Clinical outcomes and longitudinal circulating tumor DNA changes after treatment with nivolumab and olaparib in immunotherapy relapsed melanoma with detected homologous recombination deficiency

The treatment of immunotherapy relapsed cutaneous melanoma constitutes a challenge in both research and clinical practice fields given the lack of effective therapeutic options. Homologous recombination deficiency (HRD) has been identified in several solid cancers including cutaneous melanoma. However, the utility of medications targeting HRD cancer cells is an uncharted territory in melanoma. Moreover, preclinical evidence suggests a synergistic role of combining immune checkpoint blockade (ICB) with drugs targeting HRD cancer cells such as PARP inhibitors. Here, we present a case study of a patient with immunotherapy relapsed melanoma who was found to have detected HRD and was treated with nivolumab (ICB) and olaparib (PARP inhibitors)

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter

BACKGROUND: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase III randomized CheckMate 548 study was to evaluate RT + TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587). METHODS: Patients (N = 716) were randomized 1:1 to NIVO [(240 mg every 2 weeks × 8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 once daily during RT, then 150-200 mg/m2 once daily on days 1-5 of every 28-day cycle × 6)] or PBO + RT + TMZ following the same regimen. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in patients without baseline corticosteroids and in all randomized patients. RESULTS: As of December 22, 2020, median (m)PFS (blinded independent central review) was 10.6 months (95% CI, 8.9-11.8) with NIVO + RT + TMZ vs 10.3 months (95% CI, 9.7-12.5) with PBO + RT + TMZ (HR, 1.1; 95% CI, 0.9-1.3) and mOS was 28.9 months (95% CI, 24.4-31.6) vs 32.1 months (95% CI, 29.4-33.8), respectively (HR, 1.1; 95% CI, 0.9-1.3). In patients without baseline corticosteroids, mOS was 31.3 months (95% CI, 28.6-34.8) with NIVO + RT + TMZ vs 33.0 months (95% CI, 31.0-35.1) with PBO + RT + TMZ (HR, 1.1; 95% CI, 0.9-1.4). Grade 3/4 treatment-related adverse event rates were 52.4% vs 33.6%, respectively. CONCLUSIONS: NIVO added to RT + TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated or indeterminate MGMT promoter. No new safety signals were observed

Physician-Controlled Wire-Guided Cannulation of the Minor Papilla

Background. Minor papilla (MiP) cannulation is frequently performed using specialized small-caliber accessories. Outcomes data for MiP cannulation with standard-sized accessories are lacking. Methods. This is a case series describing MiP cannulation outcomes in consecutive patients treated by two endoscopists between July 2005 and November 2008 at two tertiary referral centers. MiP cannulation was attempted using a 4.4 Fr tip sphincterotome loaded with a 0.035″, 260 cm hydrophilic-tip guidewire, using a wire-guided technique under physician control. Results. 25 patients were identified (14 women, mean age 45). Procedure indications included recurrent acute pancreatitis in 16 patients (64%) and chronic pancreatitis in 2 (8%), among other indications. MiP cannulation was successful in 24 patients (96%). Sphincterotomy followed by pancreatic stent placement was performed in 21 patients (84%). Mild post-ERCP pancreatitis occurred in 3 patients (12%). Conclusion. Physician-controlled wire-guided MiP cannulation using a 4.4 Fr sphincterotome and 0.035″ guidewire is an effective and safe technique

Salvage therapies for radiation-relapsed isocitrate dehydrogenase-mutant astrocytoma and 1p/19q codeleted oligodendroglioma

BACKGROUND: Optimal management for recurrent IDH-mutant glioma after radiation therapy (RT) is not well-defined. This study assesses practice patterns for managing recurrent IDH-mutant astrocytoma (Astro) and 1p/19q codeleted oligodendroglioma (Oligo) after RT and surveys their clinical outcomes after different salvage approaches. METHODS: Ninety-four recurrent Astro or Oligo patients after RT who received salvage systemic therapy (SST) between 2001 and 2019 at a tertiary cancer center were retrospectively analyzed. SST was defined as either alkylating chemotherapy (AC) or nonalkylating therapy (non-AC). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method from the start of SST. Multivariable analysis (MVA) was conducted using Cox regression analysis. RESULTS: Recurrent Oligo (n = 35) had significantly higher PFS (median: 3.1 vs 0.8 years, respectively, CONCLUSIONS: Recurrent radiation-relapsed IDH-mutant gliomas represent a heterogeneous group with variable treatment approaches. Surgery, AC, and reirradiation remain the mainstay of salvage options for retreatment

Metachronous cutaneous squamous cell carcinoma in a young patient as the only presenting symptom to uncover Lynch syndrome with MLH1 germline mutation

BACKGROUND: Cutaneous malignancies are rare complications of Lynch syndrome and can include Muir-Torre and Turcot syndromes that are associated with sebaceous gland tumors and keratoacanthomas. The incidence and clinical course of cutaneous squamous cell carcinoma have not been well documented in Lynch syndrome due to its rarity. CASE PRESENTATION: A 49-year male presented with an enlarging groin skin lesion that was biopsed and demonstrated cutaneous squamous cell carcinoma for which he underwent a surgical resection. The patient experienced later a recurrence of cutaneous squamous cell carcinoma around the resected margins. Next generation sequencing of tumor tissue revealed mutations in MSH6 and MLH1, in addition to high microsatellite instability. The patient underwent pembrolizumab treatment with complete resolution of the cutaneous lesion in the groin, but subsequently developed a new mass in the right antecubital fossa shortly after discontinuation of pembrolizumab. Repeat biopsy of the antecubital fossa lesion revealed a recurrence of cutaneous squamous cell carcinoma. Germline mutation testing revealed MLH1 mutation, compatible with Lynch syndrome, and the patient restarted pembrolizumab which was associated with a complete response. The patient was referred for genetic counseling and cancer screening. CONCLUSIONS: Cutaneous squamous cell carcinoma, although rare, can be the initial presenting symptom in patients with Lynch syndrome. This association has been described in patients with germline mutations in MLH1. Lynch syndrome should be considered when evaluating young patients presenting with recurrent cutaneous squamous cell carcinoma with positive family history of malignancy and/ or without any identifiable risk factors for skin cancers, including those with a durable and rapid response to immunotherapy

BESPOKE IO protocol: A multicentre, prospective observational study evaluating the utility of ctDNA in guiding immunotherapy in patients with advanced solid tumours

INTRODUCTION: Immunotherapy (IO) has transformed the treatment paradigm for a wide variety of solid tumours. However, assessment of response can be challenging with conventional radiological imaging (eg, iRECIST), which do not precisely capture the unique response patterns of tumours treated with IO. Emerging data suggest that circulating tumour DNA (ctDNA) can aid in response assessment in patients with solid tumours receiving IO. The short half-life of ctDNA puts it in a unique position for early treatment response monitoring. The BESPOKE IO study is designed to investigate the clinical utility of serial ctDNA testing to assess treatment response using a tumour-informed, bespoke ctDNA assay (Signatera) and to determine its impact on clinical decision-making with respect to continuation/discontinuation, or escalation/de-escalation of immunotherapy in patients with advanced solid tumours. METHODS AND ANALYSIS: The BESPOKE IO is a multicentre, prospective, observational study with a goal to enroll over 1500 patients with solid tumours receiving IO in up to 100 US sites. Patients will be followed for up to 2 years with serial ctDNA analysis, timed with every other treatment cycle. The primary endpoint is to determine the percentage of patients who will have their treatment regimen changed as guided by post-treatment bespoke ctDNA results along with standard response assessment tools. The major secondary endpoints include progression-free survival, overall survival and overall response rate based on the ctDNA dynamics. ETHICS AND DISSEMINATION: The BESPOKE IO study was approved by the WCG Institutional Review Board (Natera-20-043-NCP BESPOKE Study of ctDNA Guided Immunotherapy (BESPOKE IO)) on 22 February 2021. Data protection and privacy regulations will be strictly observed in the capturing, forwarding, processing and storing patients\u27 data. Natera will approve the publication of any study results in accordance with the site-specific contract. TRIAL REGISTRATION NUMBER: NCT04761783