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Background: Both PD-L1 and VEGFR are legitimate therapeutic targets in recurrent glioblastoma (rGB). Axitinib, a potent, selective small molecule VEGFR 1-3 inhibitor with single-agent activity in rGB, may synergize with the PD-L1 blocking IgG1 mAb avelumab for the treatment of rGB. Methods: A phase II clinical trial investigating avelumab plus axitinib in patients (pts) with rGB is ongoing (NCT03291314). Pts with rGB are stratified according to their baseline use of corticosteroids (CS). Pts without baseline CS use initiated treatment with axitinib (AXI, 5 mg po BID) plus avelumab (AVELU, 10 mg/kg IV Q2w) (Cohort A). Pts with baseline CS use initiated AXI monotherapy (AXI mono); AVELU could be added after 6w if the CS dose could be tapered to ≤ 10 mg prednisolone (Cohort B). Results: From Jun 2017 to Jan 2018, 32 pts (med age 50y [range 29-70]; 62% male; 56% WHO PS 1 or 0) initiated study treatment (16 in Cohort A and 16 in -B) . All pts had failed prior radiotherapy and temozolomide. In Cohort B, 7 pts (44%)initiated treatment with AXI+AVELU after 6w of AXI mono. Treatment with AXI+AVELU was ongoing in 10 pts (across both cohorts). Safety data are available for a total of 280 AXI+AVELU treatment weeks (median 8w [range 4-30]/pt). Treatment-related AEs (TRAE) of any grade occurred in 100% of pts. All-cause grade 3 AE occurred in 10 (43%) pts; 7 [30%] pts experienced a grade 3 TRAE. There were no gr 4 or 5 AE. PD was the only reason for stopping AXI+AVELU treatment. Conclusions: The safety profile of avelumab plus axitinib appears manageable in pts with rGB. This clinical trial is currently being continued for the evaluation of efficacy.

After the first wave of the tsunami of immune checkpoint inhibitors, 2016 was marked by the second wave, revealed by numerous US FDA approvals, publications and abstracts in relation with these drugs in different cancers and settings. First, we reported all new indications of anti-CTLA4, anti-programmed cell death protein 1 and anti-PDL1 approved by the FDA, the positive clinical trials published and the abstracts reported at important scientific meetings during 2016. Then, we highlighted the updates on debatable issues related to checkpoint inhibitors, since the first wave published in a previous issue. We focused on the predictive biomarkers, combination therapies, tumor response patterns and efficacy in particular settings and the side effect management. Finally, the impact of checkpoint inhibitors development on the care management of cancer centers will be discussed.

e14012 Background: Intratumoral (IT) myDC play a pivotal role in initiating antitumor immune responses and "re-licensing” of antitumor cytotoxic T-lymphocytes within the tumor microenvironment. IT injection of anti-PD-L1 IgG1 mAb AVE and anti-CTLA-4 IgG1 mAb IPI may reduce the number of regulatory T cells and lyse PD-L1+ tumor cells, thereby releasing tumor antigens that can be captured and processed by IT co-administered CD1c (BDCA-1)+ myDC, reinvigorating the cancer immunity cycle. Methods: Patients (pts) with advanced solid tumors who failed standard therapy were eligible for IT injections of ≥1 non-visceral metastasis with IPI (max total dose of 10 mg) and AVE (max total dose of 40 mg) plus IV NIVO (10 mg) on day 1 followed by IT injection of autologous, non-substantially manipulated CD1c (BDCA-1)+ myDC on day 2. Administration of AVE, IPI, and NIVO was repeated every 14 days thereafter. Primary endpoints were safety and feasibility. Repetitive FNA cytology/IHC of treated lesions was performed. Results: In this ongoing trial, 6 pts (3x melanoma, 1x epithelial ovarian carcinoma, 2x triple negative breast carcinoma) were treated with IT injection of a median of 27,2x106 (range 10-43x106) CD1c (BDCA-1)+ myDC and a median of 5 (range 2-10) study drug administrations. At time of this analysis 3 pts are evaluable for response: an ongoing PR ( > 8 months) was documented in a melanoma pt who previously progressed on PD-1 and CTLA-4 inhibitors. In 2 other melanoma pts regression of the injected metastases coincided with progression of non-injected metastases. Adverse events consisted of transient grade(G)2 local pain at injection site in 2 pts, G1 pruritus in 2 pts, G2 pneumonitis in 1 pt, G1 rash in 1 pt, and pruritus and redness of the skin overlaying the injected lesion in 1 pt. Analysis of cytology/IHC results is ongoing. Conclusions: IT injection of autologous CD1c (BDCA-1)+ myDC with IT co-injection of AVE and IPI plus IV low-dose NIVO is feasible and tolerable and resulted in encouraging early signs of anti-tumor activity in injected as well as non-injected lesions. Clinical trial information: NCT03707808.

97 Background: Immunotherapy with the CTLA-4 blocking mAb ipilimumab (IPI) has improved the long-term (>3 y) survival of a subpopulation (15-20%) of patients (pts) with metastatic melanoma. Little is known about the psychosocial outcome and the long-term effects of immune-related adverse events in these survivors. Methods: Pts with advanced melanoma (AJCC stages IIIC or IV) who were in complete remission for at least 2 y after treatment initiation, were eligible for this ongoing study. Data on health related quality of life (HRQOL), psychosocial outcome and neurocognitive function (NCF) were collected using 5 validated questionnaires, a semi-structured psychiatric examination (SSPE), and computer-based NCF testing. Results: Test results from 17 pts (5 F/12 M), median age 57 y (range 33-86) were analyzed. Median time since start of IPI was 5.5 y (range 2-7). Seven pts (41%) had elevated scores on the Cognitive Failure Questionnaire (CFQ). Nine pts (53%) had elevated scores on the Hospitalization Depression Scale (HADS) indicating moderate anxiety (4 pts), severe anxiety (2 pts), and moderate depression (3 pts). The SSPE revealed that all 10 pts who were professionally active at the time of diagnosis, had to change or stop work due to their illness. Nine pts (53%) reported persisting emotional distress: anxiety, existential problems, survivor guilt, post-traumatic stress symptoms or daily worrying about the disease. Three pts were referred for suicidal ideation in relation with their disease. Four pts (24%) developed hypophysitis and suffered from comorbid depression (1 pt), adjustment disorder (2 pt), or post-traumatic stress disorder related to the symptoms of hypopituitarism (1 pt). Five years after the incidence of hypophysitis, all pts had elevated scores on the Fatigue Severity Scale, the HADS; and 3 pts on the CFQ. All cases of skin toxicity (8 pts), hepatitis (2 pts), colitis (2 pts), sarcoidosis (2 pts), and Guillain-Barre syndrome (1 pt) resolved without long-term impact on HRQOL. Conclusions: A majority of melanoma survivors treated with IPI continues to suffer from emotional distress and cognitive problems impacting their HRQOL. Timely detection and providing adaptive care is imperative.

PURPOSE OF REVIEW: The aim of this review is to draw the attention of the physicians and oncologists on the rare side-effects of checkpoint inhibitors not usually reported in clinical trials to treat them quickly and render their prognosis better. RECENT FINDINGS: Rare side-effects of checkpoint inhibitors are mainly neurologic, haematologic, rheumatologic, renal, and cardiac. The majority of reported side-effects are consequent of the treatment by ipilimumab in patients diagnosed with melanomas. Neurologic side-effects have poorer prognosis compared with other rare side-effects. There is no relationship between developing rare side-effects and the outcome of the disease. SUMMARY: It is important to be aware, when treating patients with checkpoint inhibitors, to detect as early as possible the unpredictable and uncontrollable rare side-effects of these agents. The large spectrum of these rare side-effects should be well documented and reported to assure to the physicians a road map for the diagnosis and the management of these toxicities.

2015 was marked by the tsunami of immune checkpoint inhibitors revealed by numerous FDA approvals, publications and abstracts in relation with these drugs in different cancers and settings. First, we reported all new indications of anti-CTLA4 and anti-PD1 approved by the FDA, the positive clinical trials published and the abstracts with promising results at important scientific meetings during 2015. Then, we discussed different critical issues of these new agents going from their predictive factors, combination therapies, tumor response patterns, efficacy in particular settings, side effect management to cost and economic burden.

Major advances in cancer research in the last two decades have provided us with a better understanding of the dynamics of the cancer cell and its microenvironment. This has consequently led to the development of new therapies and treatment strategies either targeting the cancer cell or the tumor microenvironment. In this review we will discuss the major existing and promising future treatment approaches in medical oncology. Therapies targeting the cancer cell include hormonal therapies, small molecules, and monoclonal antibodies. They are used mostly in the advanced disease setting. Strategies developed more recently are antibody drug conjugates (trastuzumab emtansine and radioimmunotherapy) and oncolytic viruses. Molecular therapies targeting the tumor microenvironment include angiogenesis inhibitors and the new agents and approaches that interfere with the immune system (immune checkpoint inhibitors and adoptive cell therapy). The development of resistance (primary and acquired) to targeted therapies is unfortunately a common phenomenon that can be overcome or delayed using multiple strategies like the use of second- or third-generation molecular therapies targeting the emerging resistant mutations or genetic abnormalities, multitargeted drugs, and drug combinations targeting the same or different proteins, and/or the use of modern immunotherapy. Molecular targeted therapies have a distinct array of side effects that can be mechanism-based, but can also be unpredictable. Although the progress in research brings a vast amount of new information about cancer and its environment, it renders the field of oncologic research more and more complex with fragmentation of tumor entities. These are important challenges for future research and precision oncology.

9585 Background: Optimal dosing and duration of adjuvant treatment with anti-PD-1 checkpoint inhibitors, e.g. nivolumab (NIVO), following complete resection of melanoma (MEL) lymph node metastases has not been established. We investigated a regimen of low-dose NIVO with/without low-dose ipilimumab (IPI) as adjuvant therapy in MEL pts. Methods: After complete resection of MM, pts were treated with IPI 50mg (fixed dose, 1x) plus NIVO 10mg (fixed dose, Q2w x4) (Cohort-A), or NIVO 10mg (Q2w x9, Q8w x4) (Cohort-B). One-year relapse-free survival (RFS) rate served as primary endpoint. Sample size (34 pts) was calculated according to a Fleming one-stage clinical trial design. Recruitment to Cohort-B was closed prematurely following registration of NIVO in the adjuvant setting by EMA. Secondary endpoints were safety, distant metastasis-free survival (DMFS) and overall survival (OS). Quantitative measurement of BRAF/ NRAS mutant circulating tumor DNA (ctDNA), as well as tumor gene expression profiling were performed. Results: 34 pts (15M/19F, 31 stage III/3 stage IV) and 22 pts (12M/10F, 21 stage III/1 stage IV) were enrolled in Cohort-A/-B, respectively. After a median follow-up of 86w for Cohort-A and 36w for Cohort-B, estimated 12 months (m) RFS-rate was respectively 55% (95% CI, 39–72) and 78% (95% CI, 73-82), 12m OS-rate was 97% (95% CI, 94-100) and 100%, and 12m DMFS-rate was 79% (95% CI, 92-65), no distant metastases occurred in Cohort-B. Median RFS for Cohort-A was 84w (95%, CI 28-139), not-reached in -B. Median DMFS and OS had not been reached at time of analysis in either cohort. All grade treatment-related adverse events were observed in 21 (61%)/17 (77%) with 3 (8%)/1 (4%) grade 3 irAE in Cohort-A/-B, respectively. One patient in Cohort-A had a detectable level of ctDNA at baseline and relapsed 33w after initiating treatment. Tumor profiling is ongoing at time of submission. Conclusions: The investigated adjuvant low-dose regimens have an acceptable safety profile. Survival rates resemble those of standard regimens. These regimens could be economically advantageous alternatives for pts without access to standard regimens. Clinical trial information: NCT02941744.

Background: Advanced Melanoma is a condition with a poor long-term prognosis and although the last few years there has been an enormous improvement due to the Immune Checkpoint Inhibitors (ICI), only a subset of patients benefit. Biomarkers to better guide treatment decisions are being investigated. In this study we aimed to investigate the role of pre-treatment 18F-FDG PET/CT as a predictor of survival after pembrolizumab treatment. Methods: Between Sep 2014 and Apr 2016, 141 patients where selected for therapy with pembrolizumab (2 mg/kg q3wks). Of those patients, 69 had undergone 18F-FDG PET/CT within 6 weeks prior to treatment initiation and were eligible for analysis. In these patients, the Total Metabolic Tumor Volume (TMTV) and the Total Lesional Glycolysis (TLG) was measured. A log rank was performed to correlate TMTV, TLG, LDH and presence of brain metastasis to overall survival (OS) and progression free survival (PFS) after pembrolizumab administration. Multivariate analysis was conducted for selected parameters. For each parameter, treshold values were determined to dichotomize the patients, prior to analysis. Results: The analyses showed that the TMTV (higher than 90 ml vs lower) is the best independent predictor of the OS and PFS in this patient cohort. The subgroup with a volume higher than 90 ml had a median OS of 26 weeks, whereas in the other group, the median OS was not yet reached. The one-year survival was 72,5% and 0% respectively. The difference in OS was significant (p

Over the past 10 years several effective new therapies have been developed for patients with advanced melanoma. Since 2010, the primary endpoint of every major phase III trial in this setting has been met, revolutionizing the treatment options and survival for patients with unresectable advanced melanoma. With increasing numbers of patients experiencing durable remissions with these agents, even without continuing therapy, the issue of melanoma survival care becomes of relevance to more patients than ever before.

Background Pembrolizumab (PEMBRO) improves survival in patients (pts) with advanced melanoma (MEL). Baseline (BL) parameters that predict long-term benefit for PEMBRO treatment are under investigation. Methods Outcome data of pts with advanced MEL treated with PEMBRO at our institution were collected as part of a prospective therapeutically non-interventional trial. Objective responses were evaluated using the immune-related response criteria. Total metabolic tumor volume (TMTV) was assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET/CT) using MIM Encore Software®. TMTV was defined as the sum of all tumor-associated voxels with a standardized uptake value (SUV) higher than the mean SUV measured in a reference region in normal liver tissue + 3 standard deviations. Results BL 18FDG-PET/CT disease staging results were available for 69 pts. Median progression-free survival (mPFS) was 19 w (95% CI 9-29); median overall survival (mOS) was 130 w. A cut-off value of 90 mL of BL TMTV defined a subpopulation with significantly worse PFS (mPFS 7 w [95% CI 4-9] vs 56 w [95% CI 0-118]; HR 19.10, p 5 times upper limit of normal (>5xULN), lactate dehydrogenase (LDH) >1xULN, WHO Performance Status (WHO PS) ≥1 and number of metastatic sites ≥2 were associated with significantly shorter PFS and OS in univariate analysis (log rank p 90 mL (HR 3.70 [95% CI 1.79-7.69]), HBM (HR 2.08 [95% CI 1.11-3.85]) and WHO PS ≥ 1 (HR 2.08 [95% CI 1.12-3.85]) were significantly associated with shorter PFS; BL TMTV >90 mL (HR 14.29 [95% CI 5.26-33.33]) and HBM (HR 2.56 [95% CI 1.23-5.26]) were significantly associated with shorter OS. Conclusions BL TMTV >90 mL and HBM independently correlate with worse PFS and OS in pts with advanced MEL treated with PEMBRO. Elevated BL CRP and LDH values overlap with, but are inferior to TMTV as predictive biomarkers for outcome of PEMBRO treatment. Confirmation of these results is under investigation in an independent second cohort.

2033 Background: Intracerebral administration of ipilimumab (IPI) and nivolumab (NIVO) following resection of rGB was demonstrated to be safe and resulted in encouraging survival (Duerinck, Schwarze et al. JITC 2021; Neyns et al. ESMO 2021). CD1c(BDCA-1)+ and CD141(BDCA-3)+ myDC play a pivotal role in initiating an adaptive anti-tumor immune response by re-licensing cytotoxic T lymphocytes within the tumor microenvironment. Methods: Eligible patients (pts)(diagnosed with rGB following radiation and temozolomide treatment; not in need of steroids) underwent a leukapheresis followed by immunomagnetic bead isolation and cryopreservation of CD1c (BDCA-1)+ / CD141(BDCA-3)+ myDC. At the time of surgery, an escalating number of myDC (1, 10, and 20x106 myDC) were injected into the brain tissue lining the resection cavity following maximal safe resection of the rGB (ICer) or injected intratumorally (ITum) following stereotactic biopsy (STx). IPI (5 mg) plus NIVO (10 mg) were co-injected with myDC. NIVO was administered intracavitary (ICav, 10mg) using an Ommaya port and intravenously (IV, 10mg) Q2w (max 12x). Results: Fourteen pts (9 male; median 48y [range 20-78]) were recruited (resection n = 11; STx n = 2) and underwent a successful leukapheresis and isolation of myDC; peroperative administration of myDC was preceded by resection in 10 pts (1 pt did not undergo surgery due to clinical deterioration/cerebral edema), and by STx in 2 pts. Respectively 6 (incl both pts who underwent a STx), 3, and 4 pts were treated at the 3 dose levels. All pts received ITum/ICer/IV-administrations of IPI and NIVO as planned. Median number of postoperative ICav/IV NIVO-administrations was 7 (range 2-11). Most frequent adverse events (AE) were headache (n = 11), fatigue (n = 9), transient dysphasia (n = 6), and nausea (n = 5). Bacterial colonization of the Ommaya occurred in 3 pts necessitating removal. Immune-related AE were infrequent and mild. No G5 AE occurred. No dose-limiting toxicities were seen with increasing numbers of myDC. After a median follow-up of 54w, 3 pts remain progression-free (after 42+, 51+, 54+ weeks of FU), 6 (46%) pts have died; median PFS is 13w (95% CI 0-26), median OS has not been reached; 6-months PFS- and OS-rate are respectively 30% and 84%, 12-months PFS- and OS-rate are respectively 23% and 51%. OS compares favorably to an historical cohort of Belgian rGB patients (n = 469; Log-Rank p = 0.018). Gene expression profiling of resected tissue, analysis of cellular counts, cytokines, NIVO/IPI-concentrations in on-treatment cerebrospinal fluid samples is ongoing. Conclusions: Intracranial administration of autologous myDC plus IPI and NIVO in combination with IV NIVO was found to be feasible, sufficiently safe and associated with encouraging survival justifying further investigation in pts with resectable rGB. Clinical trial information: NCT03233152.