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Supplementary Figure from A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma

Figure S1. Flowchart of study selection process with ICIs treatment. Figure S2. Flowchart of study selection process with TAs treatment. Figure S3. Overall Survival comparing HPD with non-HPD in patients with progression disease as best response in the ICIs and TAs cohorts ( RECIST 1.1 progression disease Landmark Analysis). Figure S4. Overall Survival in second line (a) and third (b) setting HPD vs non-HPD progressors by RECIST criteria in ICIs cohort. Figure S5. Concordance between RECIST and TGR criteria in ICIs cohort. Table S1. Computed tomography (CT) acquisition protocol parameters. Table S2. Clinical variables in patients treated with TAs. Table S3. Multivariate model in patients with progression disease as best response in ICIs group (using TGR).

Purpose:Most hyperprogression disease (HPD) definitions are based on tumor growth rate (TGR). However, there is still no consensus on how to evaluate this phenomenon.Patients and Methods:We investigated two independent cohorts of patients with advanced solid tumors treated in phase I trials with (i) programmed cell death 1 (PD-1)/PD-L1 antibodies in monotherapy or combination and (ii) targeted agents (TA) in unapproved indications. A Response Evaluation Criteria in Solid Tumors (RECIST) 1.1–based definition of hyperprogression was developed. The primary endpoint was the assessment of the rate of HPD in patients treated with ICIs or TAs using both criteria (RECIST and TGR) and the impact on overall survival (OS) in patients who achieved PD as best response.Results:Among 270 evaluable patients treated with PD-1/PD-L1 inhibitors, 29 PD-1/PD-L1–treated patients (10.7%) had HPD by RECIST definition. This group had a significantly lower OS (median of 5.23 months; 95% CI, 3.97–6.45) when compared with the non-HPD progressor group (median, 7.33 months; 95% CI, 4.53–10.12; HR = 1.73, 95% CI, 1.05–2.85; P = 0.04). In a subset of 221 evaluable patients, 14 (6.3%) were categorized as HPD using TGR criteria, differences in median OS (mOS) between this group (mOS 4.2 months; 95% IC, 2.07–6.33) and non-HPD progressors (n = 44) by TGR criteria (mOS 6.27 months; 95% CI, 3.88–8.67) were not statistically significant (HR 1.4, 95% IC, 0.70–2.77; P = 0.346). Among 239 evaluable patients treated with TAs, 26 (10.9%) were classified as having HPD by RECIST and 14 using TGR criteria in a subset of patients. No differences in OS were observed between HPD and non-HPD progressors treated with TAs.Conclusions:HPD measured by TGR or by RECIST was observed in both cohorts of patients; however, in our series, there was an impact on survival only in the immune-checkpoint inhibitor cohort when evaluated by RECIST. We propose a new way to capture HPD using RECIST criteria that is intuitive and easy to use in daily clinical practice.

Background Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation. Methods This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. Results Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). Conclusions Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

Background Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas. Methods In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response. Conclusions Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings.

BackgroundOX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949.MethodsPhase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7–1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics.ResultsEighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1–9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs.ConclusionNo safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors.Trial registration numberNCT02923349.

Recent advances in molecular profiling, have reclassified medulloblastoma, an undifferentiated tumor of the posterior fossa, in at least four diseases, each one with differences in prognosis, epidemiology and sensibility to different treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR 1.5 cm2, presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular findings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients benefit from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered palliative and inclusion on clinical trials, focusing on the molecular alterations that define each subgroup, should be encouraged. Selected patients can benefit from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of significant sequelae is common and patients must undergo lifelong follow-up.

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2–7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Olutasidenib (FT2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1 R132X mutation.This was an open-label, multicenter, non-randomized, phase 1b/2 clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1 R132Xmutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase 1 and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase 2.Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase 2 dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each).Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1 R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

Immunotherapy; Phase 1 trials; Prognostic model Inmunoterapia; Ensayos de fase 1; Modelo pronóstico Immunoteràpia; Assajos de fase 1; Model pronòstic Purpose Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline. Methods Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application. Results We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3–12.7) for ICIs cohort and 7.7 m (95% CI, 6.6–8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS – ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64–0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%–90%). Conclusions PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/. The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/CE07/50610001). Cellex Foundation for providing research facilities and equipment. This work was supported by the Accelerator Award (UpSMART) from Fundacion Científica – Asociacion Espanola Contra el Cancer (FC -AECC)/ Associazione Italiana per la Ricerca sul Cancro (AIRC) /Cancer Research United Kingdom (CRUK).

EO2401 includes microbial-derived, synthetically produced HLA-A2 restricted peptides with molecular mimicry to antigens (IL13Rα2, BIRC5 and FOXM1) upregulated in glioblastoma, and the CD4 helper peptide UCP2. Patients with glioblastoma at first progression received EO2401 (300µg/peptide, q2weeks x4 then q4weeks), EO2401+nivolumab (3mg/kg q2weeks), or E02401+nivolumab+bevacizumab (10mg/kg q2weeks). Cohort-1 included EO2401x2 then EO2401+nivolumab. EO2401+nivolumab was evaluated in Cohort-2a, as adjuvant treatment in Cohort-2b, and as neoadjuvant/adjuvant treatment in Cohort-2c. Cohort-3 assessed EO2401+nivolumab+bevacizumab. Part 1 included 40 patients (Cohort-1/3, Cohort-2a/23, Cohort-2b/3, Cohort-3/11). Part 2 allowed low-dose-bevacizumab (5mg/kg q2weeks) for symptomatic edema and enrolled 38 patients (Cohort-1/18, Cohort-2a/15, Cohort-2b/3; and recruiting Cohort-2c/2 target 6, Cohort-3/0 target 15).Safety assessment of part 1 showed EO2401+nivolumab+/-bevacizumab to be well tolerated with EO2401 associated toxicity limited to local administration site reactions (48%; all grade 1-2). The nivolumab-/bevacizumab-toxicity was consistent with historical single-agent data. Strong CD8 T cell ELISPOT responses against the 3 vaccine peptides and cross-reactivity against targeted antigens was demonstrated in the majority of evaluable patients. Immune response was confirmed with tetramer staining of specific CD8 either ex vivo or after in vitro stimulation. For part 1, median progression-free survival (mPFS), and median survival (mOS) for EO2401+nivolumab (Cohorts-1/2/2b, n=29 median follow-up [mFU] 14.0 months) were 1.8 and 10.6 months. Patients on EO2401+nivolumab+bevacizumab (n = 11 mFU 9.6 m) had mPFS 5.5 months and 9 patients alive 7-12.4 months. Objective Response Rate/Disease Control Rate for EO2401+nivolumab and EO2401+nivolumab+bevacizumab was 10%/34% and 55%/82%.Median treatment duration for Cohort-2a part 1 was 6.1 weeks (1/23 on treatment), while it was 10.0 weeks (8/15 on treatment) for Cohort-2a part 2. Overall, in part 2, 36% received low-dose-bevacizumab.EO2401 generated strong immune responses and was well tolerated. Addition of standard bevacizumab to EO2401+nivolumab improved PFS and tumor response. Symptom driven low-dose-bevacizumab supported longer treatment durations. Outcome of study part 2 will be presented.

Trotabresib, a novel bromodomain and extraterminal protein inhibitor, has demonstrated antitumor activity and blood–brain barrier penetration in patients with high-grade gliomas, and enhanced the antiproliferative effects of temozolomide in preclinical models. CC-90010-GBM-002 (NCT04324840) is a phase 1b/2 study investigating the addition of trotabresib to standard-of-care (SOC) concomitant temozolomide plus radiotherapy and adjuvant temozolomide, followed by maintenance trotabresib, in patients with newly diagnosed glioblastoma. The design of the dose escalation (part A) has been described previously (Vieito M, et al. SNO 2021. Abstract CTNI-51). Primary objectives of part A were to establish the safety, tolerability, and maximum tolerated dose/recommended phase 2 dose (RP2D) of trotabresib. In part A, addition of trotabresib to SOC was safe and well tolerated in the concomitant (N = 14) and adjuvant (N = 18) cohorts; the most frequent grade 3/4 treatment-related adverse event was thrombocytopenia (7/14 and 9/18 patients, respectively). The RP2D for trotabresib was 30 mg/day 4 days on/24 days off in both settings. At data cutoff (February 20, 2022), median duration of treatment was 34 weeks (concomitant cohort) and 33 weeks (adjuvant cohort); progression-free survival data are not yet mature. Trotabresib plasma pharmacokinetics and pharmacodynamics were consistent with monotherapy. At last follow-up, 6 and 5 patients remained on treatment in the concomitant and adjuvant dose-escalation cohorts, respectively, including 1 patient in cycle 20 with ongoing complete response. The ongoing randomized phase 2 dose expansion (part B; planned N = 162) is comparing concomitant trotabresib at the RP2D + SOC followed by adjuvant trotabresib at the RP2D + SOC, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off, versus SOC alone in patients with newly diagnosed IDH–wild-type glioblastoma. Key objectives are to compare progression-free and overall survival, safety, and tolerability. Longer follow-up from part A and the first disclosure of data from part B will be presented.

2524 Background: SAR439459 (SAR459) is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. In preclinical models, combining SAR459 with an anti-PD-1 showed improved anti-tumor activity compared to SAR459 single agent. In the dose escalation, acceptable tolerability was observed, the MTD was not reached and the preliminary RP2D was 22.5mg/kg Q3W when combined with cemiplimab (CEMI; S. Williamson et al. J Clin Oncol 39, 2021[suppl 15; #2510]). Reduction of plasma TGFβ was ≥90% at doses ≥0.25mg/kg Q2W, with a trend of a decrease in intra-tumoral TGFβ (D. Robbrecht et al. JITC 2021;9 [suppl 2; #250]). Here we report safety and efficacy results of the dose expansion. Methods: The expansion phase of this open-label, phase 1/1b study aimed to determine the optimal dose of SAR459 (7.5 mg/kg or 22.5 mg/kg Q3W) in patients (pts) with advanced melanoma (MEL) resistant to anti-PD(L)1 therapy (Part 2A); and the ORR (confirmed responses) in all treated pts with SAR459 22.5 mg/kg + CEMI 350 mg Q3W in pts with MEL, Non-small Cell Lung Cancer (NSCLC), or Hepatocellular Carcinoma (HCC), resistant to anti-PD(L)1; as well as in pts with mesenchymal Colorectal Cancer (CRC) or Urothelial Cancer (UC), anti-PD(L)1 naïve (Part 2B). Results: From October 2019 to September 2021, 109 pts with ECOG PS 0-1 enrolled in Part 2A (14) and Part 2B (95). Overall, the median age was 63 years and 83% of pts received up to 3 prior treatment lines for advanced disease (range 1-8). Based on preliminary data, the ORR in Part 2B was 8% (Table). No significant association between clinical response and plasma TGFb level at baseline or modulation upon treatment was observed. The correlation between tumor TGFb level and clinical benefit is inconclusive due to limited number of tumor biopsies. No response was observed in Part 2A. Overall, 100% of pts had at least one treatment emergent adverse event (AE), 67% were G≥3, 34% related G≥3, 17% G5, and 4% related G5. The limited number of patients treated with SAR459 alone at the RP2D did not allow to demonstrate added toxicity due to the combination. Overall, 51 pts (47%) reported hemorrhagic AE of any grade, 8 pts (7%) had G≥3 and 5 pts (5%) had fatal outcome. The rate of bleeding and severe hemorrhagic AE was higher in HCC pts compared to the other cohorts: 11/14 (79%) pts had a hemorrhagic AE, of which 3 (21%) G≥3 and fatal. An exploratory analysis showed a trend for higher frequency of any grade SAR459-related and fatal hemorrhagic AE in patients with higher exposure. Conclusions: The NCT03192345 study was discontinued due to a lack of efficacy, and a high bleeding risk particularly in pts with HCC. Clinical trial information: NCT03192345. [Table: see text]

9039 Background: Tusamitamab ravtansine (tusa) is a novel antibody-drug conjugate that selectively targets CEACAM5, a cell surface glycoprotein highly expressed in several tumor types. In previously reported results from an open-label Phase 1/2 study (NCT02187848), tusa showed promising antitumor activity in patients (pts) with heavily pretreated NSQ NSCLC and high CEACAM5 expression (Gazzah A et al. J Clin Oncol. 2020;38[15 suppl]:9505). Herein we report results for pts treated for ≥ 12 mo with NSQ NSCLC and high or moderate CEACAM5 expression. Methods: In the Phase 1/2 study, 92 pts with heavily pretreated NSQ NSCLC and high (n = 64) or moderate (n = 28) CEACAM5 expression (≥ 2+ intensity in ≥ 50% of tumor cells or in ≥ 1% to < 50% of tumor cells, respectively) were treated with tusa 100 mg/m2 Q2W. As of Jan 2020, among CEACAM5 high expressors, 13 had confirmed partial response (PR) and 28 had stable disease (SD); among moderate expressors, 2 had PR and 15 had SD. We focus here on pts treated ≥ 12 mo as of Dec 2021. Results: A total of 24 pts were treated for ≥ 6 mo, 15 pts for ≥ 9 mo, 11 pts for ≥ 12 mo, 6 pts for ≥ 24 mo, and 2 pts for ≥ 42 mo. At the data cutoff, 5 pts remained on treatment, 1 for > 3.5 y. For pts treated ≥ 12 mo median (range) treatment duration was 26.6 (12.1–45.3) mo. Of 15 pts with PR in the prior analysis, as of Dec 2021 PR was still observed in 10 pts (67%) treated for ≥ 6 mo, 8 pts (53%) for ≥ 9 mo, and 7 pts (47%) for ≥ 12 mo. For the 11 pts treated ≥ 12 mo, 7 had PR and 4 had SD. Of the 11 pts treated ≥ 12 mo, 9 had high CEACAM5 expression and 2 had moderate CEACAM5 expression; most had prior treatment with an anti-PD1/PD-L1. Pts treated for ≥ 12 mo had better ECOG performance status and fewer prior treatments than the overall group. Of pts treated for ≥ 12 mo, PR occurred irrespective of CEACAM5 expression level. Only 1 pt treated for ≥ 12 mo discontinued due to a treatment emergent adverse event (TEAE) (breast cancer). Corneal events (keratitis/keratopathy) were the most frequent TEAEs, occurring in 8 pts (73%); 4 pts (36%) with Grade ≥ 3; 7 pts had subsequent treatment modification (delay or delay/reduced dose). No corneal TEAE was serious or led to treatment discontinuation. Conclusions: Almost half (47%) of pts who achieved a PR were treated for ≥ 1 y, suggesting that response to tusa in heavily pretreated pts was durable and frequently sustained. No patient discontinued long-term treatment because of drug-related toxicity. Corneal toxicity in these pts was manageable with dose modification (delay/reduction). The observed long-term clinical benefit and safety profile of tusa support its further clinical development; a Phase 3 study is ongoing to evaluate tusa monotherapy in previously treated pts with high CEACAM5 expressing NSQ NSCLC. Clinical trial information: NCT02187848.

Inhibidor de BET; Limfoma no Hodgkin; Tumors sòlids Inhibidor de BET; Linfoma no Hodgkin; Tumores sólidos BET inhibitor; Non-Hodgkin's lymphoma; Solid tumors Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of genes involved in oncogenesis. CC-90010 is a novel, oral, reversible, small-molecule BET inhibitor. Patients and methods CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I dose-escalation and expansion study of CC-90010 in patients with advanced or unresectable solid tumors and relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). We report results from the dose escalation phase, which explored 11 dose levels and four dosing schedules, two weekly (2 days on/5 days off; 3 days on/4 days off), one biweekly (3 days on/11 days off), and one monthly (4 days on/24 days off). The primary objectives were to determine the safety, maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) and schedule. Secondary objectives were to evaluate signals of early antitumor activity, pharmacokinetics, and pharmacodynamics. Results This study enrolled 69 patients, 67 with solid tumors and two with diffuse large B-cell lymphoma (DLBCL). The median age was 57 years (range, 21–80) and the median number of prior regimens was four (range, 1–9). Treatment-related adverse events (TRAEs) were mostly mild and manageable; grade 3/4 TRAEs reported in more than two patients were thrombocytopenia (13%), anemia, and fatigue (4% each). Six patients had dose-limiting toxicities. MTDs were 15 mg (2 days on/5 days off), 30 mg (3 days on/11 days off), and 45 mg (4 days on/24 days off). The RP2D and schedule selected for expansion was 45 mg (4 days on/24 days off). As of 8 October 2019, one patient with grade 2 astrocytoma achieved a complete response, one patient with endometrial carcinoma had a partial response, and six patients had prolonged stable disease ≥11 months. Conclusions CC-90010 is well tolerated, with single-agent activity in patients with heavily pretreated, advanced solid tumors. This work was supported by Celgene Corporation, Summit, NJ, USA. (no grant number).

Meningioma, the second most common primary tumour of the central nervous system, is classified into three different grades based on their characteristics. Each tumour grade includes different molecular subtype, growth potential, and thus, different prognosis. Grade I meningioma is the most common subtype with a benign course, in which systemic dissemination rarely occurs. We present the case of a 48-year-old male patient with a history of grade I meningioma who was referred 3 years after the initial diagnosis to our centre due to pelvic pain. Computed tomography (CT) images showed new pelvic bone lesions whose histopathological report was compatible with a grade I meningioma. Neither hormonal therapy concomitant with octreotide nor hydroxiurea treatments were effective. Very little is known about this entity’s prevalence and treatment when disseminated disease occurs. Thus, we think it is important to increase the positive and negative clinical experiences in this setting.

Background HER2 status is a predictive biomarker of response to trastuzumab in advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. However, there is relatively little known about the role of HER2 in resected gastric or GEJ adenocarcinoma in the Western population. Methods Retrospective, observational, single centre study of patients with gastric or GEJ adenocarcinoma undergoing surgery with curative intent between January 2007 and June 2014 in the University Hospital Complex of Santiago de Compostela. The expression of HER2 was determined by immunohistochemistry (IHC) using DAKO-HercepTest™ and gene amplification with DuoCISH using a DAKO-DuoCISH kit. The study of HER2 expression and amplification was carried out in all the patients and it was correlated with classic clinicopathological parameters, survival and recurrence pattern. Results 106 patients were included. HER2 expression was as follows: 71.7% HER2 negative, 21.7% HER2 equivocal and 6.6% HER2 positive, or with HER2 overexpression. 13.2% of patients (14/106) had HER2 amplification by DuoCISH. A significant association was seen between overexpression and amplification of HER2 (p < 0.001). HER2 positivity was associated with the intestinal subtype (p = 0.010) and a low grade of differentiation (p = 0.018). Likewise, HER2 was significantly associated with a worse prognosis: overall survival (OS) 32.3 months HER2 positive versus 93.9 months HER2 negative (HR 0.42; confidence interval 95% 0.18–0.93; p = 0.028); and the presence of distant metastasis without accompanying locoregional recurrence (p = 0.048). Conclusion HER2 status defines a subgroup with differentiated clinicopathological characteristics, worse prognosis and distant dissemination, without accompanying locoregional recurrence, in patients with resected gastric or GEJ adenocarcinoma operated on in a Western population.

BACKGROUND Glioblastoma (GB) is the most aggressive primary brain tumour. Despite the survival benefit associated with adjuvant therapy, most of patients (pts) relapse after initial therapy. Nitrosoureas (NU) are the standard treatment at relapse in Europe. Both fotemustine (FM) (Addeo schema) and lomustine (LM) (administered orally every 6 weeks) are used in this context. MATERIAL AND METHODS This retrospective cohort study included pts diagnosed with GB treated with NU at relapse in four Catalonia hospitals from 2010 to 2020. Clinical and pathological data were collected from medical records. We analysed 6months-progression-free survival (6m-PFS), progression-free survival (PFS) and overall survival (OS) from the start of NU to progression or death respectively. Differences in toxicity grade using CTCAE v5.0 were analysed globally as ‘non-toxicity’, ‘mild toxicity (grade 1 or 2)’ and ‘high toxicity (grade 3 or 4)’. RESULTS We identified 236 GB pts with a median age of 58 years old. 29% of the pts presented MGMT promotor methylation and only 3%(n=7) had IDH mutation. After a median follow-up of 20 months, 94% of the pts were dead at the time of the analyses. At first line, 83 pts were treated with FM and 18 with LM. Pts treated with FM had better performance status (PS) than those treated with LM (p=.010). Median PFS was 2 months and 6m-PFS was 12% vs 6% in FM and LM group respectively (p=.87). Median OS was 3 months with LM vs 6 months with FM, with no statistically significant differences even adjusted for prognostic factors (p=.79 HR:0.9 CI 95% 0.41–1.96).At second line, 78 were treated with FM and 24 with LM, no differences between groups. Median PFS was 2 months in both groups and median OS was 3 vs 5 months for pts treated with LM vs FM respectively, with no significant differences. 6m-PFS was 13% for LM vs 0% for the FM group (p=.39).Pts received a mean of 1.7 cycles (every 6 weeks) and 4.1 cycles (every 2 weeks) in LM and FM group, respectively. Thrombocytopenia was the most common serious side-effect, with a higher proportion of grade 1–2 toxicity in the FM group (p=.03) that also required more treatment delays (p=.01). CONCLUSION Despite being retrospective study and a few pts were treated with LM, there were no differences neither in PFS nor in OS in pts treated with LM vs FM at first or second line. Higher G1-2 thrombocytopenia was shown in the FM group probably due to a higher number of hematology samples collected.

Background: INDUCE-1 is a first-in-human trial investigating FE, an IgG4 ICOS agonist non-T-cell depleting mAb, in monotherapy (mono) and combo with PD-1 inhibitor PE. ICOS is highly expressed in melanoma, an immunotherapy responsive tumor, and is a biomarker of response to anti-CTLA-4 treatment; in nonclinical models, ICOS agonism has enhanced activity in combo with immune checkpoint blockade (ICB). Preliminary data from INDUCE-1 R/R melanoma ECs are presented to support FE expansion in ICB experienced (exp) R/R melanoma patients (pts). Methods: Eligible pts had non-uveal R/R melanoma, ≤5 prior lines of systemic therapy, achieved response or stable disease (SD) on prior anti-PD-1/L1 treatment, and no prior immunotherapy-related Grade ≥3 toxicities leading to treatment discontinuation. In FE mono and FE + PE 200 mg combo ECs, pts were randomized to FE 0.3 or 1 mg/kg; treatment was given every 3 wks up to 35 cycles until disease progression or unacceptable toxicity. Safety and efficacy were assessed. Biomarkers in tumor biopsies were analyzed. Results: By 30 Mar 2020, 39 pts in the mono EC were evaluable (21 pts at 0.3; 18 pts at 1 mg/kg FE); all pts were anti-PD-1/L1 exp; 21/39 (54%) were anti-CTLA-4 exp; 7/39 (18%) had ≥4 prior lines of therapy. Of the 39 pts, 29 (74%) discontinued treatment due to progression. Response rate was 10% (4/39; 1 complete response, 3 partial responses); 8/39 (21%) pts had SD and 2/8 (25%) pts with SD had tumor size reductions (RECIST v1.1) at ≥19%; 5 pts (13%) had SD at ≥18 wks. Duration of response (DoR) was 2.0+ to 6.3 mo. BRAF and NRAS status did not impact clinical activity. Anti-CTLA-4 exp pts had a numerically higher response rate than anti-CTLA-4 naïve pts. In the combo EC, 17 anti-PD-1/L1 exp pts were evaluable (6 pts at 0.3; 11 pts at 1 mg/kg FE); 12/17 (71%) were anti-CTLA-4 exp; 15/17 (88%) discontinued treatment, all due to progression. Response rate was 18% (3/17), DoR was 7.9+ to 8.2 mo, and disease control rate (response or SD) was 53% (9/17); 1 pt with SD had tumor size reduction of 10%. Ongoing analyses with mono EC showed a 28.6% (2/7) response rate, DoR of 2.0+ to 6.3 mo, and mOS of ~26 mo in pts with ICOS high tumor-infiltrating T cells. Sample size limits comparison; however, clinical activity was similar between FE doses and between BRAF+ and BRAF− pts. Adverse events (AEs) were consistent with AEs reported for PE. Conclusions: FE is the first ICOS agonist with reported single-agent activity in ICB exp R/R melanoma, supporting ICOS as a target. FE + PE in combo shows promising clinical activity and manageable safety in R/R melanoma. Continued survival follow-up of ECs is warranted. Updated efficacy and PK/PD data to be presented. Funding: Study 204691 (NCT02723955) funded by GSK in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Citation Format: Michele Maio, Jeffrey S. Weber, Maria Vieito Villar, Frans L. Opdam, Victor Moreno, Omid Hamid, José Trigo, Michael Chisamore, Marco Balas, Sapna Yadavilli, David C. Turner, Courtney Henry, Xiao Ji, Catherine Ellis, Marc Ballas, Axel Hoos, Antoine Italiano. Inducible T cell costimulatory (ICOS) receptor agonist, feladilimab (FE), alone and in combination (combo) with pembrolizumab (PE): Results from INDUCE-1 relapsed/refractory (R/R) melanoma expansion cohorts (EC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT033.

// Luis Leon-Mateos 1, * , Helena Casas 2, * , Alicia Abalo 2, 3 , Maria Vieito 6 , Manuel Abreu 2, 3 , Urbano Anido 3 , Antonio Gomez-Tato 4 , Rafael Lopez 2, 3, 5 , Miguel Abal 3 and Laura Muinelo-Romay 3 1 Axencia Galega de Conecemento en Saude (ACIS), SERGAS, Santiago de Compostela, Spain 2 Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), CIBERONC, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain 3 Translational Medical Oncology Group, Health Research Institute of Santiago (IDIS), CIBERONC, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain 4 School of Mathematics, University of Santiago de Compostela (Campus Vida), Santiago de Compostela, Spain 5 Roche-Chus Joint Unit for Precision Oncology, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain 6 Research Unit for Molecular Therapy of Cancer, CNS Tumors, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain * Co first-authors Correspondence to: Luis Leon-Mateos, email: Luis.Leon.Mateos@sergas.es Laura Muinelo-Romay, email: lmuirom@gmail.com Keywords: prostate cancer, circulating tumour cells (CTCs), prognostic markers, taxanes resistance Received: January 17, 2017 Accepted: May 02, 2017 Published: May 19, 2017 ABSTRACT Introduction: There is a critical need of new surrogate markers for improving the therapeutic selection and monitoring of metastatic prostate cancer patients. Nowadays clinical management of these patients is been driven by biochemical and clinical parameters without enough accuracy to allow a real personalized medicine. The present study was conducted to go insight the molecular profile of circulating tumor cells (CTCs) isolated from advanced metastatic castration-resistant prostate cancer (mCRPC) with the aim of identifying prognostic marker with potential utility for therapy selection and monitoring. Materials and Methods: CTCs isolation was carried out in peripheral blood samples from 29 mCRPC patients that undergo systemic chemotherapy based on taxanes (docetaxel/cabazitaxel) and 19 healthy controls using in parallel CellSearch and an alternative EpCAM-based immunoisolation followed by RT-qPCR analysis to characterize the CTC population. A panel of 17 genes related with prostate biology, hormone regulation, stem properties, tumor aggressiveness and taxanes responsiveness was analysed to identify an expression signature characterizing the CTCs. Results: Patients with ≥ 5 CTCs/7.5ml of peripheral blood at baseline and during the treatment showed lower progression free survival (PFS) and overall survival (OS). Changes of CTCs levels during the treatment were also associated with the patient’s outcome. These results confirmed previous data obtained using CellSearch in mCRPC. In addition, we found a CTC profile mainly characterized by the expression of relevant genes for the hormone dependent regulation of PCa such as AR and CYP19 together with genes strongly implicated in PCa progression and resistance development such as BIRC5 , TUB1A , GDF15 , RAB7 and SPINK1 . Our gene-expression profiling also permitted the identification of valuable prognostic biomarkers. Thus, high levels of AR, CYP19 and GDF15 were associated with poor PFS rates while AR, GDF15 and BIRC5 were also found as reliable predictors of OS. Besides, a logistic model using KLK3 and BIRC5 showed a high specificity and sensitivity compared to CellSearch to discriminate patients with a more aggressive evolution. Conclusions: The molecular characterization of CTCs from advanced mCRPC patients provided with a panel of specific biomarkers, including genes related to taxanes resistance, with a promising applicability as “liquid biopsy” for the management of these patients.

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival., LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8+ T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.

6081 Background: Treatment selection based on actionable alterations (AAs) is an appealing strategy for pts with R/M SGT. The GEMS-001 study (NCT02069730) at Princess Margaret Cancer Centre (PM) and the Vall D´Hebron Institute of Oncology (VHIO) pre-screening program facilitate the identification of AAs for R/M SGT pts and treatment selection. Methods: We analyzed R/M SGT treated at PM and VHIO from 2015 to 2020. Clinicopathological features, molecular alterations and treatment modalities were correlated with outcomes. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Clinical benefit rate (CBR) was defined by pts with partial response or stable disease ≥4 months. Clinical actionability of multigene panel testing (NGS) and immunohistochemistry (IHC) were assessed as per institutional molecular tumor boards or investigators. Pts were opportunistically matched to available therapies from each center. Results: In total 206 pts were enrolled. On IHC, HER2 overexpression was present in 9%, Androgen Receptor (AR) 33%, Estrogen/Progesterone Receptor (ER/PR) 11% and ALK overexpression 0%. On NGS, PIK3CA mutation (mut) was in 9%, NTRK fusion 6%, NOTCH1-3 mut 5%, HRAS mut 6%, ERBB2/3 alterations (alt) 4% and FGFR1-4 alt 3%. Up to 92 pts (45%) displayed at least 1 AA and 36 pts (18%) had ≥2 AAs. A total of 60 pts (29%) were matched to AAs. Of those matched, median age was 60 years (range 33-84), M:F 21:39, 95% ECOG≤1 with a median number of prior treatment lines 0 (range 0-3), and their AAs included 26 AR, 9 HER2 or ERBB2 overexpression, 9 PIK3CA mut, 3 NTRK fusion, 3 FGFR1-3 alt and 10 other AAs (2 ER/PR overexpression, 2 EGFR mut, 1 c-kit mut, 1 BAP1 mut, 1 Non-V600 BRAF mut, 1 CDKN2A mut, 1 CHEK2 mut and 1 PTCH1 mut). Overall, ORR was 27% for the matched population. See table for outcomes. Conclusions: In our cohort, almost one third of the population received therapies matched to AAs. Our results suggest that targeted therapies have promising activity in pts with R/M SGT supporting comprehensive molecular and IHC profiling in treatment determination.[Table: see text]

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

2597 Background: In order to improve the expected response rate (ORR) of less than 10% in cold tumors, several ICI combinations are being evaluated in clinical trials. However, most of these trials don’t require any biomarker and pts are included based solely in histology. We aimed to assess the benefit of ICI combinations in pts with unselected cold tumors included in early CT. Methods: ICI naïve pts with cold tumors treated from 2015 to 2021 with ICI combinations in early CT at VHIO were reviewed. Clinico-pathological data and anti-tumor activity were extracted from a prospective database. ORR was defined as per RECIST v1.1 and clinical benefit rate (CBR) as complete/partial response (CR/PR) + stable disease (SD) for ≥ 4 months (m). Kaplan Meier estimates of progression-free survival (PFS) and overall survival (OS) were calculated and a Cox model according to LIPI (Lung Immune Prognostic Index = baseline LDH and derived neutrophil to lymphocyte ratio) was constructed. Immune-related adverse events (irAE) were classified as per CTCAE v.4.03. Hyperprogressive disease (HPD) was evaluated using RECIST v1.1 (Matos et al, 2020). Results: Out of 97 pts, median age was 62y, 61% had ECOG 0 and 29.8% had LIPI 0 (good prognostic score). Most pts had microsatellite stable (MSS) colorectal cancer (60.8%) or ovarian cancer (14.4%). Regimens included anti-PD1/L1 + another ICI in 69% (most commonly anti-LAG3 [26,8%] and CD40 agonist [20.9%]), anti-PD1/L1 + other molecule in 21.7% (most commonly SHP2 inhibitor [33.3%] and anti p53-HDM2 [28.5%]) and bispecific antibodies in 9.3% (anti-PD1/L1 + anti-LAG3 or CD137 agonist). No patient achieved a response. CBR was 15.3% (11 pts with MSS colorectal cancer, 2 ovarian cancer, 1 olfactory neuroblastoma, 1 paraganglioma). 33 pts (34%) presented irAE, 15 pts (15.5%) had irAE ≥ G2, 4 pts (4.1%) had G3 irAE (dry mouth, hypertransaminasemia, myocarditis and neutrophils count decreased) and 1 patient (1%) had G4 hyperglicemia. 58 pts (59.7%) had progressive disease (PD) as best response, 19 of these pts (32.7%) presented irAE. Overall, 20 pts (20.6%) met definition of HPD, representing 34.4% of pts with PD as best response. Median PFS for overall and CBR population were 1.9 m (CI95% 1.7-2.0) and 5.9 m (5.4-NR), respectively. Median OS for overall population was 7.6 m (5.9-9.5), with a trend for improved OS if LIPI good score vs. others (12.6 m vs. 6.2 m, hazard ratio 1.9, (CI 95% 1.1-3.3), p = 0.02). Among hyperprogressors, median OS was 5.33 m (3.39 - NR) and significantly worse LIPI scores (intermediate [1] or poor [2]) were observed as compared to pts with CBR (75% vs 53.3% p = 0.001). Conclusions: ICI combinations demonstrated very limited activity in pts with unselected cold tumors. However, the risk for irAE and HPD remain substantial. Further drug-biomarker co-development strategies are urgently needed to increase the risk benefit ratio for these pts.

2557 Background: The development of human intratumoral therapy (HIT-IT) has surged as a promising strategy to overcome resistance to checkpoint inhibitors (CPI), promoting a stronger tumor-specific immune response while reducing systemic exposure. A broad variety of agents (i.e: oncolytic viruses, toll-like receptors agonists) administered both in superficial- and deep-seated lesions are being currently tested in clinical trials (CT). Due to the local intervention on tumors, radiological assessment by standard RECIST is challenging and new methods of response that capture and integrate the local and systemic response to HIT-IT are needed. We aimed to evaluate the feasibility and clinical utility of itRECIST (Goldmacher et al., 2020) in patients (pts) treated with HIT-IT in early phase CT. Methods: Retrospective analysis of a cohort of pts with different solid tumor types enrolled in CT including HIT-IT in our institution between August’18 and January’21. Clinical characteristics were collected. Efficacy in target-injected (T-I) and target-non-injected (T-NI) lesions was assessed by objective response rate (ORR) and disease control rate (DCR), as per itRECIST. Overall disease ORR and DCR were assessed per RECIST 1.1/iRECIST. Treatment-related adverse events (TRAEs) were assessed with CTCAE v.5.0. ORR was calculated with Clopper-Pearson method. Survival analysis was made using Kaplan-Meier method. Results: A total of 37 pts were included. Median age was 66 years, 19 pts (51%) were male, all pts had ECOG 0-1. 24 pts (65%) were CPI-naïve. Median previous lines of therapy was 2 (range [r]: 0-11). All pts (100%) received minimum 1 dose of HIT-IT. 6 pts (16%) were treated with monotherapy and 31 pts (84%) in combination with CPI. Median HIT-IT and CPI doses administered were 4 (r: 1-9) and 2 (r: 1-13), respectively. Injected lesions: cutaneous (16.2%), subcutaneous (21.6%), lymph node (32.4%), liver (29.7%). Median size of T-I lesions was 40 mm (r: 19-260). At data cutoff, 32 pts were evaluable. Median follow-up was 14.4 weeks (r: 1.0-81.1). Per RECIST 1.1, overall ORR was 6% (95% CI, 5-7) and DCR was 38% (95% CI, 21-56). Per itRECIST, ORR was 19% (95% CI, 7-36) and DCR was 63% (95% CI, 44-79) in T-I lesions (n = 32), and 10% (95% CI, 22-27) and 48% (95% CI, 29-67) in T-NI lesions (n = 29). Mean decrease in responding T-I and T-NI lesions was -47% (r: -21 to -100) and -41% (r: -26 to -59), respectively. No non-target (NT) lesion was injected. Median progression-free survival was 7.4 weeks (95% CI, 6.6 – 8.2). Median overall survival was 10.0 months (95% CI, 2.3 – 17.7). Incidence of TRAE was 58% (grade 1-2 IT-related pyrexia 43%; grade 3-4, 5%). No treatment-related deaths were recorded. Conclusions: ItRECIST is feasible to implement and adds precision to the radiological assessment of local and distant anti-tumor activity of HIT-IT. No safety issues were detected in our cohort.

3078 Background: PM14 is a new chemical entity that forms DNA adducts which specifically inhibit RNA synthesis and block active transcription of protein-coding genes. Antitumor activity has been demonstrated in vitro in several cell lines (e.g. lung, kidney, prostate), and in vivo in mice bearing xenografted human-derived tumors (soft tissue sarcoma, small cell lung cancer, ovarian, gastric, breast and renal cancer). Methods: Open-label, dose-escalating, phase I trial of PM14 administered as a 3-hour infusion i.v. every 3 weeks (q3wk) in patients (pts) with advanced solid tumors, adequate organ function and ECOG PS score of 0-1. Two schedules were explored: Schedule A (Day 1 [D1], Day 8 [D8]) and Schedule B (D1). Results: 37 pts were treated (Schedule A/B: 28/9 pts). Baseline characteristics of pts (A/B): median age 56/47 years; male 57%/56%; ECOG PS 0: 57%/56%; median of prior lines (range): 3 (1-8)/4 (1-10). Most common tumor types (A + B): STS (n=7 pts), ovarian (n=6), pancreatic (n=4), prostate cancer (n=3). The maximum tolerated dose was 4.5 mg/m2 for A (dose-limiting toxicities [DLTs]: D8 omission due to lack of recovery of lab parameters for re-treatment [n=2 pts]) and 5.6 mg/m2 (DLTs: G4 febrile neutropenia [n=1], G4 transaminase increase [n=1]) for B. The recommended dose (RD) was 3.0 mg/m2 on D1,D8 (A), and 4.5 mg/m2 on D1 (B). No DLTs were present at the RDs. Most common toxicities were hematological abnormalities and transaminase increase. Main toxicities at the RDs are shown below. Antitumor activity comprised stable disease ≥4 months in 7 heavily pretreated pts (6 in A; 1 in B) at all dose levels. Linear pharmacokinetics were observed for PM14 at tested doses (0.25-5.6 mg/m²), with geometric mean (CV%) total plasma clearance 5.9 L/h (88%), volume of distribution 128 L (81%) and median (range) terminal half-life 15.9 h (7.5-34.3 h). Less than 1.6% of administered dose was recovered in urine. Conclusions: RDs were determined for two PM14 schedules in pts with advanced solid tumors. At the RDs, PM14 is well tolerated and has a manageable safety profile. An expansion phase in specific tumor types, with an optional Bayesian continual reassessment method for RD fine-tuning, is ongoing with both schedules.[Table: see text]

Introduction: Gene alterations in NOTCH signaling pathway have a prevalence ranging from Methods: From Jan/2017 to Dec/2018, 1,697 patients (pts) had their FFPE tumor samples (either primary or metastasis) analyzed for mutations (mut) using a custom developed Amplicon-Seq panel of 59 cancer-related genes (including NOTCH1 [hotspots 5% exon coverage] and NOTCH4 [hotspots 3% exon coverage]) that was run in Illumina MiSeq (v1). Additionally, 502 samples were analyzed for Copy Number Alterations (CNA) using a panel of 44 genes (including NOTCH1-4) using NanoString nCounter (copy number between 4-6 copies were validated by FISH). From Jun/2018 to Jun/2019 an expanded NOTCH Amplicon-Seq panel v2 (including additional exons in NOTCH1 plus NOTCH2 and NOTCH3 hotspots regions) replaced the prior v1 panel and 618 samples were sequenced. Results: Colorectal cancer (CRC) (n= 404 [24%]; n=241 [39 %]) and breast cancer (BC) (n=283 [17%]; n= 194 [31%]) were the most frequent tumor types for v1 and v2 panel cohorts, respectively. NOTCH1-4 mut were detected in 11 cases (0.64%). The highest rate of NOTCH pathway alterations (NOTCH1-4 mut plus CN gain or loss) was detected in BC (n=14 [7.7%]) with a clear enrichment in triple negative subtype. Higher prevalence of NOTCH1-4 mut was detected using expanded v2 panel, with 17 NOTCH1-4 mut cases (2.75%). Head & neck (H&N) (n=3 [5%]); BC (n=6 [3%]); and CRC (n=6 [2.5%]) were most common tumors. From all NOTCH1-4 gene mut detected, 8 were known actionable oncogenic driver mut and 9 were variants of unknown significance. When comparing our latest v2 results with GENIE database (mostly large NGS panels with exon capture), we found a similar prevalence in NOTCH1-4 mut in BC and CRC, but lower prevalence was seen in H&N, biliary and gastric tumors. We enrolled 4 pt in clinical trials with NOTCH inhibitors (3 NOTCH1 actionable mut pt (0.48%), 1 NOTCH3 actionable mut pt (0.16%). Conclusion: Institutional efforts to increase coverage of NOTCH pathway genes improved the detection of actionable NOTCH1-4 mut. Differences in prevalence as compared to GENIE dataset may be attributed to the small number of samples tested with our v2 panel and larger panels covering all exons of NOTCH1-4 genes in GENIE cohort. Therefore, we keep evolving our NOTCH prescreening program for clinical trial enrichment. Citation Format: Analía Azaro, Susana Aguilar, Zighereda Ogbah, Omar Saavedra, María Vieito, Ignacio Matos, Irene Braña, Enriqueta Felip, Joan Carles, Lorena Fariñas, Elena Elez, Teresa Macarulla, Cristina Saura, Rodrigo Dienstmann, Elena Garralda, Ana Vivancos. Adapting a molecular prescreening program to detect notch pathway alterations in the context of early drug development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2953.

Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine, which is highly expressed in a subset of tumors and correlates with poor prognosis. LIF is hypothesized to contribute to tumor microenvironment immunosuppression and regulation of cancer stem cells. MSC-1 is a first-in-class humanized IgG1 monoclonal antibody that potently and selectively inhibits LIF. In pre-clinical models, MSC-1 decreases tumor growth through inhibition of STAT3 signaling, promoting immune stimulatory macrophages and increasing tumor infiltration of CD8 T and NK cells. The Phase Ia clinical study employed an accelerated 3 + 3 escalation design to explore safety and tolerability, dose-limiting toxicities (DLTs), preliminary efficacy, define a recommended phase II dose (RP2D), and evaluate exploratory tumor biomarkers. Eligible patients had advanced relapsed/refractory solid tumors and received treatment with MSC-1 intravenously (75mg-1500 mg) once every 3-weeks as a single agent until disease progression. The three highest dose cohorts were expanded to further assess safety, PK, engagement of LIF in the periphery, and assess immuno-regulatory tumor activity in matched pre- and on-treatment tumor biopsies. Forty-one patients (pts) were enrolled (14 in dose escalation; 27 in expanded cohorts) with the last pt completing the study on September 23, 2019. The most common tumor types were pancreatic (13), colorectal (5), head & neck (4) and ovarian (4). Pts had received a median of 3 prior lines of therapy. All pts experienced at least one adverse event (AE). The most common considered drug-related AEs were fatigue (N=8, 20%) and gastrointestinal disorder (N=8, 20%), and there was 1 considered drug-related SAE (Gr 2 osteonecrosis of jaw in a head and neck cancer patient who previously received radiation to the area and denosumab). There were no Dose Limiting Toxicities observed during the first cycle of treatment and 2 pts discontinued treatment due to AEs. The PK profile of MSC-1 was linear with an estimated terminal half-life of ∼13 days and benign anti-drug antibody profile. There was evidence of durable peripheral saturation of LIF binding demonstrating high level of target engagement. Results supported the selection of a RP2D of 1500 mg Q3W. Prolonged stable disease (≥ 16 weeks) was observed in 9 pts. Analysis of paired biopsies collected from matched metastatic lesions supported MSC-1 mediated STAT3 signaling inhibition, stimulatory (M1) to suppressive (M2) macrophage skewing in the majority of paired biopsies evaluated and increased CD8 T-cell infiltration in a subset of samples. Single agent MSC-1 was well tolerated in doses ranged from 75 mg to 1500 mg IV OD in patients with advanced solid tumors, showed promising activity as an anti-cancer therapy, and is Phase 1b/2 ready for combination with other agents. The updated final safety, efficacy, PK, LIF stabilization analyses, and tumor biopsy data will be presented. Citation Format: Alison Schram, Erkut Borazanci, Irene Brana, Maria Vieito Villar, Elena Garralda, Anna Spreafico, Marc Oliva, Nehal Lakhani, Robert Wasserman, Kimberly Hoffmann, Robin Hallett, Judit Anido, Dorotea Maetzel, Patricia Giblin, Enda Moran, Adrianne Kelly, Joan Seoane, Daniel D. Von Hoff, Lillian Siu, Josep Tabernero. Phase 1 dose escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT147.