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The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Methods: Clinical translation followed characterization of PEG-AVP0458 drug product and preclinical biodistribution and imaging assessments of Iodine-124 trace labeled PEG-AVP0458 (124I-PEG-AVP0458). The primary study objective of the first-in-human study was the safety of a single protein dose of 1.0 or 10 mg/m2 124I-PEG-AVP0458 in patients with TAG-72 positive relapsed/ metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor uptake, pharmacokinetics and immunogenicity. Patients were infused with a single-dose of 124I labeled PEG-AVP0458 (3-5 mCi (111-185 MBq) for positron emission tomography (PET) imaging, performed sequentially over a one-week period. Safety, pharmacokinetics, biodistribution, and immunogenicity were assessed up to 28 days after infusion. Results: PEG-AVP0458 was radiolabeled with 124I and shown to retain high TAG-72 affinity and excellent targeting of TAG-72 positive xenografts by biodistribution analysis and PET imaging. In the first-in-human trial, no adverse events or toxicity attributable to 124I-PEG-AVP0458 were observed. Imaging was evaluable in 5 patients, with rapid and highly specific targeting of tumor and minimal normal organ uptake, leading to high tumor:blood ratios. Serum concentration values of 124I-PEG-AVP0458 showed consistent values between patients, and there was no significant difference in T½α and T½β between dose levels with mean (± SD) results of T½α = 5.10 ± 4.58 hours, T½β = 46.19 ± 13.06 hours. Conclusions: These data demonstrates the safety and feasibility of using pegylated diabodies for selective tumor imaging and potential delivery of therapeutic payloads in cancer patients.

IntroductionGrades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsiesMethods and analysisThis study will be a multicentre pilot study enrolling patients with recurrent grade 2/3 gliomas that have previously been treated with radiotherapy and chemotherapy at diagnosis or at first relapse. Contemporaneous tumour tissue at the time of first relapse, defined as tissue obtained within 6 months of relapse and without subsequent intervening therapy, will be obtained from patients. Molecular screening will be performed by targeted next-generation sequencing at the reference laboratory (PathWest, Perth, Australia). RNA and DNA will be extracted from representative formalin-fixed paraffin embedded tissue scrolls or microdissected from sections on glass slides tissue sections following a review of the histology by pathologists. Extracted nucleic acid will be quantified by Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Library preparation and targeted capture will be performed using the TruSight Tumor 170 (TST170) kit and samples sequenced on NextSeq 550 (Illumina) using NextSeq V.2.5 hi output reagents, according to the manufacturer’s instructions. Data analysis will be performed using the Illumina BaseSpace TST170 app v1.02 and a custom tertiary pipeline, implemented within the Clinical Genomics Workspace software platform from PierianDx (also refer to section 3.2). Primary outcomes for the study will be the number of patients enrolled and the number of patients who complete molecular screening. Secondary outcomes will include the proportion of screened patients enrolled; proportion of patients who complete molecular screening; the turn-around time of molecular screening; and the value of a brain tumour specific multi-disciplinary tumour board, called the molecular tumour advisory panel as measured by the proportion of patients in whom the treatment recommendation was refined compared with the recommendations from the automated bioinformatics platform of the reference laboratory testing.Ethics and disseminationThe study was approved by the lead Human Research Ethics Committee of the Sydney Local Health District: Protocol No. X19-0383. The study will be conducted in accordance with the principles of the Declaration of Helsinki 2013, guidelines for Good Clinical Practice and the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007, updated 2018 and as amended periodically). Results will be disseminated using a range of media channels including newsletters, social media, scientific conferences and peer-reviewed publications.Trial registration numberACTRN12620000087954; Pre-results.

Diffuse glioma is characterized by a poor prognosis and a universal resistance to therapy, though the evolutionary processes behind this resistance remain unclear. The Glioma Longitudinal Analysis (GLASS) Consortium has previously demonstrated that therapy-induced selective pressures shape the genetic evolution of glioma in a stochastic manner. However, single-cell studies have revealed that malignant glioma cells are highly plastic and transition their cell state in response to diverse challenges, including changes in the microenvironment and the administration of standard-of-care therapy. To interrogate the factors driving therapy resistance in diffuse glioma, we collected and analyzed RNA- and/or DNA-sequencing data from temporally separated tumor pairs of over 300 adult patients with IDH-wild-type or IDH-mutant glioma. In a subset of these tumor pairs, we complemented these data with single-nucleus RNAseq and multiplex imaging mass cytometry at each time point. Recurrent tumors exhibited diverse changes that were attributable to changes in histological features, somatic alterations, and microenvironment interactions. IDH-wild-type tumors overall were more invasive at recurrence and exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. In contrast, recurrent IDH-mutant tumors exhibited a significant increase in proliferative expression programs that correlated with discrete genetic changes. Hypermutation and acquired CDKN2A homozygous deletions associated with an increase in proliferating stem-like malignant cells at recurrence in both glioma subtypes, reflecting active tumor expansion. A transition to the mesenchymal phenotype was associated with the presence of a specific myeloid cell state defined by unique ligand-receptor interactions with malignant cells, providing opportunities to target this transition through therapy. Collectively, our results uncover recurrence-associated changes in genetics and the microenvironment that can be targeted to shape disease progression following initial diagnosis.

Simple Summary Radiotherapy (RT) is an effective treatment for head and neck squamous cell carcinoma (HNSCC). Concurrent RT with high dose cisplatin (100 mg/m2, days 1, 22, and 42) is the standard of care (SOC) for non-operative HNSCC in curative settings, however, it is associated with both significant toxicities. In this review, we discussed the evidence of combination of anti-epidermal growth factor receptor, cetuximab, or immune checkpoint inhibitors (ICIs) with RT to compare with SOC. Cetuximab has been shown to be a less effective agent than cisplatin multiple recent trials, but it remains a reasonable alternative for those who are not fit for cisplatin. ICIs are active agents in recurrent and metastatic HNSCC. The role of ICIs with RT in the curative setting is yet to be defined. Multiple clinical trials are currently recruiting. Combining ICIs with stereotactic body radiotherapy (SBRT) is an attractive treatment in patients with oligometastatic or oligoprogressive HNSCC to boost the anti-tumor immune response. Abstract Radiotherapy plays an important role of managing head and neck squamous cell carcinoma (HNSCC). Concurrent radiotherapy with radiosensitizing cisplastin chemotherapy is the standard of care (SOC) for non-operable locally advanced HNSCC. Cetuximab, a monoclonal antibody of epidermal growth factor receptor, was the most extensively studied targeted therapy as a chemo-sparing agent that was used concurrently with radiotherapy. Immunotherapy is used in the treatment of metastatic HNSCC. There is evidence to support the synergistic effect when combining radiotherapy with immunotherapy to potentiate anti-tumor immune response. There has been increasing interest to incorporate immune checkpoint inhibitor (ICI) with radiotherapy in the curative setting for HNSCC. In this review, we discuss the latest evidence that supports concurrent radiotherapy with cisplatin which remains the SOC for locally advanced HNSCC (LA-HNSCC). Cetuximab is suitable for patients who are not fit for cisplatin. We then summarize the clinical trials that incorporate ICI with radiotherapy for LA-HNSCC in concurrent, neoadjuvant, and adjuvant settings. We also discuss the potential of combining immunotherapy with radiotherapy as a treatment de-escalating strategy in HPV-associated oropharyngeal carcinoma. Finally, the pre-clinical and clinical evidence of the abscopal effect when combining stereotactic body radiotherapy with ICIs is presented.

Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5–1.5 mg/kg) on days 1 and 15, and TMZ (150–200 mg/m2) on days 1–5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20–79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

Simple Summary A key molecule, EGFRvIII has been shown to provide several growth advantages for brain tumors. However, we have found a new mechanism in which the EGFRvIII provides increased survival to brain cancer cells when under sub-optimal conditions. Specifically, we have found that the EGFRvIII drives the expression of a molecule called Reticulocalbin 1 (RCN1) and that RCN1 blocks cell stress and cell death, thereby allowing cells to survive and proliferate. Importantly, these findings will allow for the generation of drugs that block the function of EGFRvIII and RCN1 with the hope that these drugs will induce brain cancer cell death. Abstract Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab (TTAC-0001) is a fully humanised VEGFR2 Mab that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of Olinvacimab in recurrent GBM. We conducted a two-site, 3 arm, open-label study of Olinvacimab in recurrent GBM. Eligible patients were ≥18 years with RANO-measurable lesion, KPS ≥ 80, and had completed chemoradiotherapy without prior bevacizumab therapy. We assessed three arms, 8 mg/kg and 12mg/kg weekly for 3 of every 4 weeks, and 12 mg/kg weekly. Three patients were treated in arms 1 and 2 and 6 in arm 3. Safety assessments were performed prior to dose escalation. The main toxicity was development of grade 1 (67%) and 2 (8%%) cutaneous haemangiomas. Common toxicities seen with other VEGF directed therapies, including hypertension, impaired wound healing, and proteinuria were not seen in this cohort. Efficacy was assessed by MRI using RANO criteria. 6 month PFS was 17%, with disease control in 25%, with steroid dose reduction. The longest response was 15 months. On DCE MRI, there was no significant difference in perfusion parameters between baseline and 1st follow-up MRI comparing those with SD and PD. However, 6 of 12 patients showed decreased Ktrans > 20 % of baseline, consistent with an anti-angiogenic effect of Olinvacimab. Pharmacokinetics showed a decreased clearance rate and increased half-life of Olinvacimab compared to the prior Phase I study. Pharmacodynamic studies showed significantly higher levels of angiogenic markers, particularly VEGF-A in those treated at 12mg/kg vs arm 1. VEGF-A, C and D levels were elevated in patients with SD compared to those with PD. Conclusion: Olinvacimab was well tolerated with a different toxicity profile to other VEGFR directed therapies. There were promising responses in 25% of patients.

Background AK117 is a novel humanized IgG4 monoclonal antibody (mAb) targeting CD47, a macrophage immune checkpoint and ‘don’t eat me’ signal that allows tumor cells to evade immune destruction by phagocytic cells. Most human cancers express CD47 to varying degrees, making CD47 a universal target. The efficacy of anti-CD47 therapy has been studied, as monotherapy and in combination with other antineoplastic agents, in various malignancies, including acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, colorectal cancer, hepatocellular carcinoma and breast cancer. Anemia is common with anti-CD47 therapy because CD47 is ubiquitously expressed on senescent red blood cells (RBCs). However, in comparison to other anti-CD7 mAbs, AK117 exhibits significantly weaker binding to human RBCs than tumor cells. In both in vitro and in vivo nonclinical studies, AK117 demonstrated robust anti-tumor activity without causing significant agglutination of human RBCs in vitro or anemia in monkeys. Methods This is a first-in-human, Phase 1, multicenter, open label, single arm, dose escalation and dose expansion study of AK117 administered intravenously to adult subjects with relapsed/refractory advanced or metastatic solid tumors or lymphomas. The primary objective is to assess the safety and tolerability of AK117 monotherapy; and determine the maximum tolerated dose (MTD). Antitumor activity, PK, pharmacodynamic profile and immunogenicity of AK117 will be studied as secondary objectives.The dose escalation parts of the study uses a 3+3+3 design to determine the Recommended Phase 2 Dose (RP2D) dose between 0.3 mg/kg to 45 mg/kg QW. Dose escalation is performed exclusively in solid tumors; and any dose escalation cohort not exceeding the MTD may be expanded up to a maximum of approximately 18 subjects, with a minimum of 6 subjects with lymphomas, to provide additional clinical data to inform the optimal dose level and treatment schedule for tumor type-specific dose expansion and subsequent clinical studies. In the dose expansion phase, AK117 will be studied in cohorts of 30 subjects each with selected solid tumors and selected lymphomas.Subjects with active or prior autoimmune disease that may relapse, history of hemolytic anemia of any cause within 3 months of first dose, hemophagocytic lymphohistiocytosis, defects in RBC production; or defects in hemoglobin production or metabolism will not be eligible for this study. Results N/A Conclusions N/A Trial Registration NCT04349969 Ethics Approval The study was approved by Bellberry Human Research Ethics Committee (Application No. 2020-02-016).

Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a 89Zr-labeled immunoconjugate&mdash, ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using 89Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.

Antibody–drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.

The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with tumor initiation, angiogenesis and metastasis. Eph receptors are thus attractive therapeutic targets, and monoclonal antibodies have been commonly developed and tested for anti-cancer activity in preclinical models, and in some cases in the clinic. This review summarizes 20 years of research on various antibody-based approaches to target Eph receptors in tumors and the tumor microenvironment, including their mode of action, tumor specificity, and efficacy in pre-clinical and clinical testing.

BACKGROUND Approximately 50% of nGBMs harbor EGFR-amp. Depatuxizumab mafodotin (depatux-m) is an antibody drug conjugate: a monoclonal antibody that binds activated EGFR (wild-type and EGFRvIII mutant) linked to a microtubule-inhibitor toxin. Pre-clinical and earlier clinical trials suggested efficacy. METHODS RTOGF 3508/AbbVie M13-813 (INTELLANCE-1, NCT02573324) was a phase 3 academic-industry collaboration (RTOG-Foundation, AbbVie). Eligible adults (KPS ≥ 70, EGFR-amp nGBM, centrally confirmed histology and biomarkers) were randomized 1:1 to radiotherapy (RT) and temozolomide and either depatux-m (2.0 mg/kg during RT, 1.25 mg/kg thereafter, q 14 days) or placebo, stratified by region of world, RPA class, MGMT methylation, and EGFRvIII mutation. Primary endpoint was overall survival (OS), with 640 patients planned for randomization; 441 events yielded 85% power to detect 25% reduction in hazard of death (HR 0.75), one-sided 2.5% level of significance by stratified weighted log-rank. RESULTS 2229 patients were screened and 639 (median age 60, range 22–84; 394 men, 62%) randomized. Pre-specified interim analysis after 346 events (≥ 75% required) found no OS improvement for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.01, 95% CI 0.82–1.25, one-sided p= 0.63). Progression-free survival (PFS) trended toward depatux-m (median 8.0 vs. 6.3 months; HR 0.84, 95% CI 0.70–1.02), particularly among the ~50% with EGFRvIII mutation (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93) but without an OS improvement (median 19.8 vs. 18.2, HR=0.95, 95% CI 0.71–1.27). Ocular side effects (grade ≥ 1) occurred in 95% of depatux-m treated patients, 61% grade 3–4, causing 12% to discontinue, and were the most common treatment related adverse events. CONCLUSION Interim analysis demonstrated no OS benefit for treating EGFR-amp nGBM with depatux-m. PFS trended toward favoring depatux-m, particularly in the EGFRvIII harboring subgroup. No new important safety risks were identified. The trial was stopped for futility. Active patients are permitted to continue treatment.

Purpose: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation among fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods. Experimental Design: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH (N = 206) and whole-exome sequencing (WES, N = 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N = 206) and transcriptome profiling (RNAseq, N = 64). EGFR protein expression was determined by immunohistochemistry (IHC, N = 34). Significant correlations among various methods were determined using Cohen's kappa (κ = 0.61–0.80 defines substantial agreement) or R2 statistics. Results: EGFR mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with EGFR amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating EGFR amplification. Conclusions: Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches.

Background The objective of this study was to describe the implementation of comprehensive geriatric assessment (CGA) in clinical trials dedicated to older patients before and after the creation of the International Society of Geriatric Oncology in the early 2000s. Subjects, Materials, and Methods All phase I, II, and III trials dedicated to the treatment of cancer among older patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. We considered that a CGA was performed when the authors indicated an intention to do so in the Methods section of the article. We collected each geriatric domain assessed using a validated tool even in the absence of a clear CGA, including nutritional, functional, cognitive, and psychological status, comorbidity, comedication, overmedication, social status and support, and geriatric syndromes. Results A total of 260 clinical trials dedicated to older patients were identified over the two time periods: 27 phase I, 193 phase II, and 40 phase III trials. CGA was used in 9% and 8% of phase II and III trials, respectively; it was never used in phase I trials. Performance status was reported in 67%, 79%, and 75% of phase I, II, and III trials, respectively. Functional assessment was reported in 4%, 11%, and 13% of phase I, II, and III trials, respectively. Between the two time periods, use of CGA increased from 1% to 11% (p = .0051) and assessment of functional status increased from 3% to 14% (p = .0094). Conclusion The use of CGA in trials dedicated to older patients increased significantly but remained insufficient.

BACKGROUND: Durva is a human IgG1 mAb against PD-L1. Blockade of PD-1/PD-L1 has shown benefit among solid tumors; data implicate PD-1/PD-L1 signaling as a significant contributor to immunosuppression in GBM. BEV is an approved angiogenesis inhibitor for recurrent GBM; angiogenesis inhibition may promote antitumor benefit of immunotherapies. A review showed that lower dose BEV resulted in longer PFS/OS than the standard. METHODS: Ongoing Phase 2 open-label study (NCT02336165) evaluates safety and efficacy of durva (10mg/kg Q2W) in 5 GBM cohorts. Results are presented for Cohorts B2 (durva + BEV 10mg/kg Q2W) and B3 (durva +BEV 3mg/kg Q2W) in BEV-naïve recurrent GBM. Primary efficacy endpoint for Cohorts B2/B3 is 6-month progression-free survival (PFS6), by modified RANO per investigator assessment; secondary endpoints include safety/tolerability. Comparative benchmark for BEV in recurrent GBM is PFS6 of 42%. The null hypothesis (PFS6 ≤42%) was tested in Intent-to-Treat (ITT) population against the alternative hypothesis (PFS6 ≥62%). ITT includes patients receiving any dose of durva and having at least baseline and 1 post-baseline tumor assessment. Durva alone in Cohort B of this study demonstrated PFS6 of 20% (90% CI: 9.7, 33.0). RESULTS: As of 02Apr2018, 33 patients were treated in each cohort (B2, male: 54.5%, median age: 57.0 [40–74] years; B3, male: 60.6%, median age: 54.0 [23–73] years). Most common treatment-related adverse events (TRAEs, in ≥4 [12.1%] patients in either cohort): fatigue, dysphonia, increased ALT, AST, amylase, or lipase, diarrhea, hypertension, arthralgia, headache, and proteinuria. Incidences of TRAEs by maximum CTCAE grade (Gr) ≥3 for Cohorts B2/B3 were Gr3: 24.2/6.1%; Gr4: 0/6.1%; and Gr5: 0/0%. Kaplan-Meier estimate for PFS6 (n=33 each): B2, 15.2% (80% CI: 8.2, 24.0); B3, 21.1% (80% CI: 12.4, 31.4); 3 patients in each cohort showed partial response. CONCLUSIONS: The addition of durva to BEV did not improve on the outcome of durva alone.

BACKGROUND: Depatuxizumab mafodotin (depatux-m, formerly ABT-414) is an EGFR-directed antibody-drug conjugate being developed for treatment of EGFR-amplified glioblastoma (GBM). As therapeutic pressure engenders tumor adaptations, it is important to understand the stability of biomarkers targeted by precision medicine approaches such as depatux-m. Therefore, we assessed EGFR amplification (amp) and expression in longitudinally-sampled GBMs from patients (pts) treated +/- depatux-m to explore biomarker stability. MATERIAL AND METHODS: Formalin-fixed, paraffin embedded GBM tumor tissue was analyzed from 68 patients who underwent at least 2 surgeries; EGFR amp was detected by in situ hybridization (e.g., FISH) or next-generation sequencing in all samples. Fifty-six pts did not receive depatux-m; among 12 pts who did, EGFR expression was also evaluated by RNA sequencing. RESULTS: Of 56 pts who did not receive depatux-m, 31 (55%) had tumors harboring EGFR amp at 1st surgery (initial diagnosis); among those, EGFR amp was maintained at re-operation in 27 (87%), and not maintained in 4 (13%). None of the 25 cases without baseline EGFR amp acquired it at the 2nd surgery. Of 12 pts treated with depatux-m between surgeries, 9 cases harbored EGFR amp at baseline which was maintained in 4 (44%) at the 2(nd) surgery, all 4 of which had the highest levels of EGFR expression at baseline. Of the 3 cases without EGFR amp at baseline, none acquired amplification at the 2(nd) surgery, and all 3 had the lowest levels of EGFR expression at study start. CONCLUSION: The presence of EGFR amp in GBM tissue at baseline was maintained at 2(nd) surgery in 87% of pts who received treatment other than depatux-m, and in 44% following depatux-m exposure. Therefore, depatux-m exposure appears to reduce EGFR amp maintenance (p=0.0159 by Fisher’s exact test); accordingly, the therapeutic approach may influence EGFR status. In no case was EGFR amp acquired at recurrence, regardless of depatux-m therapy. Ongoing analyses of additional tumor samples will increase power and further examine concordance among EGFR amp assays.

Background Physicians need well-addressed clinical trials assessing benefits and harm of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to present an overview of end points used in clinical trials dedicated to elderly patients; and to assess the evolution in chosen end points before and after the creation of the International Society of Geriatric Oncology in the early 2000s. Patients and methods All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to identify subgroup analyses of elderly patients among these trials. Results Among phase III trials dedicated to elderly patients, overall survival was a common primary end point. Interestingly, tumor centered end points were very common in the first time period and very uncommon in the second time period, whereas composite end points were very uncommon in the first time period but very common in the second time period. Concerningly, disease-specific survival was very infrequently reported in dedicated clinical trials of elderly patients despite their importance in evaluating competing risk of death from non-oncology causes. The use of patient-reported outcomes (PROs) as a primary end point remained very uncommon but the reporting of PROs as a secondary end point tended to increase in the second time period, from 19% to 33% (P = 0.10). Functional status was infrequently reported. Conclusion During the past decade, the use of clinically meaningful end points such as PROs and functional status in elderly patients remained moderate. Yet, the use of PROs as a secondary end point tended to increase between the two time periods.

This paper presents results from the phase I study of the focal adhesion kinase inhibitor GSK2256098 in patients with advanced solid tumors. The MTD was identified as 1000 mg, oral BID. Treatment with GSK2256098 showed a good tolerability, evidence of target engagement, and clinical activity in patients with recurrent, merlin-negative mesothelioma. Background Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. Patients and methods The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. Results Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21–84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1–2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4–9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (−26%) and three patients with mesothelioma (−13%, −15%, and −17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). Conclusions GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

International audience; BACKGROUND: Physicians need clinical trials assessing benefits and harms of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to examine how data regarding elderly oncology patients were presented in medical literature; and to assess the evolution of this presentation between two time periods. PATIENTS AND METHODS: All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to evaluate potential subgroup analyses in elderly patients in these studies. Key characteristics of interest were extracted by two investigators before descriptive and comparative analyses were undertaken. RESULTS: A total of 1084 trials were included: 366 and 718 from the first and second time period, respectively. Twenty-seven and 193 of these trials were phase I and II trials dedicated to elderly or frail patients, respectively. A large proportion of phase III trials published between 2011 and 2014 reported at least one analysis dedicated to elderly patients (46.7%) versus 19.3% during the first time period. The use of subgroup analyses of elderly patients in phase III trials was the most frequent source of information. Subgroup analyses were more frequent among trials with industrial funding, trials published in high impact factor journal, intercontinental trials and trials with large sample size. The age threshold defining the elderly subgroup increased over time. CONCLUSION: Elderly patients have become a topic of interest during the past decade. However, data available are mostly extracted from subgroup analyses, which can only be regarded as preliminary evidence.

Purpose: The aims of the study were to develop and evaluate a novel residualizing peptide for labeling internalizing antibodies with 124 I to support clinical development using immuno-positron emission tomography (PET). Methods: The anti-epidermal growth factor receptor antibody ch806 was radiolabeled directly or indirectly with isotopes and various residualizing peptides. Azido-derivatized radiolabeled peptides were conjugated to dibenzylcyclooctyne-derivatized ch806 antibody via click chemistry. The radiochemical purities, antigen-expressing U87MG.de2-7 human glioblastoma cell-binding properties, and targeting of xenografts at 72 hours post injection of all radioconjugates were compared. Biodistribution of 124 I-PEG 4 -tptddYddtpt-ch806 and immuno-PET imaging were evaluated in tumor-bearing mice. Results: Biodistribution studies using xenografts at 72 hours post injection showed that 131 I-PEG 4 -tptddYddtpt-ch806 tumor uptake was similar to 111 In-CHX-A″-DTPA-ch806. 125 I-PEG 4 -tptddyddtpt-ch806 showed a lower tumor uptake value but higher than directly labeled 125 I-ch806. 124 I-PEG 4 -tptddYddtpt-ch806 was produced at 23% labeling efficiency, 98% radiochemical purity, 25.9 MBq/mg specific activity, and 64% cell binding in the presence of antigen excess. Tumor uptake for 124 I-PEG 4 -tptddYddtpt-ch806 was similar to 111 In-CHX-A″-DTPA-ch806. High-resolution immuno-PET/magnetic resonance imaging of tumors showed good correlation with biodistribution data. Conclusions: The mixed d / l -enantiomeric peptide, d Thr- d Pro- d Thr- dA sp -dA sp-Tyr -dA sp -dA sp- d Thr- d Pro- d Thr, is suitable for radiolabeling antibodies with radiohalogens such as 124 I for high-resolution immuno-PET imaging of tumors and for evaluation in early-phase clinical trials.

International audience; BACKGROUND: Randomised controlled trials (RCTs) represent a major source of information on treatment-related adverse events (AEs). In this study, we reviewed the use and the reporting methods of aggregated-AEs (A-AEs) outcomes in RCTs reports published in oncology and compared that to the expectations of European Organisation for Research and Treatment of Cancer (EORTC) membership. METHODS: RCTs reports published between 2007 and 2011 were reviewed regarding the reporting of A-AEs-outcomes. A-AEs were defined as summary outcome combining several related AEs, usually grouped by organ system e.g. cardiac-AEs, dermatologic-AEs. Trial characteristics associated with the use of A-AEs outcomes were investigated. The expectation of EORTC members concerning A-AEs utilisation was queried through a survey. RESULTS: Among 325 RCTs published between 2007 and 2011, 94 (29%) included one or more A-AE outcomes. A clear description of the nature of AEs included in such aggregations was provided in 19 articles (20%). No description of A-AEs was conversely provided in the other 75 articles (80%). The most commonly used A-AEs-outcomes were dermatologic-AEs (45%) and cardiac-AEs (33%). In multivariate analysis, the use of A-AEs outcomes was more frequent when trials were conducted in Europe (p = 0.038) and in trials performed on colon/rectal cancers (p = 0.016). Finally, there is no consensus of EORTC members regarding the utilisation of A-AEs but a majority of them (88%) felt that a clear description of A-AEs should systematically be reported. CONCLUSIONS: The use of A-AEs is infrequent in oncology RCT manuscripts although their use is accepted by most clinicians. However, a clear definition of A-AEs is strongly recommended if they are to be used in order to avoid a loss of important details about drug toxicities that is useful to clinicians

International audience; BACKGROUND: Determination of drug safety and tolerability is usually based on the frequency of certain key adverse events (AEs) rather than the frequency of all-grade toxicities. We assessed the reporting of key AEs in oncology randomized, controlled trials (RCTs) and compared that with the expectations of the European Organization for Research and Treatment of Cancer (EORTC) membership. MATERIALS AND METHODS: RCTs reports published between 2007 and 2011 were reviewed regarding the reporting of key AEs, namely: grade 3/4 AEs, grade 5 AEs, and AEs resulting in study withdrawal or in dose reduction. Study characteristics associated with better reporting of key AEs were investigated. Finally, a survey was conducted among the EORTC membership to determine their expectations on key AEs reporting. RESULTS: Although the frequency of grade 3/4 was reported in most reports (96%), only 17% of them described the reporting threshold above which grade 3/4 AEs were included for reporting, raising the possibility that important but less frequent grade 3/4 AEs might be underreported. Frequency and nature of grade 5 AEs were adequately reported in 161 (50%) of manuscripts; AEs leading to study withdrawal in 61 manuscripts (19%); and AEs leading to dose reduction in 43 manuscripts (13%). In contrast, most EORTC members expected a comprehensive reporting of grade 5 AEs (96% of EORTC member's responses), AEs leading to study withdrawal (86%) and AEs leading to dose reduction (70%). In multivariate analysis, frequencies of grade 5 AEs were less frequently reported in European trials (P = 0.004). Frequencies of AEs leading to withdrawals were more frequently reported in trials funded by industry (P = 0.005) and in trials including patients with breast or urological cancers (P = 0.006). CONCLUSIONS: These findings suggest that current practice of key AEs reporting remains highly variable and sometimes inadequate in oncology RCTs reports. Current standards for safety reporting in RCTs should be revised to emphasize the importance of key AEs reporting

The toxicities of new, targeted drugs may diminish their effectiveness in advanced kidney cancer if those toxicities are not recognized and properly addressed early in patient treatment. Most of the drug-related toxicities in advanced kidney cancer are manageable with supportive care, obviating a need for long interruptions, dose reductions, or permanent discontinuation of the treatment.

We report the generation of a chimeric monoclonal antibody (ch806) with specificity for an epitope on the epidermal growth factor receptor (EGFR) that is different from that targeted by all other anti-EGFR therapies. Ch806 antibody is reactive to both de2-7 and overexpressed wild-type (wt) EGFR but not native EGFR expressed in normal tissues at physiological levels. Ch806 was stably expressed in CHO (DHFR -/-) cells and purified for subsequent characterisation and validated for use in preliminary immunotherapy investigations. Ch806 retained the antigen binding specificity and affinity of the murine parental antibody. Furthermore, ch806 displayed enhanced antibody-dependent cellular cytotoxicity against target cells expressing the 806 antigen in the presence of human effector cells. Ch806 was successfully radiolabelled with both iodine-125 and indium-111 without loss of antigen binding affinity or specificity. The radioimmunoconjugates were stable in the presence of human serum at 37 degrees C for up to 9 days and displayed a terminal half-life (T(1/2beta)) of approximately 78 h in nude mice. Biodistribution studies undertaken in BALB/c nude mice bearing de2-7 EGFR-expressing or amplified EGFR-expressing xenografts revealed that (125)I-labelled ch806 failed to display any significant tumour retention. However, specific and prolonged tumour localisation of (111)In-labelled ch806 was demonstrated with uptake of 31%ID g(-1) and a tumour to blood ratio of 5 : 1 observed at 7 days postinjection. In vivo therapy studies with ch806 demonstrated significant antitumour effects on established de2-7 EGFR xenografts in BALB/c nude mice compared to control, and both murine 806 and the anti-EGFR 528 antibodies. These results support a potential therapeutic role of ch806 in the treatment of suitable EGFR-expressing tumours, and warrants further investigation of the potential of ch806 as a therapeutic agent.

Background Statistical simulations have consistently demonstrated that new dose-escalation designs such as accelerated titration design (ATD) and continual reassessment method (CRM)-type designs outperform the standard “3+3” design in phase I cancer clinical trials. Methods We evaluated the actual efficiency of different dose escalation methods employed in first-in-human phase I clinical trials of targeted agents administered as single agents published over the last decade. Results Forty-nine per cent of the 84 retrieved trials used the standard “3+3” design. Newer designs used included ATD in 42%, modified CRM [mCRM] in 7%, and pharmacologically guided dose escalation in 1%. The median numbers of dose levels explored in trials using “3+3”, ATD and mCRM designs were 6, 8 and 10, respectively. More strikingly, the mean MTD to starting dose ratio appeared to be at least twice as high for trials using mCRM or ATD designs as for trials using a standard “3+3” design. Despite this, the mean number of patients exposed to a dose below the MTD was similar in trials using “3+3”, ATD and mCRM designs. Conclusion Our results support a more extensive implementation of innovative dose escalation designs such as mCRM and ATD in phase I cancer clinical trials of molecularly targeted agents.

BACKGROUND The Consolidated Standards of Reporting Trials (CONSORT) guidelines were developed in the mid-1990s for the explicit purpose of improving clinical trial reporting. However, there is little information regarding the adherence to CONSORT guidelines of recent publications of randomized controlled trials (RCTs) in oncology. METHODS All phase III RCTs published between 2005 and 2009 were reviewed using an 18-point overall quality score for reporting based on the 2001 CONSORT statement. Multivariable linear regression was used to identify features associated with improved reporting quality. To provide baseline data for future evaluations of reporting quality, RCTs were also assessed according to the 2010 revised CONSORT statement. All statistical tests were two-sided. RESULTS A total of 357 RCTs were reviewed. The mean 2001 overall quality score was 13.4 on a scale of 0-18, whereas the mean 2010 overall quality score was 19.3 on a scale of 0-27. The overall RCT reporting quality score improved by 0.21 points per year from 2005 to 2009. Poorly reported items included method used to generate the random allocation (adequately reported in 29% of trials), whether and how blinding was applied (41%), method of allocation concealment (51%), and participant flow (59%). High impact factor (IF, P = .003), recent publication date (P = .008), and geographic origin of RCTs (P = .003) were independent factors statistically significantly associated with higher reporting quality in a multivariable regression model. Sample size, tumor type, and positivity of trial results were not associated with higher reporting quality, whereas funding source and treatment type had a borderline statistically significant impact. CONCLUSION The results show that numerous items remained unreported for many trials. Thus, given the potential impact of poorly reported trials, oncology journals should require even stricter adherence to the CONSORT guidelines.

Neurolymphomatosis (NL) is an uncommon syndrome of peripheral or cranial nerve root dysfunction secondary to infiltration by B-cell non-Hodgkin's lymphoma (NHL). A high index of suspicion is required as presenting symptoms are varied, conventional radiology has only modest sensitivity, and pathological diagnosis is often difficult. Treatment with chemotherapy alone has an objective response rate of 82%, although long-term outcomes are highly variable. This case series describes outcomes in four patients whose management incorporated PET scanning and the use of rituximab in combination with chemotherapy. PET scanning could often diagnose NL where other diagnostic modalities were non-diagnostic. Although combination therapy with rituximab and chemotherapy has been shown to be superior to chemotherapy alone in other forms of NHL, this does not appear to be the case in patients with NL. This may reflect the inability of rituximab to adequately penetrate into the central and peripheral nervous system. This is supported by the common finding that patients will relapse solely with NL despite on-going complete remission at sites outside the nervous system. The prognosis of these patients is poor, with the disease often following a progressive course despite treatment.

Background The ability of recombinant antibodies to adequately penetrate into tumours is a key factor in achieving therapeutic effect; however, the behaviour of antibodies at a cellular level in tumours is poorly understood. The purpose of this study was to investigate those factors that influence the macroscopic and microscopic intratumoural distribution of an IgG1-humanized antibody, huA33, in colorectal tumours. Methods Twelve patients were infused with radiolabelled huA33 at 7 days prior to elective surgery for colorectal carcinoma. Macroscopic huA33 uptake was determined by both gamma well counter and autoradiography measurements of the resected tumour specimens. Microscopic uptake was then quantitated at a cellular level and compared to vascular penetrance. The impact of variation in tumour antigen (GPA33) expression, tumour size, specimen type (primary vs metastatic), presence of macroscopic necrosis, and tumour vasculature on huA33 uptake were examined. Results The I-huA33 uptake in whole tumour sections was (mean ± SD) 5.13 ± 2.71 × 10−3% injected dose per gram (ID/g). GPA33 was expressed in all viable tumour cells, and huA33 uptake was excellent regardless of tumour size and specimen type. In tumours with macroscopically evident central necrosis (n = 5), huA33 uptake in tumour necrotic centres was lower than in viable peripheries (0.606 ± 0.493 vs 2.98 ± 2.17 × 10−3%ID, p = 0.06). However, when corrected for low cell viability in necrotic centres, uptake of huA33 at the cellular level was highly comparable to that in the more viable tumour periphery (7.10 ± 5.10 × 10−9 vs 3.82 ± 3.67 × 10−9%ID/cell, p = 0.4). In the five patients who exhibited macroscopic necrosis in their tumours, huA33 showed excellent tissue penetration, with a maximum penetration distance of 26 μm in peripheral tumour regions and 118 μm in central regions. No correlation was observed between 131I-huA33 uptake in tumour on a cellular basis and tumour vascularity. Conclusions In patients with colorectal carcinoma, monoclonal antibody huA33 effectively targets viable tumour cells in all cellular milieus examined, including effective penetration into necrotic tumour centres, a novel and therapeutically important finding.