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Background: Triple-negative breast cancer (TNBC) is associated with poor survival outcomes and treatment options are limited. These tumors lack therapeutic targets and become rapidly resistant to chemotherapy. The anti–PD-1 antibody pembrolizumab showed durable antitumor activity and manageable safety in patients with TNBC in the KEYNOTE-012, KEYNOTE-086, and KEYNOTE-119 studies. The combination of lenvatinib, an antiangiogenic multiple receptor tyrosine kinase inhibitor, with pembrolizumab has shown promising clinical outcomes in early-phase clinical trials across several cancer types. LEAP-005 (ClinicalTrials.gov, NCT03797326) is an ongoing study evaluating the efficacy and safety of lenvatinib combined with pembrolizumab in patients with previously treated advanced solid tumors. Here, we report the first results from the TNBC cohort of LEAP-005. Methods: This ongoing, multicohort, open-label, phase 2 study enrolled patients aged ≥18 y with previously treated, histologically or cytologically confirmed advanced TNBC. PD-L1 expression was assessed at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay and measured using the combined positive score (CPS; number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by total number of tumor cells x 100). Patients received lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg every 3 weeks intravenously for a maximum of 35 pembrolizumab doses, then lenvatinib alone until progressive disease or unacceptable toxicity. Primary endpoints were objective response rate (ORR) by blinded independent central review per RECIST version 1.1 and safety. Key secondary endpoints were disease control rate (DCR; defined as best overall response of complete response [CR], partial response [PR], or stable disease [SD] per RECIST v1.1), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety was monitored through 30 days after the last dose of study drug (90 days for serious AEs), with AEs graded using NCI CTCAE v4.0. Results: 31 patients have been enrolled in the TNBC cohort of LEAP-005. Median age was 56 y (range, 37 to 85), 58% had received ≥2 prior lines of therapy, and 26% had CPS ≥10 tumors. As of the April 10, 2020 data cutoff, median follow-up was 7 mo (range, 4 to 13). ORR was 29% (95% CI: 14–48), with 1 CR and 8 PRs. 9 pts had SD, and the DCR (CR + PR + SD) was 58% (95% CI: 39–76). 4 responses (1 CR and 3 PRs) were in patients with CPS ≥10 tumors (n=8) for an ORR of 50% (95% CI: 16–84), and 5 responses (all PRs) were in patients with CPS Citation Format: Hyun Cheol Chung, Esma Saada-Bouzid, Federico Longo Muñoz, Eduardo Yanez, Seock-Ah Im, Eduardo Castanon, Donna M. Graham, Javier Garcia-Corbacho, Juanita Lopez, Razi Ghori, Corina Dutcus, Alan Smith, Kevin Norwood, Carlos Gomez-Roca. Lenvatinib plus pembrolizumab for previously treated, advanced triple-negative breast cancer: Early results from the multicohort phase 2 LEAP-005 study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-07.

Background: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine that mimics a viral infection. Through dendritic cells activation, increase in CD8 T-cell infiltration and interferons induction, it produces an immunogenic cell death. Phase 1 study (NCT02828098) showed ORR 20% in patients (pts) with anti PD-1 resistant melanoma (mel). Hence phase 2 trial was designed. Study design: Single arm study (NCT04570332) with intratumoral BO-112 plus intravenous pembrolizumab in pts with mel (cutaneous, acral or mucosal) and confirmed progressive disease (PD) while on anti-PD1 based therapy. Pts were treated with BO-112, 1-2 mg on a weekly basis for 7 weeks and thereafter Q3W in 1-8 different lesions. Pembrolizumab 200 mg was administered Q3W. Primary endpoint was overall response rate (ORR) by RECIST 1.1 by independent reviewer. Secondary endpoints included disease control rate (DCR), progression free survival (PFS) and safety. Exploratory objectives included radiomic signatures, itRECIST and evaluation of tumor microenvironment. At least 20% of pts had to achieve response in order to consider primary endpoint met. Results: Recruitment was completed 24th August 2021 with 42 pts; female 43%; median age 66 (rank 27-88). Table summarizes basal characteristics. With 40 evaluable for response pts, 10 achieved response (25%): 3 complete response (CR) and 7 partial response (PR). 17 pts (44%) achieved a stable disease (SD), meaning a DCR of 68% with 18 pts still on treatment. The 4 pts with a baseline LDH>3xULN developed PD no later than week 8. Responses per histology were: 66% mucosal, 28% cutaneous, 0% acral. Responses per BRAF/NRAS status were: BRAF mutant (Mut) 43%, NRAS Mut 31%, and BRAF/NRAS wild type (WT) 17%. 33 pts (79%) had at least one BO-112 related adverse event (AE) being only in 2 cases grade>3 (G4 infusion reaction and G3 myalgia). Most common related AEs were asthenia, pyrexia, diarrhea, vomiting and chills. Study treatment was not discontinued in any pts due to related AE. Conclusions: The primary efficacy endpoint has been met. Additionally, disease control (PR+CR+SD) is meaningful and durable in a population with no current standard treatment options. Very high LDH levels (LDH >3xULN) and acral mel could predict poor outcome. Safety profile was manageable without treatment discontinuation due to AEs. N (ITT pts, 42) (%) AJCC8 M1C/D 19 (45) BRAF Mut 7 (17) WT 35 (83) Previous treatment Ipilimumab-nivolumab 6 (15) Anti PD-1 monotherapy 33 (79) Other combo 3 (7) Prior line indication Adjuvant 11 (26) Advanced 31 (74) LDH >ULN 17 (41) Best ORR (IRCR evaluable pts, N=40) Global Mucosal Cutaneous Acral ORR 10 (25) 2 (66) 8 (28) 0 PR 7 (18) 1 (33) 6 (21) 0 CR 3 (8) 1 (33) 2* (7) 0 SD 17 (43) 1 (33) 13 (45) 3 (37) PD 13 (33) 0 8 (28) 5 (63) *2 pts had pathologic CR and RECIST SD Citation Format: Iván Márquez-Rodas, Caroline Dutriaux, Philippe Saiag, Luis de la Cruz Merino, Eduardo Castanon Álvarez, Caroline Robert, Juan F. Rodríguez-Moreno, Ana M. Arance, Pablo Cerezuela-Fuentes, Henry Montaudié, Miguel F. Sanmamed, María González Cao, Julie Charles, María Pilar López Criado, Alfonso Berrocal, Enrique de Miguel, Elisa Funk-Brentano, Sorilla Prey, María del Carmen Álamo de la Gala, Javier Sánchez López, Helena Escuin-Ordinas, Sonia Macia, Marisol Quintero, Marya F. Chaney, Stéphane Dalle. Efficacy of intratumoral BO-112 with systemic pembrolizumab in patients with advanced melanoma refractory to anti-PD-1-based therapy: Final results of SPOTLIGHT203 phase 2 study [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 CT014.

Background: There is a lack of predictive biomarkers for immunotherapy in melanoma. Immunohistochemistry and gene sequencing are frequently assessed as part of clinical research. Radiomic signatures may also add valuable information, based on parameters which can be related to immune infiltration, therefore defining an imaging biomarkers panel for this clinical scenario. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that, by mimicking the effect of a viral infection, mobilizes the immune system. The role of imaging biomarkers is being explored in the present phase II clinical trial. Study design: Single arm study with BO-112 plus pembrolizumab (NCT04570332) in patients with advanced melanoma in progression to anti-PD1 therapy. As part of exploratory objectives, a radiomics analysis was performed to detect changes in lesion texture features. Quantitative features were obtained by using Quibim Precision 2.9 platform (Quibim, Valencia, Spain) after the manual delineation of lesions on the CT study of each subject at each timepoint to obtain information about injected/non-injected lesions. Images were normalized by taking into account Hounsfield Units (HU) bias across scanners in a cross-calibration phantom and the Z-score. The difference (Delta) in the features between baseline and week 8 was calculated. Results: Studies were assessed based on event (progression) and based on whether lesions had been injected. Patients with only cutaneous disease were not included in this analysis. Out of 23 patients who had at least two imaging assessments, 6 developed progressive disease by week 8, and 17 subjects had no event by that time. Due to the small sample size, the radiomic analysis was based on hypothesis testing. With regards to volume, 50% of the non-progressing lesions reduced their value from that of the baseline. Regarding injected versus non-injected changes, up to 50% of injected lesions decreased their volume after 8 weeks of injected treatment whereas in non-injected lesions volume decreased in less than 25% of lesions. From the independent sample t-test of delta radiomics features against the injected/non-injected lesions variable, there were 4 features with a statistically significant difference between groups; all of them related to the Low Grey-Level Zone Emphasis. Specifically, Delta original GLRLM Low Grey-Level Run Emphasis showed the highest significant difference between injected and non-injected lesions (p=0.004), with higher and positive delta values in the injected group (75% injected lesions were above 0). Conclusions: Imaging biomarkers provide a large number of quantitative image features with a wide span of information, from size to heterogeneity of the tissue which may be indicator of tumor progression and immune infiltrate. In the analysis of radiomics features, delta GLRLM low grey-level zone emphasis was sensitive to the tumoral changes happening in injected lesions at week 8. This might add insights into the imaging-based evaluation of immune infiltration in intratumoral immunotherapy and the creation of associated imaging biomarkers panels. Citation Format: Paula Moreno, Philippe Saiag, Luis de la Cruz Merino, Caroline Dutriaux, Eduardo Castanon Álvarez, Caroline Robert, Juan F. Rodríguez-Moreno, Pablo Cerezuela-Fuentes, Ana M. Arance, Henry Montaudié, Miguel F. Sanmamed, María González Cao, María Pilar López Criado, Julie Charles, Alfonso Berrocal, Enrique de Miguel, Elisa Funk-Brentano, Pablo Sau Llanas, Sorilla Prey, Eva Muñoz-Couselo, Delvys Rodríguez Abreu, Juan Martin-Liberal, Ángel Alberich-Bayarri, Javier Sánchez López, Sonia Macia, Marisol Quintero, Marya F. Chaney, Stéphane Dalle, Iván Márquez-Rodas. Radiomic features in tumor assessment, preliminary results from a phase 2 study of intratumoral administration of BO-112 with pembrolizumab in patients with anti PD1 refractory melanoma [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 CT109.

Background: There is a lack of predictive biomarkers for immunotherapy in melanoma. In terms of IHC, there is no strong rational to support the use of PD-L1 expression. BRAF mutations occur in 40-50% of melanomas and the MAPK pathway may also be activated by NRAS mutations. Patients harboring these mutations face usually a worse prognosis. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that, by mimicking the effect of a viral infection, mobilizes the immune system. Prior data from a phase I trial (NCT02828098) suggest that, when administered intratumorally, it causes an increase in CD8 infiltration and PD-L1 expression. The role of these and other biomarkers is being explored in the present phase II clinical trial. Study Design: Single arm study with BO-112 plus pembrolizumab (NCT04570332) in patients with advanced melanoma in progression to anti-PD1 therapy. Tumors were genotyped by next generation sequencing, whole exome sequencing and tumor mutation burden. Antitumor and immunological effects of the treatment in the tumor microenvironment were assessed by PDL1 and CD8 immunohistochemistry with a paired biopsy performed after 21 days of treatment. Results: A preliminary analysis has been performed, based on patients evaluable for clinical benefit (defined as response or stable disease>16 weeks). Samples from 35 patients have been analyzed, with 24 patients paired biopsies available. Patients with “cold” tumors (PD-L1 negative and CD8 low) at baseline had a trend to lack of clinical benefit. Only basal PD-L1 in the inflammatory component showed a statistically significant correlation with clinical outcome (4/20 (25%) tumors PDL1 IC negative had benefit versus 10/15 (67%) positive), p=0.0053. Fifteen patients had an increase in PD-L1 and 14 patients had increase in CD8 infiltrate after BO-112 treatment; the lack of increase in PDL1 and CD8 after treatment was also predictive of lack of response (p=0.04). BRAF/NRAS driver mutations correlated with positive outcome. Clinical benefit was observed in 4 of 17 (24%) patients not carrying activating mutations whereas 11 out of 18 (61%) patients with BRAF/NRAS activating mutations had clinical benefit (p=0.02), mainly in cutaneous histology (14% versus 65%, p=0.02). Mucosal melanoma patients (n=3) achieved an ORR 66.7% and DCR 100%. The two mucosal melanoma patients with partial response harbored SETD2 mutations and one of them showed extensive cyclic nucleotide-gated (CNGs), indicative of defects in DNA repair pathways. Regarding acral melanoma patients (n=9), no responses were observed, even in the single case with a NRAS mutation. The only patient achieving clinical benefit, with stable disease>16 weeks; had a unique mutation profile, with TP53 (inactivating) and KIT (activating) mutations. Conclusions: Patients basal mutant BRAF/NRAS could have more probability of benefit from BO-112 and pembrolizumab combination. PD-L1 and/or CD8 increase is an early marker of response. These findings could help to select patients in future clinical trials. Further investigation into predictive biomarkers is warranted. Citation Format: Ruth Roman, Philippe Saiag, Caroline Dutriaux, Luis de la Cruz Merino, Eduardo Castanon, Miguel F. Sanmamed, Caroline Robert, Juan F. Rodríguez-Moreno, Pablo Cerezuela-Fuentes, Ana M. Arance, María González Cao, Henry Montaudié, María Pilar López Criado, Julie Charles, Alfonso Berrocal, María del Carmen Álamo de la Gala, Enrique de Miguel, Elisa Funk-Brentano, Sorilla Prey, Eva Muñoz-Couselo, Delvys Rodríguez Abreu, Juan Martín-Liberal, Helena Escuin-Ordinas, Mark Branum, Sonia Macia, Marisol Quintero, Javier Sánchez López, Marya F. Chaney, Beatriz García-Peláez, Marta Vives-Usano, Miguel Ángel Molina, Stéphane Dalle, Iván Márquez-Rodas. Correlation of biomarkers and clinical benefit of intratumoral BO112 and pembrolizumab in patients with anti PD1 refractory melanoma [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 CT107.

Background: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI), that acts as an agonist to toll-like receptor 3 and targets the cytosolic helicase melanoma differentiation-associated gene 5 and retinoic acid-inducible gene I. By mimicking the effect of a viral infection, it mobilizes the immune system, including activation of dendritic cells, CD8 T-cell infiltration, induction of interferons (IFNs), induction of apoptosis and enhancement of immunogenic cell death. Clinical data are available from the first-in-human study (NCT02828098) which evaluated single intratumoral (IT) BO-112 (Part 1; N = 16) and the combination of IT BO-112 with pembrolizumab or nivolumab (Part 2; N = 28). Part 2 showed an ORR of 11% and DCR of 46% in patients with multiple tumor types. Of them, 2 out of 10 (20%) patients with melanoma resistant to anti PD-1 achieved a partial response. Safety profile of BO-112, both as single agent and in combination with anti-PD-1, is manageable and currently characterized by Grade 1 fever and other flu-like symptoms. A phase 2 clinical study of IT BO-112 in combination with pembrolizumab in patients with liver metastases from colorectal or gastric/gastro-esophageal junction cancer patients is currently ongoing. Methods: Phase 2, single arm, open label study of IT BO-112 in combination with pembrolizumab in patients with advanced and/or metastatic melanoma that have progressed on anti-PD-1-containing treatment (NCT04570332). BO-112 will be administered once weekly (QW) in 1 to 8 tumor lesions, total dose 1-2 mg (depending on the number of injected lesions), for the first 7 weeks and then once every three weeks (Q3W); pembrolizumab 200 mg will be administered Q3W. Key eligibility criteria include histologically confirmed, unresectable cutaneous or mucosal melanoma with known BRAF status. Patients must have progressed on or after treatment with an anti-PD-1/L1 mAb. At least one lesion RECIST 1.1 measurable and amenable for weekly IT injection is needed. Primary efficacy variable is ORR by RECIST 1.1, assessed by independent central radiologist (by QUIBIM Precision platform). Secondary efficacy variables include clinical activity in terms of DCR, DOR, PFS, OS, iRECIST, safety and PKs. Exploratory objectives include itRECIST and evaluation of tumor microenvironment (by Pangaea laboratory). A 1-sided alpha of 4.19% and power of 81.8% are used. A total of 40 patients will be enrolled. If less than 8 patients out of 40 have ORR, the study will not meet the statistical bar. Study was approved on 14 December in Spain; enrollment is open; two sites are active as of 18 December 2020. Nineteen sites (12 in Spain and 7 in France) are planned to be activated. Citation Format: Iván Márquez-Rodas, Miguel Fernández de Sanmamed Gutiérrez, María González Cao, Ana M. Arance, Alfonso Berrocal, Eduardo Castañon, Sofía España, Pablo Cerezuela-Fuentes, Juan F. Rodríguez-Moreno, Pilar López Criado, Juana Oramas, Luis de la Cruz Merino, Stéphane Dalle, Caroline Dutriaux, Julie Charles, Caroline Robert, Brigitte Dréno, Henri Montaudié, Philippe Saiag, Javier Sánchez-López, María Rojas, Helena Escuin-Ordinas, Vanesa Pons Sanz, Sonia Maciá, Marisol Quintero. Phase 2 clinical study to evaluate the efficacy and safety of intratumoral BO-112 in combination with pembrolizumab in patients with advanced melanoma that have progressive disease on anti-PD-1-based therapy [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 CT233.

Background The limited efficacy of neoadjuvant schedules to obtain pCR in breast cancer together with a prompt relapse of triple negative breast cancers has opened up the development of new strategies involving the immune system, which is essential in cancer control. We have elaborated an autologous vaccine with dendritic cells loaded with patients' own tumor antigens. Based on the synergistic effect between immunotherapy and chemotherapy our hypothesis is that the combination of both strategies could improve pCR with an excellent tolerance and could increase DFS and OS. Methods Two centers are enrolling patients from February 2011. Twenty-one patients with stage II-III HER2 negative breast cancer have started on sequential neoadjuvant chemotherapy based on dose dense antracyclines (E 100mg/m2 and C 600 mgr/m2) × 4 cycles plus GM-CSF followed by taxanes (DOC 75–100 mgr/m2) × 4 cycles plus vaccination. Vaccine calendar was started after the 4th EC and alternated with taxane schedule and after chemotherapy up to a maximum of a 2 year-period. SNB biopsy was performed before neoadjuvant chemotherapy. pCR in the breast and the axilla is the main endpoint, measured by Miller&Paine classification. Data were analyzed using SPSS and alpha was set at 0.05 (two-tailed). We have compared these results in the vaccinated cohort (V) with our historic cohort (C) of 19 patients treated in the same way but without the vaccine. Results Both cohorts (V and C) were well balanced for age, histologyc type, differentiation grade, Ki67>15%, tumor size ≤ 5 cm, stage and expression of hormone receptors. All patients except one in the vaccine cohort achieved 8 cycles of chemotherapy. According to grade ¾ toxicities we did not find significant differences except for hand-foot syndrome in the V cohort (19% vs 0%; p = 0.04) and vomiting in the C cohort (0% vs 21%; p = 0.02). Lymphopenia was the most common adverse event (81% in V vs 89.5% in C; p = 0.45). Other toxicities were anemia (0% vs 5.3%; p = 0.28), thrombopenia (0% vs 10% p = 0.12), leukopenia (9.5% vs 15.8% p = 0.55) and neutropenia (14% vs 21%, p = 0.57). Gastrointestinal toxicity was similar in both groups: mucositis (0% vs 5.3%, p = 0.28); gastritis (5% in both cohorts), nausea (19% vs 16%, p = 0.78), diarrhea (5% in both cohorts), constipation (0% vs 15% in C, p = 0.06). Myalgias were seen in 19% in V vs 11% in C (p = 0.45). We did not see any local grade ¾ toxicity related to the intradermal vaccines. Regarding efficacy data, clinical complete response by MRI was shown in 38% in the V as compared to 16% in the C (p = 0.06). Breast-conserving surgery was more common in the V cohort (62% vs 53%, p = 0.55). Total pCR (T plus N) was superior with the addition of the vaccine (24% vs 5% p = 0.014). Moreover in three more patients in the V group we find isolated tumor cells in the breast (Titc). Conclusions The addition of autologous dendritic cell vaccines to neoadjuvant chemotherapy significantly increased the rate of pathological complete responses among patients with HER2-negative breast cancer. Vaccination does not seem to add any toxicity to the schedule. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-03.

Background: Liver metastasis (LM) occurs in 30% of non-small cell lung cancer patients but the contribution of the patient's genetic background to the hepatic metastasis development is unclear. Previously, we reported that inflammation contributes to the prometastatic microenvironment of the liver. Upregulation of transcriptional regulator Id1 gene has been associated with inflammation while ablation of Id1 in mice reduced inflammation. In this study Id1 deficient mice were used to analyze the role of host Id1 in the hepatic colonization of an experimental lung cancer. Methods: Lewis lung carcinoma cells were used for the experimental production of hepatic metastasis via intrasplenic injection of cancer cells in C57BL/6 wild-type and Id1-knockout (KO) mice. Animals were splenectomized to avoid flank tumor formation and weekly FDG-micro-positron emission tomographies (PET) were performed to monitor LM formation. Animals were sacrificed at the time of LM occurrence and total RNA was purified from LM. A microarray gene expression analysis (Affymetrix) with the support of Ingenuity Pathways Analysis (IPA) was performed to evaluate the potential impact of Id1 deficiency on the regulation of genes mediating cancer cell invasion and proliferation, angiogenesis and metastasis. Results: By week two after cancer cell injection, 70% wild-type and 10% Id1-KO mice had detectable hepatic metastasis by FDG-PET (p=0.02). Three weeks after injection, when 100% wild-type had LM, still just 20% Id1-KO mice had LM (p=0.015). Moreover, 50% Id1-KO mice remained LM-free >4 weeks after cancer cell injection. No other metastasis sites were detected at necropsy. A microarray gene expression analysis of LM from Id1-KO animals uncovered a remarkable downregulation (p Conclusion: Our results demonstrate that Id1 expression deficiency impaired the metastatic process of lung cancer cells to the liver through the specific downregulation of key metastasis-associated genes and suggest that Id1-dependent mechanisms are new targets for hepatic metastasis therapeutic. This study has been partially funded by “UTE project CIMA” and an ISCIII-FIS grant 2011. Citation Format: Ignacio Gil-Bazo, Eduardo Castanon, Inés López, Victor Segura, Mariano Ponz-Sarvise, José M. López-Picazo, Maria Collantes, Margarita Ecay, Isabel Gil-Aldea, Alfonso Calvo, Fernando Vidal-Vanaclocha. Inhibitor of differentiation-1 (Id1) expression deficiency in the tumor microenvironment impairs experimental hepatic metastasis of lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1996. doi:10.1158/1538-7445.AM2014-1996