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Background Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. Methods In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. Results There were 639 randomized patients (median age 60, range 22–84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82–1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70–1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61–0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3–4), causing 12% to discontinue. Conclusions Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

BACKGROUND Nivolumab is a PD-1 inhibitor with known safety profile. An increase in mutations as we age is well documented in glioblastoma and other cancers. Higher mutational load is associated with increased response to nivolumab in extracranial malignancies. NUTMEG examined the activity of nivolumab added to temozolomide in glioblastoma patients aged ≥ 65 years. METHODS NUTMEG was an international multicenter phase II trial for newly diagnosed glioblastoma patients aged ≥ 65 years, randomized 2:1 to experimental (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide 150-200mg/m2 D1-5 Q28D + nivolumab 240mg D1,15 Q28D C1-4 and 480mg D1 Q28D C5-6) versus standard arm (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide alone 150-200mg/m2 D1-5 Q28D), stratified by age, ECOG status, MGMT status and resection extent. RESULTS 103 patients were enrolled (69 in experimental arm, 34 in standard arm). Median age was 73 years, 36% ECOG 0, 57% MGMT-unmethylated and 51% gross macroscopic resection. Median follow-up is 31 months to date, with 77 deaths (surviving patients to continue follow-up and final results will be presented). Median overall survival was 11.8 months in the experimental arm versus 12.0 months in the standard arm (HR 0.95 95%CI 0.59-1.53 for experimental relative to control). Six-month progression-free survival rate using mRANO was 64% in the experimental arm versus 49% in the standard arm (HR 0.81 95%CI 0.51-1.26). Grade 3/4 adverse events were reported in 46% of experimental arm (7% lung infection, 7% thromboembolic events, 6% fatigue, 6% muscle weakness) and in 29% of control arm (9% fatigue, 6% seizure, 6% thromboembolic events). CONCLUSIONS There was insufficient evidence of clinical benefit with nivolumab in this population. No new safety signals were identified. Central imaging review is underway and correlative studies will characterize the immune landscape, including mutational load, neoantigen and other immune markers. NCT04195139.

Diffuse midline glioma (DMG) is a high-grade glioma with a median overall survival of 9-11 months. Radiotherapy is the only recognized treatment. The DMG tumor microenvironment (TME) contains few, if any, tumor infiltrating lymphocytes (TILs) or inflammatory cytokines, thus is distinctive of an ‘immunologically cold’ tumor/TME.1 DMG lack the expression of immunosuppressive immune checkpoint proteins, likely explaining the failure of immune checkpoint inhibitors (ICI) tested under clinical trials for DMG patients, and suggestive of an alternative mechanism underpinning the cold TME. 1 Glioblastomas also harbor a cold TME, which can be somewhat explained by T cell lymphopenia, influenced by the sequestration of T cells in the bone marrow (through Beta-arrestin-induced internalization of Sphingosine-1-phosphate receptor 1 [S1PR1]). 2 Dopaminergic activation of Beta-arrestin and hence S1PR1 internalization, is potentially regulated through dopaminergic peripheral nerves in primary and secondary lymphoid organs, regulated by the Dopamine receptor D2 (DRD2), that is highly expressed on T cells. ONC201 is a potent DRD2 antagonist, currently in phase I-III clinical trials for DMG patients, alone and in combination with radiotherapy and the PI3K/AKT inhibitor paxalisib (NCT05009992). Proteomic profiling of DMG patient-derived cells +/-ONC201 showed increased expression of several antigen presenting pathway proteins, including Beta-2-microglobulin (B2M) and HLA class I histocompatibility antigen, A alpha chain (HLA-A). This was confirmed in vivo using SU-DIPG-VI patient-derived xenograft mouse model tissues +/-ONC201 alone, and together with paxalisib. Excitingly, this combination (given orally) promoted the recruitment of TILs to the tumor, revealing novel immunomodulatory effects. In vivo, ONC201 promoted the expression of EMILIN-3, a TGF-β antagonist that is known to inhibit HLA-A/B2M expression, possibly explaining the increased MHC-I activity. This study uncovers a novel link between treatment of DMG with ONC201 and paxalisib and the role dopaminergic peripheral nerves signaling may play on the sequestration of T cells within lymphoid organs and lymphopenia.

BACKGROUND Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide. METHODS Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities. PROGRESS Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.

RTOG 3508/AbbVie M13-813/INTELLANCE-1 was a phase 3 trial of depatuximab-mafodotin (depatux-m, formerly ABT-414) that accrued 639 patients with EGFR-amplified newly diagnosed GBM. At the pre-specified interim OS analysis, the futility criteria were met and there was no survival benefit from adding depatux-m to SOC. Pre-specified secondary NCF analyses included time to decline in verbal learning and memory as assessed by the HVLT-R Total Recall based on the reliable change index. Exploratory NCF analyses examined changes in other HVLT-R outcomes over time. As corneal epitheliopathy causing visual impairment is a known toxicity of depatux-m, NCF tests that did not depend on visual acuity were employed. NCF testing occurred at baseline, day 1 of the first cycle of adjuvant depatux-m, every other cycle (i.e., 8 weeks) thereafter, and at progression. Compliance with test completion was 95% at screening and 80%, 70%, 58%, 51%, 47% thereafter through cycle 9. The most common reasons for missing data was site error. Time to HVLT-R Total Recall decline trended worse in the depatux-m arm compared to placebo but the difference was not significant (12 month deterioration: 41.2%, 95% CI: 3.50–47.2 vs 32.4%, 95% CI: 26.6- 38.4, p=0.052). The depatux-m arm, in comparison to the placebo arm, showed greater decline from baseline on the HVLT-R at the following time points: cycle 3 (Total Recall: mean= -1.8, SD=5.7 vs mean= -0.5, SD=5.5, respectively, p=0.046; Delayed Recall: mean= -1.1, SD=3.0 vs. mean= -0.2, SD=2.7, respectively, p=0.01), cycle 7 (Total Recall: mean= -0.6, SD=5.1 vs mean= 1.4, SD=5.0, respectively, p=0.009; Delayed Recall: mean -0.6, SD=3.0 vs. mean= 0.5, SD=2.7, respectively, p=0.01), and cycle 9 (Delayed Recall: mean=-0.4, SD=2.7 vs. mean= 0.8, SD=2.4, respectively, p=0.003). Depatux-m added to concurrent chemoradiation and adjuvant temozolomide was associated with faster time to deterioration and worse episodic learning and memory over time than placebo.

BACKGROUND: An increase of mutations as we age is well documented in GBM and in cancer in general. Elderly patients with GBM may have higher mutational burden and may be more likely to respond to immunotherapies. NUTMEG is a randomised Phase II study comparing post radiation NivolUmab and TMZ versus TMZ alone in Elderly patients with newly diagnosed GBM. METHODS: 102 patients will be randomized in a 2:1 allocation to receive short course RT (40Gy/15 daily fractions) and TMZ 75mg/m2) followed by 6 cycles of adjuvant TMZ (150-200mg/m2 days (D) 1–5 q28 days) with Nivolumab (240 mg D1, 15 q28 days for cycles (C) (1–4; 480 mg D1 Q 28 days for C5-6) versus 6 cycles of adjuvant TMZ (150-200mg/m2 D1-5 q28) alone. The study is stratified for ECOG performance status, age (< 70 vs 70), MGMT methylation and extent of resection. An independent safety monitoring committee is overseeing the trial and will review safety data for the first 10 patients treated on the experimental arm (TMZ + Nivolumab). The primary endpoint is Overall Survival (OS). Secondary endpoints include: 6 month Progression Free Survival, adverse events (AEs) and immune AEs, Quality of life, neurological function (NANO Scale), and correlation of modified RANO and iRANO in the experimental arm. Translational research endpoints include correlation of clinical endpoints with mutational burden, comprehensive immune characteristics and novel MRI sequences including pH-weighted MRIs. The expected proportion of patients alive at 24 months is predicted to be 15.7%. A hazard ratio of more than 0.69 in favour of the Nivolumab + TMZ arm will be considered sufficient to warrant further investigation including converting this study into a phase III trial. PROGRESS: At 3 June 2018, 6/18 study sites are open in Australia with 5 patients randomized. ACTRN12617000267358.

Although the measurements of clinical outcomes for cancer treatments have become diverse and complex, there remains a need for clear, easily interpreted representations of patients' experiences. With oncology trials increasingly reporting non-time-to-event outcomes, data visualization has evolved to incorporate parameters such as responses to therapy, duration and degree of response, and novel representations of underlying tumor biology. We review both commonly used and newly developed methods to display outcomes in oncology, with a focus on those that have evolved to represent complex datasets.