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Background: The identification of proteins in the cellular membrane of the tumoral cell is a key to the design of therapeutic agents. Recently, the bi-specific antibody amivantamab, targeting the oncogenic membrane proteins EGFR and MET, received regulatory approval for the treatment of adult patients with locally advanced or metastatic NSCLC. Methods: The authors interrogated several publicly available genomic datasets to evaluate the expression of both receptors and PD-L1 in most of the solid and hematologic malignancies and focused on prostate adenocarcinoma (PRAD) and pancreatic adenocarcinoma (PAAD). Results: In PAAD, EGFR highly correlated with PD-L1 and MET, and MET showed a moderate correlation with PD-L1, while in PRAD, EGFR, MET and PD-L1 showed a strong correlation. In addition, in tumors treated with immune checkpoint inhibitors, including anti-PD(L)1 and anti-CTLA4, a high expression of EGFR and MET predicted detrimental survival. When exploring the relationship of immune populations with these receptors, the authors observed that in PAAD and PRAD, EGFR moderately correlated with CD8+ T cells. Furthermore, EGFR and MET correlated with neutrophils in PRAD. Conclusions: The authors identified tumor types where EGFR and MET were highly expressed and correlated with a high expression of PD-L1, opening the door for the future combination of bi-specific EGFR/MET antibodies with anti-PD(L)1 inhibitors.

PURPOSE Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte–associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882 ) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. PATIENTS AND METHODS Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. RESULTS In total, 155 women (median age, 50 years [range, 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1–positive and programmed death ligand-1–negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. CONCLUSION Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte–associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.

Purpose This phase I study assessed the safety of first-in-class radioenhancer nanoparticles, NBTXR3, in elderly or frail patients with locally advanced head and neck squamous cell carcinoma (HNSCC), ineligible for chemoradiation. Methods Patients with stage III or IVA (American Joint Committee on Cancer (AJCC) guidelines, 7th edition, 2010) HNSCC of the oral cavity or oropharynx, aged ≥70 or ≥65 years and ineligible to receive cisplatin, amenable to radiotherapy (RT) with curative intent, received NBTXR3 as a single intratumoural (IT) injection followed by activation by intensity-modulated radiation therapy (IMRT; 70 Gy). The NBTXR3 dose corresponded to a percentage of the baseline tumour volume, measured by magnetic resonance imaging. The primary objectives were to determine the recommended phase II dose (RP2D), dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Safety and tolerability were assessed using National Cancer Institute CTCAE version 4.0. Antitumour activity was assessed by Response Evaluation Criteria in Solid Tumours 1.1. Results Nineteen patients were enrolled: 3 at the dose level of 5%, 3 at the dose level of 10%, 5 at the dose level of 15% and 8 at the dose level of 22% of the tumour volume. The MTD was not reached, and no DLTs or serious adverse event (SAEs) related to NBTXR3 were observed. Four adverse events related to NBTXR3 and/or the IT injection were reported (grade I–II). NBTXR3 remained in the injected tumour throughout RT, with no leakage in the surrounding healthy tissues. Specific RT-related toxicity was as expected with IMRT. The RP2D was determined as 22% baseline tumour volume. Preliminary signs of antitumour activity were observed. Conclusion Intratumoural injection of NBTXR3 followed by IMRT is feasible and demonstrated a good safety profile, supporting further evaluation at the RP2D in this patient population. Trial registration ClinicalTrials.gov NCT01946867 .

INTRODUCTION: Activated Tregs in the tumor micro-environment are correlated with poor outcomes, and are considered as key players in tumor immune-escape. So far, Treg depletion has not been successful in patients, either because adequate Treg depletion was not achieved or because Teff cells have either been impacted or depleted as well. RG6292 is the first anti-human CD25 antibody developed to specifically deplete human Tregs while preserving IL-2R STAT5 signaling and Teff activity. It has been optimized for ADCC and selective depletion of cells with high CD25 density (Treg). MATERIALS and METHODS: Adult patients with advanced solid tumors were given RG6292 i.v. Q3W as monotherapy (S1: NCT04158583) or in combination with atezolizumab 1200 mg Q3W (S2: NCT04642365) in a Ph1 dose escalation study. 76 pts have been treated at dose levels ranging from 0.3 mg to 165 mg in S1 and 48 pts at dose levels ranging from 0.3 mg to 160 mg in S2. In both studies a Bayesian logistic regression model with overdose control guided dose escalation was utilized. Data cutoff was May 27, 2022. Pharmacokinetic and pharmacodynamic analyses were undertaken in peripheral blood and tumor tissue. PK/PD modeling applied to Treg and Teff cells helped characterize and identify the optimal therapeutic window to ensure (1) relevant Treg depletion and (2) limited impact on T effector. RESULTS: RG6292 has a linear and time independent PK with no ADA detected. A Population PK-PD modeling approach was applied to Treg and Teff cells in the periphery. To predict the RG6292 effects in the tumor microenvironment (TME), the PK/PD relationships observed and characterized in the periphery for all cell subpopulations were considered the same, a tumor uptake factor of 15% was considered. At steady-state trough, a 70 mg Q3W dose was predicted to lead to 72% of patients with concentration above the Treg (%CD4) EC50 in tumor and 40% of patients with concentration above the Non-Treg (%CD4) EC50 in plasma. RG6292 induced a dose-dependent peripheral and intratumoral Treg depletion in on-treatment biopsies taken 28 days after initiation of treatment. Treatment did not appear to impact the number nor the functionality of intratumoral CD8 T cells nor any evident effect observed on PDL1 expression. In blood, stable levels of all other immune cells were observed after treatment. Moreover, in both studies a marginal increase of IFNg, CXCL10, IL-10, TNF was observed. No consistent gene expression alterations nor immune signatures could be observed when comparing BSL vs OT biopsies in S1. CONCLUSION: RG6292, consistent with its proposed mechanism of action, induces profound and preferential depletion of Treg cells over CD8+CD25+ in the periphery and in the TME at clinically safe doses between 35-70mg. Further development of RG6292 is currently being explored. Citation Format: Tamara Tanos, Kevin Smart, Valentina Gambardella, Kristoffer Rohrberg, Michael Ong, Maria Esperanza Rodriguez Ruiz, Jean-Pascal Machiels, Miguel Fernández Sanmamed, Josep Tabernero, Anna Spreafico, Daniel Renouf, Stephen Luen, Rachel Galot, Bernard Doger, Emiliano Calvo, Aung Naing, Samira Curdt, Nicolas Staedler, Mike Flores, Enrique Gómez Alcaide, Chiahuey Ooi, Michael Hettich, Sebastian Dziadek, Yuying Xie, Gabriel Schnetzler, Theresa Kolben, Linxinyu Xu, Vaios Karanikas, Christophe Boetsch. Pharmacokinetic/pharmacodynamic (PK/PD) relationships of the novel Treg depleter RG6292 in Phase Ia and Ib studies in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT176.

Background: MYC is a key transcription factor driving and maintaining human tumors. Since MYC has long been perceived as an “undruggable” target, to date, there is still no MYC inhibitor approved for clinical use. However, we designed and validated Omomyc, a MYC dominant negative mini-protein, demonstrating its potent therapeutic impact in various mouse models of cancer. Importantly, a Phase 1 study testing OMO-103, an Omomyc-based mini-protein developed by Peptomyc S.L., was successfully completed in 2022. Here, we present the main findings of the study and associated biomarker program. Material and Methods: A phase I dose escalation study was performed in all-comers solid tumor patients, with a 3+3 design of 6 dose levels ranging from 0.48 to 9.72mg/kg, as a weekly 30-min i.v. infusion. Tumor and liquid biopsies were collected at screening, upon and at the end of treatment, to assess different biomarkers of drug activity. Results: 22 patients with advanced solid tumors were included and 18 patients were considered evaluable for response by CT scan. Of these, 9 achieved SD. The PK analysis revealed a plasma half-life of >40h. No ADAs were detected in any of the patients. Drug pharmacodynamics supported target engagement, as demonstrated by Digital Spatial Profiling analysis showing shut down of MYC transcriptional signature in patients’ tumor biopsies. In addition, a distinctive pharmacodynamic cytokine signature that correlated with stable disease was found through liquid biopsies already 3 to 4 weeks before CT scan. Importantly, a cytokine signature was also identified as being predictive of disease stabilization at baseline and could help stratify patients in upcoming additional clinical studies. Finally, several anti-tumor immune related markers were also found modulated upon OMO-103 treatment. Conclusion: OMO-103 demonstrates a favorable safety profile, with encouraging signs of activity supported by predictive and pharmacodynamic biomarkers worthy of further investigation. Citation Format: Marie-Eve Beaulieu, Elena Garralda, Sílvia Casacuberta-Serra, Sandra Sandra Martínez-Martín, Emiliano Calvo, Víctor Moreno, Sergio López-Estévez, Laia Foradada, Guzman Alonso, Elena Corral, Bernard Doger, Tatiana Hernández, Judit Grueso, Íñigo Íñigo González-Larreategui, Erika Serrano del Pozo, Hugo Thabussot, Virginia Castillo Cano, Mariano F. Mariano F. Zacarías-Fluck, Jastrinjan Kaur, Fabio Giuntini, Jonathan R. Whitfield, Josefa Morales, Manuela Niewel, Laura Soucek. Identification of potential biomarkers of response to OMO-103, a first-in-modality pan-MYC inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3435.

Background: MEN1611 (MEN) is an oral PI3K inhibitor active on the p110α mutant and wild type, β and γ isoforms, while sparing the δ. B-PRECISE-01 is an open-label, 2-arm, phase 1b study investigating MEN1611 in combination with trastuzumab ± fulvestrant in patients with HER2 positive/PIK3CA mutated metastatic breast cancer (MBC). No dose-limiting toxicities were observed during the dose-escalation step and MEN1611 48 mg BID was selected as the recommended phase 2 dose (RP2D) for cohort expansion (CE). Methods: Eligible patients had HER2+/PIK3CA-mutated MBC and were treated with at least 2 prior lines of anti-HER2-based therapy in the advanced/metastatic setting including trastuzumab. Patients received MEN1611 + trastuzumab (MEN+T); hormone receptor positive (HR+) postmenopausal women received M+ T + fulvestrant (MEN+T+F). Recruitment was closed in December 2021. Pooled safety and efficacy data from the two subpopulations of CE are presented herein. Results: As of June 2022, 62 female patients were treated: 56 of them with MEN1611 48 mg BID (25 MEN+T and 31 MEN+T+F). Median age 55.5 years (range 34-78), 21% premenopausal, ECOG PS 0-1: 95.2%. Median metastatic regimens 4; 71.0% had prior pertuzumab and 91.9% had prior T-DM1. Common treatment-emergent adverse events (TEAEs, ≥20%) were diarrhea 66.1%, nausea 45.2%, hyperglycemia 43.6%, anemia 35.5%, asthenia 29.0%, decreased appetite 27.4%, rash 25.8%, aspartate aminotransferase increased 22.6%, vomiting 22.6%, and pyrexia 22.6%. Common TEAEs with CTCAE grade ≥3 (≥10%) were hyperglycemia (22.6%) and diarrhea (11.3%). Most treatment-related AEs (TRAEs) were reversible and manageable by supportive care. TEAEs leading to permanent treatment discontinuation occurred in 9 patients (14.5%), the only TEAE occurring in more than one patient was lipase increased (3.2%). TEAEs caused temporary treatment interruptions in 32 patients (51.6%), the most common being hyperglycemia (21.0%) and diarrhea (9.7%). TEAEs leading to dose reduction occurred in 14 patients (22.6%), the most common being diarrhea (6.5%), hyperglycemia (3.2%) and stomatitis (3.2%). Serious TRAEs were experienced by 12 patients (19.4%): hyperglycemia 6 patients, diarrhea 3 patients, anemia, general physical health deterioration, generalized edema, lipase increased, ketoacidosis and pneumonitis (1 patient each). In the efficacy-evaluable population at the RP2D (n=41) 14 patients (34.1%) showed partial response (MEN+T 5/15, MEN+T+F 9/26), 1 patient (2.4%) had a complete response (MEN+T 1/15) and 23 patients (56.1%) had stable disease (MEN+T 6/15, MEN+T+F 17/26) as best response. At the RP2D, the median (95% CI) overall survival (OS) was 21.9 (11.9, NE) months and the median (95% CI) progression free survival (PFS) 5.6 (3.7, 7.2) months. In the MEN+T group, the median OS was 11.9 (5.7, NE) months and median PFS 3.9 (2.3, 6.7) months. In the MEN+T+F group the median OS was 21.9 (16.9, NE) months and median PFS 5.7 (3.7, 11.5) months. Five patients continue on treatment. Conclusions: Updated results from B-PRECISE-01 demonstrated that MEN1611 combined with trastuzumab ± fulvestrant continued to show a manageable safety profile with encouraging anti-tumor activity and duration of response in heavily pre-treated patients with HER2+/PIK3CA-mutated advanced or metastatic breast cancer. Citation Format: Martine Piccart, Audrey Hennequin, Manuel Ruiz Borrego, Santiago Escrivá-de-Romani, Anja Williams, Begoña Jiménez Rodríguez, Gianluca Del Conte, Sacha J. Howell, Michela Palleschi, Matteo Simonelli, Francois P. Duhoux, Diego Tosi, Bernard Doger de Speville Uribe, Yolanda Jerez Gilarranz, Pierfrancesco Tassone, Giuseppe Curigliano, Simon Waters, Philippe Aftimos, Hans Wildiers, Simona Scartoni, Bartomeu Piza Vallespir, Ram Charan Shankaraiah, Krzysztof Grzegorzewski, Nassir Habboubi. MEN1611, a PI3K inhibitor, combined with trastuzumab ± fulvestrant for HER2+/PIK3CA mutant advanced or metastatic breast cancer: updated safety and efficacy results from the ongoing phase 1b study (B-PRECISE-01) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-05.

BackgroundADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10+ tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577).MethodsEligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08–0.12×109 (dose group 1), 0.5–1.2×109 (dose group 2), and 1.2–15×109 (dose group 3/expansion) transduced cells.ResultsEleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m2 on days –5 to –2 and cyclophosphamide 1800 mg/m2 on days −5 to −4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10.ConclusionsADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing.

Novel antibody formats such as bispecifics have increased risk of immunogenicity, impacting safety and efficacy. LY3415244, a novel T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM3)-PDL1 (programmed death (ligand) 1) bispecific caused neutralizing antibody–drug antibodies (ADA) in 12 of 12 patients and required study termination. Novel approaches are needed to ameliorate and manage this undesirable effect of therapeutic antibodies. See related article by Hellmann et al., p. 2773

498 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules comprising a small (~2 kDa) bicyclic peptide targeting Nectin-4 tumor antigen linked to cytotoxin MMAE via a valine-citrulline cleavable linker. BTCs represent a unique therapeutic class, distinct from ADCs and with pharmacokinetic properties analogous to small molecules. Presented are the monotherapy dose escalation results of the ongoing Phase I/II clinical trial of BT8009 (NCT04561362). Methods: In the Part A 3+3 dose escalation portion of the study, BT8009 monotherapy was administered weekly (2.5, 5, 7.5 mg/m2) or every other week (7.5, 10 mg/m2) of a 28-day cycle, or on days 1 and 8 of a 21-day cycle (7.5 mg/m2). Primary objectives were to assess safety of the monotherapy and define maximum tolerated and recommended Phase II dose(s) (RP2D). Key secondary objectives were antitumor activity per RECIST v1.1 and PK parameters. Results: At time of the 20 Sept 2022 data cut-off, 49 pts had received BT8009 (24 pts with UC): weekly (7 pts at 2.5 mg/m2, 20 pts at 5 mg/m2, 5 pts at 7.5 mg/m2); biweekly (5 pts at 7.5 mg/m2, 7 pts at 10 mg/m2); and days 1+8 of a 21-day cycle (5 pts at 7.5 mg/m2). Two RP2Ds have been determined: 5 mg/m2 given weekly on a 28-day cycle and 7.5 mg/m2 given on days 1+8 of a 21-day cycle. Median age was 66 y, 59% pts were male, and median prior lines of therapy was 3 (range 1-15). Most common treatment-related adverse events of any grade experienced by ≥15% of pts were nausea, fatigue, diarrhea, decreased appetite, alopecia, asthenia, pyrexia, and neutrophil count decreased/neutropenia; majority were mild to moderate in severity. One DLT (G3 asthenia) was reported at the 7.5 mg/m2 weekly dose level and 1 DLT (G4 sepsis) at the 10 mg/m2 biweekly dose level. Treatment-related SAEs occurred in 5 pts. No pt discontinued treatment due to an AE. No treatment-related deaths occurred. Of 8 efficacy evaluable pts with UC treated with a RP2D of 5 mg/m2, there was 1 complete response, 3 partial responses (PR), and 3 stable diseases (SD), for an ORR of 50% and clinical benefit rate of 75% (CR+PR+SD≥16 wks). Median duration of response has not yet been reached, but as of 20 Sept 2022 was at least 11 months. Both plasma BT8009 and MMAE exhibited linear pharmacokinetics, with short half-life for BT8009 (

Monoclonal antibodies (mAbs) have become one of the main therapeutic weapons in modern oncology, mainly as targeted therapies, and immune checkpoint inhibitors. The generation of anti-drug antibodies (ADAs) after their administration can alter their pharmacokinetic, pharmacodynamic, efficacy and safety profile causing infusion-related reactions. Several risk factors have been associated with ADAs development, notably host genetics and immune status, comorbidity, concomitant medications, mAbs molecular structure, dose and route of administration. ADAs are not usually tested on daily clinical practice, being their analysis generally placed in early stages of drug development. ELISA-type assay the most common method. ADAs detection can involve important implications for treatment strategies of cancer patients, guiding therapeutic adjustment. In oncology, some studies about ADAs synthesis related to targeted therapies and immune checkpoint inhibitors have been recently published. Several strategies are proposed to reduce mAbs immunogenicity, such as different schedules, routes of administration or even the use of immunosuppressants. Another question that arises in relation to ADAs generation is the need to measure the concentration levels of active drug to guide the administration schedule. In this review, we will discuss all the aspects that are currently under discussion in relation with ADAs in oncology.

Adoptive cell therapy with chimeric antigen receptor T cells has caused a significant revolution in the treatment of hematological malignancies. Unfortunately, for solid tumors, this treatment modality has been proven insufficient to achieve significant antitumor activity. The use of modified T cell receptors towards tumor-associated antigens (NY-ESO, MAGE-A4) has recently shown antitumor activity in synovial sarcoma. Also, treatment with tumor-infiltrating lymphocytes shows clinical activity in metastatic cervical cancer and melanoma resistant to checkpoint inhibitors. Strategies to improve results and broaden the applicability of therapeutic lymphocytes for solid tumors include local delivery, fourth generation chimeric antigen receptor T cells, off-the-shelf T lymphocytes and private neoantigen-directed cells, among others. In this review, we summarize the status of adoptive cell therapy using T cells for solid tumors and the investigational strategies being tested in this field.

BT8009 is a Bicycle® Toxin Conjugate (BTC™), a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting Nectin-4 tumor antigen, linked to cytotoxin (monomethyl auristatin E [MMAE]) via a valine-citrulline (val-cit) cleavable linker. Due to their small size, BTCs represent a unique therapeutic class, combining the pharmacology normally associated with a biologic with the pharmacokinetic properties of a small molecule. Here, we describe the preliminary monotherapy dose escalation results of the ongoing multicenter Phase I/II clinical trial (NCT04561362) that assesses the safety and tolerability of BT8009 administration in patients with advanced solid tumors associated with Nectin-4 expression, not exposed to enfortumab vedotin. Patients were treated until disease progression or intolerable toxicity, with tumor assessments for response per RECIST taken every two months. Nectin-4 expression levels were measured in tumor tissue. Thirty-four patients were initiated on weekly BT8009 (7 patients at 2.5 mg/m2, 20 patients at 5.0 mg/m2, and 4 patients at 7.5 mg/m2) or biweekly BT8009 (3 patient at 7.5 mg/m2). Baseline demographics were 62% patients were male, 44% and 56% were ECOG 0 and ECOG 1, respectively, median age was 65.5 years. BT8009 exhibits linear pharmacokinetics. The most common treatment-related adverse events were nausea (14 patients, 41%; ≥ G3 1 patient, 3%), fatigue (13 patients, 38%; ≥ G3 2 patients, 6%), anorexia (11 patients, 32%; ≥ G3 0 patients), constipation (10 patients, 29%; ≥ G3 1 patient, 3%) and anemia (10 patients, 29%; ≥ G3 3 patients, 9%). To date, BT8009 had low incidences of ocular disorders (3%), hyperglycemia (6%), neuropathy (6%), and rash (18%). There was 1 dose-limiting toxicity (G3 asthenia) reported at the 7.5 mg/m2 weekly dose level. Six patients (18%) experienced an SAE, with only 1 related SAE (vomiting). Treatment-emergent AEs resulting in treatment discontinuation, dose interruption, or reductions were observed in 2 patients (6%), 11 patients (32%), and 5 patients (15%), respectively. Preliminary confirmed responses observed in patients with urothelial carcinoma (UC) enrolled in the 5 mg/m2 cohort show 4/8 patients with a complete response (CR) or partial response (PR), including 1/8 patients with a CR and 3/8 patients with a PR, and 2/8 patients (25%) with stable disease (SD), reflecting a 50% overall response rate and a 75% disease control rate in UC patients for this cohort. BT8009 exhibits a promising preliminary tolerability profile and preliminary antitumor activity. The molecule will continue to be explored in the current dose-escalation/dose-expansion study of BT8009 monotherapy and in combination with nivolumab. Citation Format: Meredith McKean, Capucine Baldini, Loic Verlingue, Bernard Doger, Gerald Falchook, Antoine Italiano, Julia Lostes, Oscar Reig, Roshawn Watson, Sebastien Hazard, Dominic Smethurst, Giulia Fulci, Hongmei Xu, Phil Jeffery, Kevin Lee, Irene Braña, Sophie Cousin, Elisa Fontana, Hendrik-Tobias Arkenau. BT8009-100 phase I/II study of novel bi-cyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies associated with nectin-4 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT025.

TPS6099 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein targeting a subset of MHC class II molecules that mediate antigen presenting cell (APC) and CD8 T-cell activation. Data from a non-randomized, phase II trial of efti plus pembrolizumab (TACTI-002) showed encouraging antitumor activity and manageable safety when given as second-line treatment of patients with recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC). TACTI-003 (NCT04811027) is a multicenter, open label, randomized phase IIb trial to investigate efti plus pembrolizumab in the first-line setting for RM-HNSCC. Methods: A total of 154 patients (pts) are currently being recruited into two cohorts (A+B). In cohort A, pts with tumors that are CPS≥1 will be randomly assigned 1:1 to receive either efti (30 mg subcutaneously Q2W for initial 6 months, thereafter Q3W) plus pembrolizumab (400 mg intravenously Q6W) for up to two years or pembrolizumab alone. Randomization will be stratified by CPS (1-19 vs. ≥ 20) and ECOG PS (0 vs. 1). Pts with tumors that are CPS < 1 will receive efti plus pembrolizumab (cohort B). Imaging will be performed every 9 weeks. The primary endpoint (EP) is objective response rate (ORR) by RECIST1.1. Secondary EPs include overall survival, ORR according to iRECIST, time to and duration of response, disease control rate, progression-free survival, occurrence of anti-efti -specific antibodies, safety, and quality of life. Exploratory endpoints comprise biomarkers. The study has been approved by relevant competent authorities, ethic committees and IRBs. Clinical trial information: NCT04811027.

e15069 Background: PDXs have become a core component of translational cancer research. Developing these models can become challenging since little is known about which factors influence engraftment rates. We sought to determine which clinical, pathological, or molecular factors may predict better engraftment rates in PDXs. Methods: Between March 2017 and January 2021, biopsies obtained from patients with primary or metastatic cancer were implanted into athymic nude mice. Statistical analyses were performed to identify factors that could correlate with final engraftment defined as achievement of at least three passes and sampling of PDXs tumors. We focused on clinical (patient factors) pathological (patients’ tumor samples) and molecular characteristics (patients’ tumor samples) analyzed either by immunohistochemistry (IHC) or next generation sequencing (NGS). Results: 585 tumor samples were collected and implanted. 21 failed to engraft due lack of malignant cells. Of 564 tumor-positive samples, 187 (33.2%) PDXs achieved successful growth at time of analysis (Feb, 21). The following clinical characteristics were correlated with engraftment: systemic antibiotics within 2 weeks of sampling: (38.1% (72/117) antibiotics- group vs 30.7% (115/260) no-antibiotics) (p = 0.048); systemic steroids within 2 weeks (41.5% (34/48) the steroids-receiving group vs 31.7% (153/329) no-steroids) (p: 0.05). For women, menopausal status was predictive: 34.9% (95/177) in postmenopausal achieved growth, Vs 20,4% (10/39) for premenopausal (p = 0.031). Baseline LDH levels: 74.9% (140/187) LDH levels above the upper limit of normality (ULN) against 25.1% (47/187) with normal LDH (p = 0.034). Tumor grade: Grade 1: 25.4% (47/187); grade 2: 34.8% (65/187) and grade 3: 40.1% (75/187) tumors achieved successful growth (p = 0.043). Similarly, higher ki67 levels were also correlated with better engraftment rates: (low (Ki67 < 15%): 8.9% (9/45) achieved growth, Vs high (Ki67 > 15%): 31% (35/113) (p:0.002). Presence of lymphovascular invasion in tumor sample was also predictive: 42.2% (97/230) with lymphovascular Vs 26.9% (90/334) of samples with no invasion (p = 0.0001). Likewise, 41.8% (59/141) of neural invasion-positive samples achieved growth against 30.3% (128/428) (p = 0.008). Mismatch repair deficient tumors showed better engraftment rates: 62.1% (18/29) achieved growth vs 40.8% (75/184) of proficient tumors (p = 0.026). 84 PDX were breast models, among which 57.9% (11/19) ER negative models grew, Vs 15.4% (10/65) of ER positive models (p = 0.0001). Conclusions: tumors with higher grade and Ki67, lymphovascular and/or perineural invasion, with dMMR and ER expression negative have higher chance of PDX development. Some clinical characteristics can also interfere with PDXs development such as use of steroids or antibiotics prior sampling.

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]

8581 Background: L is a novel anticancer agent that inhibits trans-activated transcription and modulates the tumor microenvironment. L is approved by the FDA for metastatic SCLC patients (pts) with progressive disease (PD) on or after platinum-based chemotherapy (CT). The LUPER study is assessing the safety, tolerability, and preliminary efficacy of L+P as second-line regimen for SCLC pts after failure of platinum-based CT. Phase 1 data are presented here. Methods: In this phase 1/2 trial (NCT04358237), adult pts with histologically confirmed SCLC, PD to a previous CT-containing regimen (≥4 weeks before study initiation), no prior exposure to immunotherapy, ECOG PS of 0-1, and measurable disease as per RECIST 1.1 are eligible. Pts with treated, stable, and asymptomatic brain metastases (BMs) are allowed. A 3+3 dose-escalation was done to determine the recommended phase 2 dose (RP2D) of L+P. L was dosed at 2.4 mg/m2 and 3.2 mg/m2 IV Q3W in the dose level (DL)1 and 2, respectively, in combination with fixed dose of P (200 mg IV Q3W). The RP2D was the highest DL at which 0/3 pts or ≤1/6 pts experienced dose-limiting toxicities (DLTs) during the first cycle. Treatment was administered until PD, unacceptable toxicity, or consent withdrawal. Secondary endpoints include safety as per CTCAE 5.0, preliminary efficacy, and pharmacokinetics. Results: Thirteen pts were enrolled across 3 hospitals in Spain (DL1, n = 7; DL2, n = 6). Median age was 66 (range 43–78) years, 46.2% were female, 61.5% had ECOG PS of 1, 38.5% had platinum-free interval < 90 days, 30.8% had LDH > upper normal limit, and 15.4% had BMs. One DLT (G3 asthenia) and one G4 neutropenia lasting > 3 days (controlled with G-CSF prophylaxis upon C2, without requiring dose delay or modification) occurred in the DL1. No DLT were reported in the DL2. The RP2D was identified as 3.2 mg/m2 L and 200 mg P IV Q3W. At data cutoff (Jan 21, 2022), 5 (38.4%) pts remained on treatment (1 pt in DL1 discontinued due to COVID-19 in cycle 1). Median duration of treatment was 2.1 (0–11.8) months, 5 (38.5%) pts had ≥8 cycles, and median relative dose intensity of L and P were 91.1% and 95.7%, respectively. Immune-related AEs (G2 pneumonitis; G3 ALT increased) led to P discontinuation in 2 (15.4%) pts. Responses were shown in both DLs, with ORR of 30.8% (1 confirmed complete response and 3 partial responses); 3 pts had stable disease (SD; including 1 patient with SD > 12 weeks) and 5 (38.5%) pts experienced PD. Conclusions: This is the first report to demonstrate a manageable safety profile and preliminary efficacy of second-line L+P for relapsed SCLC pts. This combination warrants further confirmation in the ongoing expansion phase 2. Clinical trial information: NCT04358237.

9003 Background: Eftilagimod alpha (E) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen presenting cell (APC)/CD8 T-cell activation. Stimulation of the APCs and subsequent T cell recruitment with E may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We hereby report results of the extended first-line non-small cell lung carcinoma (NSCLC) cohort of the TACTI-002 (“Two ACTive Immunotherapies”) phase II trial. Methods: Pts with untreated metastatic NSCLC, unselected for PD-L1 expression were recruited. Objective response rate (ORR) by iRECIST was the primary endpoint (EP) and secondary EPs include ORR by RECIST 1.1, tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS) and exploratory biomarker. Pts received 30 mg E SC q2w for 8 cycles (1 cycle= 3 weeks) and then q3w for up to 1 year with P (200 mg IV q3w for up to 2 years). Imaging was done every 8 weeks. PD-L1 was assessed centrally. This has been approved by relevant CAs, ECs, and IRBs. Results: From Mar 2019 to Nov 2021 114 pts were enrolled. Median age was 67 years (44-85) and 74% were male. ECOG PS was 0 and 1 in 37% and 63% of pts, respectively. Pts presented squamous (35%) or non-squamous (62%) NSCLC with 88% of pts at stage IV at the time of study entry. All PD-L1 subgroups were represented (Table). Pts received median 6.0 (range 1–35) P and 7.0 (1-22) E administrations. 19 (17%) pts discontinued treatment due to adverse events (AEs). The most common (≥15%) AEs were dyspnea (33%), asthenia (30%), decreased appetite (22%), cough (20%), anemia (20%), fatigue (19%), pruritus (18%), constipation (17%) and diarrhea (15%). At data cut-off (Jan 2022), 75 pts with a minimum follow-up of 6 months were evaluated for efficacy. ORR (iRECIST) was 37.3% in the ITT and 41.8%% in the evaluable pts assessed by local read. DCR 73.3% was reported. Response rate for squamous and non-squamous pathology were 33.3 % and 40.3 %, respectively. Results according to RECIST 1.1 were comparable. Responses were observed in all PD-L1 subgroups (Table). 24/28 (86%) responses were already confirmed while median duration of response was not yet reached (5 events). Conclusions: E + P is safe and shows encouraging antitumor activity in first-line metastatic NSCLC patients unselected for PD-L1, warranting further investigation. Clinical trial information: NCT03625323. [Table: see text]

BackgroundA majority of patients with advanced NSCLC develop disease progression with first-line immune-checkpoint inhibitors (ICI) ± chemotherapy. In the setting of ICI resistance, effective strategies to provide deep and durable responses are urgently needed. Lifileucel (LN-144) and LN-145 are centrally manufactured (cryopreserved drug-product, 22-day manufacturing process) autologous TIL products that have demonstrated activity in advanced melanoma, cervical cancer, and head and neck carcinoma.1–4 Here, we report the first safety and efficacy data for LN-145 as monotherapy in patients with advanced NSCLC.MethodsIOV-COM-202 (NCT03645928) is a phase 2 multicenter, multicohort, open-label study evaluating autologous TIL cell therapy in patients with solid tumors. We report data from Cohort 3B, investigating LN-145 monotherapy in patients with advanced or metastatic NSCLC. Eligibility required 1–3 prior lines of systemic therapy, including either ICI or oncogene-directed therapy. Treatment included nonmyeloablative lymphodepletion, TIL infusion, and ≤6 interleukin-2 doses. Primary endpoints were safety (incidence of Grade ≥3 treatment-emergent adverse events [TEAEs]) and objective response rate (ORR, investigator-assessed using RECIST v1.1). Exploratory biomarker analyses, including T-cell receptor (TCR) repertoire, were performed.ResultsAs of 24June2021, 28 patients received LN-145 (full-analysis set [FAS]; table 1) and 24 were efficacy-evaluable; all had received prior ICI. TIL were most commonly harvested from lung metastases (57.1%). Safety was consistent with the underlying disease and known TEAE profiles of nonmyeloablative lymphodepletion and interleukin-2. Grade ≥3 TEAEs in ≥30% of patients were thrombocytopenia and anemia. The ORR in the FAS and efficacy-evaluable set was 21.4% (6/28) and 25.0% (6/24; figure 1), respectively. Median duration of response was not reached and 83% (5/6) of responses were ongoing at last follow-up (median study follow-up, 8.2 months). One patient had a complete metabolic response, ongoing at 20.7 months; 2 responses occurred in patients who were PD-L1–negative. All responders received ≥2 prior lines of systemic therapy. Twenty-six patients had TIL available from the final drug-product for TCR repertoire analysis; mean (min-max) number of unique TCR clones was 13,142 (3093–35,734) and Shannon Entropy index was 7.34 (3.7–12). Updated data will be presented.Abstract 458 Figure 1Best percentage change from baseline in target lesion sum of diameters for efficacy-evaluable setAbstract 458 Table 1Baseline patient demographic and clinical characteristics; efficacy parametersConclusionsLN-145 was successfully manufactured and one-time treatment produced an expected safety profile and durable responses in heavily pretreated patients with NSCLC, regardless of PD-L1 expression. The activity of LN-145 monotherapy is encouraging and warrants further investigation of LN-145 as a single-agent and in combination in patients with NSCLC in ongoing studies IOV-LUN-202 (NCT04614103) and IOV-COM-202 Cohorts 3A and 3C (3B closed to enrollment).AcknowledgementsThis study and analysis were funded by Iovance Biotherapeutics, Inc. (San Carlos, CA, USA). Writing support was provided by Amanda Kelly (Iovance); graphics support was provided by Cognition Studio (Seattle, WA, USA).Trial RegistrationNCT03645928ReferencesSarnaik AA, et al. J Clin Oncol 2021; doi: 10.1200/JCO.21.00612.. Thomas SS, et al. J Clin Oncol 2021;39: (suppl; abstract 9537).Jazaeri A, et al. J Clin Oncol 2019;37: (suppl; abstract 2538).Jimeno A, et al. J Immunother Cancer 2020;8: (suppl; abstract A378).Ethics ApprovalThe study was approved by Advarra Institutional Review Board, approval number Pro00035064 and all study participants provided written consent via signature of the IRB-approved Informed Consent form.

Background Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment may lead to stronger anti-tumor responses in combination with pembrolizumab than observed with pembrolizumab alone. We report results from stage 1 of all parts of the study (NCT03625323). Methods Patients (pts) with unselected PD-L1 expression were recruited into 3 cohorts: part A; 1st line, immunotherapy naive NSCLC; part B; 2nd line, immunotherapy refractory NSCLC and part C; 2nd line immunotherapy naive HNSCC. The study uses a Simon’s 2-stage design, with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, PD and immunogenicity. Fifty-eight (58) pts were recruited into stage 1. Up to additional 51 pts will be recruited if a pre-specified ORR threshold is met for the respective part. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles; pembrolizumab is administered at 200 mg intravenous infusion every 3 wks for up to 2 yrs. The study was approved by ethic committees and institutional review boards. Results Between Mar 2019 and Jul 2020 88 pts were enrolled. The median age was 67 yrs (range 53-84) and 70% were male. ECOG PS 0:1 was 42% and 58% respectively. Pts from all PD-L1 tumor expression subgroups were recruited. Pts received a median of 4 (1-25) pembrolizumab and 5.5 (1-22) efti administrations. The most common (≥ 15%) treatment emergent adverse events (TEAEs) were asthenia (28%), cough (27%), decreased appetite (22%), dyspnea (21%), fatigue (18%) and diarrhea (15%). Three (3) pts discontinued due to treatment related AEs. The ORR (acc. to iRECIST) of the 58 patients enrolled into stage 1 is shown in (table1). PK profiles after the first or repeated efti dosing were in line with previous studies, with a mean Cmax at7 ng/ml reached ≤ 24h. Circulating TH1 biomarkers 2 weeks after the last efti administration were increased (3 months vs. baseline) by a mean 61% and 209% for CXCL10 (Student paired t-test, p=0.02, n=31) and IFN-γ(p= 0.02, n=19), respectively. Conclusions Efti plus pembrolizumab is safe and shows encouraging antitumor responses in NSCLC and HNSCC patients Trial Registration NCT03625323 Ethics Approval The study was approved by relevant ethic committees and institutional review boards.

SummaryBackground A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; median overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, decreased appetite, vomiting, alopecia) were mostly mild or moderate. Conclusion Doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2 on Day 1 q3wk has shown noteworthy activity in relapsed SCLC and a manageable safety profile. The combination is being evaluated as second-line therapy for SCLC in an ongoing, randomized phase III trial. Clinical trial registrationwww.ClinicalTrials.gov code: NCT01970540. Date of registration: 22 October, 2013.

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).

Lay Summary Currently, the complexity of clinical trial development in oncology is being further complicated by the coronavirus disease 2019 (COVID‐19) pandemic, which is reducing the resources needed to comply with protocol‐specific procedures while putting patients in units, who are already vulnerable, at increased general risk not only for COVID‐19 infection but also with respect to their baseline disease.Individualizing the management of patients while ensuring their safety and adherence to the study protocol, establishing specific staff contingency plans, and maintaining sponsor and contract research organization (CRO) alignment are some of the key issues for maintaining the continuity of cancer patients’ investigational treatment and minimizing their infection risk as well as the risk to staff members of the unit, sponsors, and CROs while maintaining the integrity of data quality and compliance with good clinical practice., This commentary describes the potentially deep, specific, and rapid impact of the coronavirus disease 2019 pandemic on clinical research units in oncology, and it establishes different processes and action plans in order to allow the performance of clinical research activities during this challenging period.

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors.Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model.The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.15-2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01-1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: -0.15 to -0.02; p = 0.01) per month in responders compared with non-responders.hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy.

Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

BackgroundEftilagimod alpha (efti) is a soluble LAG-3 protein targeting a subset of MHC class II, thus mediating antigen presenting cell (APC) and CD8 T-cell activation. Such stimulation of the dendritic cell network and resulting T cell recruitment by efti may lead to stronger anti-tumor responses than observed with pembrolizumab alone. We hereby report results of the 2nd line metastatic head and neck squamous cell carcinoma (HNSCC) cohort (part C) of the TACTI-002 phase II trial (NCT03625323).MethodsEligible patients (pts) with HNSCC, unselected for PD-L1 expression with disease progression on or after 1st line platinum-based therapy, received 30 mg subcutaneous efti Q2W for 24 weeks and 200 mg pembrolizumab Q3W for up to 2 years or until disease progression. The study used a Simon’s 2-stage design with objective response rate (ORR) as the primary endpoint (EP). Secondary EPs included tolerability, progression free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics, and immunogenicity. Tumor response was assessed Q9W. PD-L1 was assessed centrally (22C3 clone). The study was approved by ethic committees and institutional review boards.ResultsBetween Mar 2019 and Jan 2021, 39 pts were enrolled (cut-off Apr 2021). The median age was 62 yrs (range 37–84) with 90% male pts. ECOG was 0 and 1 in 33% and 67%, respectively. Primary tumor location at diagnosis was oropharynx (36%), oral cavity (31%), hypopharynx (18%) and larynx (15%) with all PD-L1 subgroups (CPS< 1, ≥1 to ≤19; ≥20) being represented. All pts were pre-treated with platinum-based chemotherapy. Thirty-seven (37) pts were evaluated for response with ORR (iRECIST) of 30% (95% CI 16–47%) with 5 (14%) CRs; 6 (16%) PRs; 3 (8%) SDs; 17 (46%) PDs and 6 (16%) pts not evaluable. Median PFS was 2.1 months and 30+% were progression-free at 6 months. One patient (3%) discontinued due to pembro-related adverse event. The most common (>10%) treatment emergent adverse events were hypothyroidism (21%), cough (18%), asthenia (15%), fatigue (13%), anemia (13%), diarrhea (13%) and weight decreased (13%).ConclusionsEfti in combination with pembrolizumab is safe, showing encouraging antitumor activity in platinum pre-treated, 2nd line HNSCC patients. For further investigation of this combination, a 1st line HNSCC trial (NCT04811027) has been initiated.Trial RegistrationNCT03625323Ethics ApprovalThe study was approved by relevant ethic committees and institutional review boards

PURPOSE/OBJECTIVE(S) Concurrent radiotherapy (RT) with high-dose cisplatin, or cetuximab in case of intolerance to cisplatin, are the non-surgical standard treatment for locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, elderly patients, patients with poor performance status, comorbidities, and/or intolerance may not benefit from these treatments and represent a high unmet medical need. New approaches are thus needed to improve the patient clinical outcomes without adding toxicity. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by RT. NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, without adding toxicity to healthy tissues. We present here current results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population (ClinicalTrials.gov: NCT01946867). MATERIALS/METHODS Patients with stage III-VA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks). A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part of the study. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST v1.1. Safety is also evaluated. RESULTS As of August 13, 2020, 43 patients have been treated in the dose expansion part of the study. The median age was 70.7 years old (range: 50.7- 89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3 - 222.3). In the evaluable population for efficacy (N = 31), the ORR of the primary lesion was 83.9% and the CRR 67.7% at a median time of 7.8 months after NBTXR3 injection. Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. The recruitment is ongoing and updated efficacy and safety results will be presented. CONCLUSION NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial.

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent type of malignancy in Caucasians worldwide. Several factors have been correlated with aggressiveness and likelihood of recurrence and distant metastases, which are challenging to control. Metastatic disease has a dismal prognosis, and standard chemotherapy has failed to significantly improve outcomes. Recently, it has been recognized that cSCCs are highly mutated tumors with a denoting potential likelihood of response to immune checkpoint blockade. Cemiplimab is an anti-programmed cell death protein 1 (PD-1) antibody recently approved for the treatment of unresectable locally advanced or metastatic cSCC by the U.S. Food and Drug Administration (FDA) and the European Commission with a compelling response rate and an acceptable safety profile.

Background TIL (especially CD8+ T cells) in the tumor microenvironment is associated with survival outcomes in many solid tumors, including melanoma (Mel), head and neck squamous cell carcinoma (HNSCC), and non-small cell lung cancer (NSCLC). Lifileucel (LN-144), has shown efficacy with durable responses in advanced melanoma (Mel) (Sarnaik et al., ASCO 2020), metastatic cervical cancer (Jazaeri et al., ASCO 2019), and LN-145 + pembrolizumab in HNSCC (Jimeno et al., SITC 2020). TIL therapy has shown evidence of efficacy in metastatic NSCLC in a Phase 1 study (Creelan et al., ASCO 2020). Methods IOV-COM-202 (NCT03645928) is a Phase 2 global, open-label multi-cohort, non-randomized study designed to evaluate the safety and efficacy of TIL therapy as a single agent or in combination with immune checkpoint inhibitors. All patients receive either, lifileucel, LN-145 or LN-145-S1 (PD-1 select TIL), which is manufactured at centralized GMP facilities generating a cryopreserved infusion product which is shipped to the treatment centers. Cohort 1, 2 and 3 enroll Mel, HNSCC and NSCLC patients, respectively (Table 1). Patients undergo a nonmyeloablative lymphodepletion (NMA-LD) regimen prior to TIL infusion, followed by up to 6 doses of intravenous IL-2. Patients in Cohorts 1A, 2A, and 3A start pembrolizumab following tumor harvest for TIL generation, but prior to NMA-LD. Pembrolizumab is dosed per label. Patients in Cohorts 1B, IC and 3B receive LN-145-S1, lifileucel, and LN-145, respectively. Cohort 3C patients receive a dose of ipilimumab and nivolumab prior to tumor harvest, with nivolumab continuing Q4W for up to 2 years, or until progression or unacceptable toxicity. Key eligibility includes: ≥ 18 years of age; RECIST measurable disease; ≥ 1 lesion(s) available for TIL generation; ECOG PS 0-1. The primary endpoint: ORR per RECIST v1.1. Secondary endpoints: safety, CR rate, DOR, DCR, PFS, and OS. Table 1.IOV-COM-202 Study DesignCohortTIL ManufacturingCohort 1A: Melanoma PD-1/ PD-L1 Naïve LN-144 + Pembrolizumab N=12LN-144: 22-day manufacturingCohort 1B: Melanoma ≥1 prior systemic therapies LN-145-S1 N up to 27LN-145-S1: PD-1 selected TILCohort 1C: Melanoma ≥1 prior systemic therapies LN-144 Gen 3 N up to 27LN-144 Gen 3: 16-day manufacturingCohort 2A: Head and Neck PD-1/ PD-L1 Naïve LN-145 + Pembrolizumab N=19LN-145: 22-day manufacturingCohort 3A: NSCLC PD-1/ PD-L1 Naïve LN-145 + Pembrolizumab N=12LN-145: 22-day manufacturingCohort 3B: NSCLC ≥1 prior systemic therapies LN-145 N=12LN-145: 22-day manufacturingCohort 3C: NSCLC 1 prior systemic therapy TIL + Ipilimumab / Nivolumab N up to 26 Citation Format: Scott Gettinger, Harriet Kluger, Adam Schoenfeld, Allison Betof-Warner, Kai He, Ammar Sukari, Bernard Doger de Speville Uribe, Sylvia Lee, Simon Haefliger, Zelanna Goldberg, Alex Cacovean, Rana Fiaz, Guang Chen, Madan Jagasia, Friedrich Graf Finckenstein, Maria Fardis, Antonio Jimeno. A Phase 2, multicenter study of autologous tumor infiltrating lymphocytes (TIL, LN 144/LN-145/LN-145-S1) in patients with solid tumors [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 CT235.

6028 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 2nd line metastatic squamous head and neck carcinoma (HNSCC) cohort (part C) of phase II trial (NCT03625323). Methods: Patients (pts) with HNSCC progressed on or after 1st line platinum-based therapy and unselected for PD-L1 expression were recruited into part C. The study used a Simon's 2-stage design (18 pts planned for stage 1 and 19 for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics and immunogenicity. Efti was administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks. PD-L1 was assessed centrally (22C3 clone). The study was approved by ethics committees and institutional review boards. Results: In total 38 pts were enrolled. The median age was 62 yrs (range 37-84) and 89 % were male. The ECOG PS was 0 and 1 in 34% and 66%, respectively. Primary location at diagnosis was the oral cavity (29%), oropharynx (37%), hypopharynx (18%) and the larynx (16%). All PD-L1 subgroups (CPS < 1 %, ≥ 1 to ≤19; ≥20) were included. All pts were pre-treated with platinum-based chemotherapy. Pts received a median of 3.0 (range 1 – 21) pembrolizumab and 5.0 (range 1-31) efti administrations. Thirty-five (35) pts were evaluated for response (cut-off Jan 2021) with 4 (11 %) pts showing CR, 7 (20 %) pts PR, 3 (9 %) pts SD, 16 (46 %) pts PD with 5 (14 %) pts being not evaluable as per iRECIST. ORR was reported with 31.4 % (95 % CI 16.9 % - 49.3 %) and DCR 40 %Median PFS was 2.1 months and 35 % were progression free at 6 months. Median OS (46 % events) was 12.6 months. There were no adverse reactions leading to treatment discontinuation. The most common ( > 10 %) treatment emergent adverse events were cough (18 %), asthenia (16 %), dyspnea (11 %), fatigue (13 %), diarrhea (11 %), hypothyroidism (11%), upper respiratory tract infection (11%) and back pain (11%). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in platinum pre-treated 2nd line HNSCC patients. Clinical trial information: NCT03625323.