with PD1, alone or in combination with ipilimumab, were retrospectively identified from 10 cancer centers. Fifty-eight patients were included, and the median time from treatment initiation to development of neurological adverse effects was 7 weeks (range, 1-86.5 weeks). Thirty-seven (64%) toxicities affected the peripheral nervous system. Fifty (86%) patients were treated with corticosteroids, with 22 (37%) patients requiring further immunomodulation including intravenous immunoglobulin (16), plasmapheresis (7), mycophenolate mofetil (4), cyclophosphamide (1), and rituximab (1). Twenty-seven (46%) had a complete resolution of their neurological symptoms, and two (4%) patients died secondary to complications from their neurological adverse effects. The response rate of the cancer to immunotherapy was 78%, and the median progression free survival was not reached. Neurological adverse effects can occur with PD1 treatment, do not appear to impact treatment response, but may be irreversible or worsen in some patients. Management may require immunomodulation beyond corticosteroids.

<div>Abstract<p>Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (<i>n</i> = 13) and -negative (<i>n</i> = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in <i>RB1</i>, <i>TP53</i>, and a high frequency of mutations in <i>NOTCH1</i> and <i>FAT1</i>. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (<i>PIK3CA</i>, <i>AKT1</i>, <i>PIK3CG</i>) and MAPK (<i>HRAS</i>, <i>NF1</i>) pathway members and the receptor tyrosine kinase <i>FGFR2</i>. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. <i>Cancer Res; 75(24); 5228–34. ©2015 AACR</i>.</p></div>

As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel. Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m−2 q3w, paclitaxel 80 mg m−2 every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m−2 q3w. The primary endpoint was safety/tolerability. A total of 116 patients received saracatinib 125 (N=20), 175 (N=44), 225 (N=40), 250 (N=9), or 300 mg (N=3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade ⩾3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; ⩾225 mg, 33%), and grade ⩾3 neutropenia occurred more commonly at doses ⩾225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w. Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.

<p>Supplementary legend</p>

<p>Supplementary Table S2. Common (≥20%) treatment-emergent adverse events.</p>

<div>AbstractPurpose:<p>Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future molecularly targeted therapies.</p>Patients and Methods:<p>An investigational clinical trial assay, based on the FoundationOneCDx tissue test, was used to prospectively identify patients with qualifying homologous recombination repair gene alterations in the phase III PROfound study. Evaluation of next-generation sequencing (NGS) tissue test outcome against preanalytic parameters was performed to identify key factors influencing NGS result generation.</p>Results:<p>A total of 4,858 tissue samples from 4,047 patients were tested and reported centrally. NGS results were obtained in 58% (2,792/4,858) of samples (69% of patients). Of samples submitted, 83% were primary tumor samples (96% were archival and 4% newly obtained). Almost 17% were metastatic tumor samples (60% were archival and 33% newly obtained). NGS results were generated more frequently from newly obtained compared with archival samples (63.9% vs. 56.9%) and metastatic compared with primary samples (63.9% vs. 56.2%). Although generation of an NGS result declined with increasing sample age, approximately 50% of samples ages >10 years generated results. While higher tumor content and DNA yield resulted in greater success in obtaining NGS results, other factors, including selection and preservation of samples, may also have had an impact.</p>Conclusions:<p>The PROfound study shows that tissue testing to identify homologous recombination repair alterations is feasible and that high-quality tumor tissue samples are key to obtaining NGS results and identifying patients with mCRPC who may benefit from olaparib treatment.</p></div>

e21525 Background: Induction BRAF/MEK inhibitor (TT) with a planned switch to doublet ICI has been evaluated in 2 clinical trials of patients (pts) with metastatic BRAF -mutant melanoma, with benefit noted in high-risk pts. In practice, this approach is typically reserved for highly symptomatic pts requiring rapid disease control. Reported outcomes from a real-world population, including those with brain metastases, are limited. Methods: In this retrospective study, all pts with metastatic BRAF V600-mutant melanoma that received induction TT with a planned ICI switch within 16 weeks were identified via chart review. Pts who did not initiate ICI as intended were included in analyses. Primary endpoint was overall survival (OS) with secondary endpoints of intracranial (IC) and extracranial (EC) progression-free survival (PFS) and time to strategy failure (TTSF; time to definitive progression requiring change in systemic treatment, or death). Survival analyses were performed using Kaplan-Meier estimates and Cox regression. Results: 17 pts met criteria (median age 53y [IQR 47-67], 7 [44%] male). In 12 (70%) with previous stage I-III melanoma, 1 (6%) had adjuvant therapy with TT and metastatic relapse occurred at a median of 3.8 years. 11 (65%) had brain metastases, 5 (29%) liver metastases, 7 (of 13 available; 54%) raised baseline LDH, 8 (47%) ECOG ≥2, and 6 (35%) had non-V600E mutation. 13 (76%) required corticosteroids (CS) for symptomatic disease. Of those with paired LDH pre and post TT (n = 9), 5 (56%) increased and 4 (44%) fell or remained normal. 4 pts (24%) did not proceed to ICI due to death (n = 2) or poor performance status (n = 2). 13 pts (76%) proceeded to combination ICI with ipilimumab (3mg/kg; median 3 cycles) + nivolumab (1mg/kg) at a median of 51 days (range 4-126) from TT initiation. All pts requiring CS that received ICI were weaned off prior to ICI initiation (n = 10). 6 (35%) received local therapy at any point after TT initiation. Following strategy failure (n = 9), all received an alternative second-line TT. At a median follow up of 23.8 months, median OS was 14.7mths (3.9–25.5) (secondary survival outcomes in Table 1). De novo metastatic disease (p = 0.005) and raised baseline LDH (p = 0.03) were associated with poor OS, however presence of brain metastases was not (p = 0.9). Conclusions: In this poor prognosis, real-world cohort, a TT-ICI switch strategy resulted in clinically meaningful median OS of over 14 months. Importantly, TT allowed all patients to cease steroids prior to ICI. De novo metastatic disease and elevated LDH portended poorer outcomes. Encouragingly, patients with and without brain metastases demonstrated similar benefit. Survival outcomes for TT-ICI switch strategy. Outcome Median (95% CI) PFS 4.1m (1.7-12.1) IC-PFS 5.6m (2.4-9.8) EC-PFS 6.4m (3.9-NR) TTSF 5.1m (1.7-12.1) OS 14.7m (3.9-25.5)

The management of oligometastatic clear cell renal cell carcinoma (ccRCC) varies widely, ranging from observation to resection or systemic therapies. Prolonged survival has been observed following resection or stereotactic ablative body radiotherapy (SABR). Immunotherapy combinations have shown survival benefits, however, toxicity is higher than that for monotherapy and complete response rates remain less than 10%. The combination of effective local therapies in conjunction with immunotherapy may provide more durable control and pre-clinical models have suggested a synergistic immune-priming effect of SABR. and Methods: RAPPORT is a prospective, single arm, phase I/II study assessing the safety, efficacy and biological effects of single fraction SABR followed by pembrolizumab for oligometastatic ccRCC. The study will include 30 patients with histological confirmed ccRCC and 1–5 oligometastases, one or more of which must be suitable for SABR. Patients can have received prior systemic therapy but not prior immunotherapy. A single 20Gy of SABR is followed 5 days later by 8 cycles of 200 mg pembrolizumab, every 3 weeks. Adverse events are recorded using CTCAE V4.03 and tumour response evaluated by Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). Tumour tissue and peripheral blood samples will be collected pre-, during and post‐treatment to assess longitudinal changes in immune subsets. The RAPPORT study will provide important safety and early efficacy data on the combination of SABR and pembrolizumab in oligometastatic ccRCC and will provide an insight into the underlying biological effects of combination therapy. clinicaltrials.gov ID NCT02855203.

The reporting quality of clinical practice guidelines (CPGs) for gliomas has not yet been thoroughly assessed. The International Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement developed in 2016 provides a reporting framework to improve the quality of CPGs. We aimed to estimate the reporting quality of glioma guidelines using the RIGHT checklist and investigate how the reporting quality differs by selected characteristics.We systematically searched electronic databases, guideline databases, and medical society websites to retrieve CPGs on glioma published between 2018 and 2020. We calculated the compliance of the CPGs to individual items, domains and the RIGHT checklist overall. We performed stratified analyses by publication year, country of development, reporting of funding, and impact factor (IF) of the journal.Our search revealed 20 eligible guidelines. Mean overall adherence to the RIGHT statement was 54.6%. Eight CPGs reported more than 60% of the items, and five reported less than 50%. All guidelines adhered to the items 1a, 3, 7a, 13a, while no guidelines reported the items 17 or 18b (see http://www.right-statement.org/right-statement/checklist for a description of the items). Two of the seven domains, "Basic information" and "Background", had mean reporting rates above 60%. The "Review and quality assurance" domain had the lowest mean reporting rate, 12.5%. The reporting quality of guidelines published in 2020, guidelines developed in the United States, and guidelines that reported funding tended to be above average.The reporting quality of CPGs on gliomas is low and needs improvement. Particular attention should be paid on reporting the external review and quality assurance process. The use of the RIGHT criteria should be encouraged to guide the development, reporting and evaluation of CPGs.