Juan Martin-Liberal

The expanding role of immunotherapy

The use of agents able to modulate the immune system to induce or potentiate its anti-tumour activity is not a new strategy in oncology. However, the development of new agents such as immune checkpoint inhibitors has achieved unprecedented efficacy results in a wide variety of tumours, dramatically changing the landscape of cancer treatment in recent years. Ipilimumab, nivolumab, pembrolizumab or atezolizumab are now standard of care options in several malignancies and new indications are being approved on a regular basis in different tumours. Moreover, there are many other novel immunotherapy strategies that are currently being assessed in clinical trials. Agonists of co-stimulatory signals, adoptive cell therapies, vaccines, virotherapy and others have raised interest as therapeutic options against cancer. In addition, many of these novel approaches are being developed both in monotherapy and as part of combinatory regimes in order to synergize their activity. The results from those studies will help to define the expanding role of immunotherapy in cancer treatment in a forthcoming future.

Immuno-Oncology: The Third Paradigm in Early Drug Development

Clinical researchers in oncology face the difficulty of developing new drugs for treating cancer patients. This challenge nowadays extends towards new horizons since a high number of drugs are developed in each of the three paradigms: classical cytotoxics, new targeted agents, and emergent immunotherapeutic approaches. Over the last decade, there has been an unstoppable progress in this third paradigm, to the extent that in 2013 immunotherapy was granted the scientific breakthrough of the year. However, the novel mechanisms of action of these immunotherapeutic agents entail a whole new series of concepts, resulting in a number of unresolved questions to which clarification is crucial for their success: establishment of accurate preclinical models able to predict human toxicities, better selection of candidate populations, finding and validation of predictive biomarkers, definition of suitable endpoints, improvements in first-in-human study designs, proposal of more accurate radiological response criteria, management of novel immune-related toxicities and development of combinations based on a biological rationale. In this article, we review the major challenges to overcome in forthcoming years. The final role of immunotherapy in cancer will be determined by our capacity to shed some light on some of these key points.

Phase II Study of Gemcitabine Plus Sirolimus in Previously Treated Patients with Advanced Soft-Tissue Sarcoma: a Spanish Group for Research on Sarcomas (GEIS) Study

BackgroundGemcitabine plus sirolimus enhances apoptosis in vitro and increases anti-tumor efficacy in vivo in soft-tissue sarcoma (STS) models.ObjectiveThe objective of this study was to evaluate the activity and toxicity of the combination of gemcitabine plus sirolimus in patients with STS after failure of standard chemotherapy.Patients and MethodsAdvanced STS patients, previously treated with doxorubicin and/or ifosfamide, were included in this single-arm phase II study. Patients received gemcitabine 800xa0mg/m2 intravenously (iv) at 10xa0mg/m2/min on days 1 and 8 every 3xa0weeks plus sirolimus 5xa0mg daily orally (po). After enrolment of the first 12 patients, the study protocol was amended due to toxicity and the starting dose of sirolimus was reduced to 3xa0mg daily po. Archival tumor samples were analyzed for extracellular signal-regulated kinase 1 and 2 (ERK1/2) expression and correlated with outcome. The primary endpoint was progression-free rate (PFR) at 3xa0months.ResultsFrom May 2012 to May 2013, 28 patients were enrolled at eight centers. PFR at 3 and 6xa0months was 44% and 20%, respectively, with 12 patients being free of progression at 3xa0months. Median progression-free survival (PFS) was 1.85xa0months (95% confidence interval [CI] 0.73–2.97) and median overall survival (OS) was 9.2xa0months (95% CI 5.8–12.5). No responses were observed. The most common grade 3–4 hematologic toxicities were neutropenia (48%) and leukopenia (41%) and the most frequent grade 3 non-hematologic toxicities were infection (18.5%), transaminitis (15%), fatigue (11%), and pneumonitis (11%). ERK1/2 expression was significantly correlated with PFS (pxa0=xa00.026).ConclusionsThe combination of gemcitabine and sirolimus is an active treatment in STS. Further investigation is warranted. ClinicalTrials.gov identifier: NCT01684449.

Abstract CT039: INDUCE-1: a phase I open-label study of GSK3359609, an ICOS agonist antibody, administered alone and in combination with pembrolizumab in patients with selected, advanced solid tumors

Background Inducible T cell Co-Stimulator (ICOS), a member of the CD28/B7/CTLA immunoglobulin receptor superfamily, is expressed on T cells after engagement with cognate antigen and activation. ICOS provides a co-stimulatory signal augmenting T cell proliferation, cytokine production, cytotoxic function and survival. GSK3359609 is a humanized IgG4 antibody selected for its potent binding agonist activity against human ICOS. Rationale for targeting ICOS with GSK33359609 as a monotherapy and in combination with other cancer immunotherapies such as pembrolizumab is supported by preclinical evidence. Methods INDUCE-1 is a first in human study evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of GSK3359609 administered as an intravenous (IV) infusion once every three weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab (Q3W IV infusion) or other immunotherapy (Part 2) in approximately 304 adult patients. In the dose escalation phase, eligible patients are required to have selected, relapsed/refractory solid tumors. Accelerated titration design is planned for the first 3 dose levels in Part 1, with 1 patient enrolled at each dose level; modified toxicity probability interval method will inform on subsequent dose escalation decisions (minimum 3 patients per dose level), and maximum tolerated dose or maximum administered dose determination. In the expansion phase, cohorts may be defined by factors such as tumor histology, biomarker features, or prior treatment. More than one GSK3359609 dose level may be evaluated in a single expansion cohort by patient random assignment. Tumor biopsies (before and on-treatment) are optional in escalation and required in expansion to provide biomarker data that may inform on optimal dose selection as well as mechanistic understanding of GSK3359609 activity. Immune-related Response Evaluation Criteria in Solid Tumors will be the primary measure of clinical activity. As of 12 January 2017, no dose limiting toxicities (DLT) were observed in the first 2 dose levels of GSK3359609 monotherapy; dose level 3 cohort enrollment is completed and under observation for DLTs. ClinicalTrials.gov identifier: NCT02723955 Study is funded by GlaxoSmithKline and is in collaboration with Merck & Co, Inc Citation Format: Eric Angevin, Todd M. Bauer, Catherine E. Ellis, Hui Gan, Rigel Hall, Aaron Hansen, Axel Hoos, Roxanne C. Jewell, Jessica Katz, Juan Martin-Liberal, Michele Maio, Patrick A. Mayes, Jolly Mazumdar, Michael Millward, Danny Rischin, Jan H. Schellens, Sapna Yadavilli, Helen Zhou. INDUCE-1: a phase I open-label study of GSK3359609, an ICOS agonist antibody, administered alone and in combination with pembrolizumab in patients with selected, advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT039. doi:10.1158/1538-7445.AM2017-CT039

Early-drug development in the era of immuno-oncology: are we ready to face the challenges?

The classical development of drugs has progressively faded away, and we are currently in an era of seamless drug-development, where first-in-human trials include unusually big expansion cohorts in the search for early signs of activity and rapid regulatory approval. The fierce competition between different pharmaceutical companies and the hype for immune combinations obliges us to question the current way in which we are evaluating these drugs. In this review, we discuss critical issues and caveats in immunotherapy development. A particular emphasis is put on the limitations of pre-clinical toxicology studies, where both murine models and cynomolgus monkeys have underpredicted toxicity in humans. Moreover, relevant issues surrounding dose determination during phase I trials, such as dose-escalation methods or flat versus body-weight dosing, are discussed. A proposal of how to face these different challenges is offered, in order to achieve maximum efficacy with minimum toxicity for our patients.

Abstract B187: Prevalence of MET copy number variation, MET expression and MET related genomic alterations in all solid tumors pre-screening program. VHIO experience

Background: Aberrant MET activation occurs in many types of malignancies and includes protein overexpression, increased gene copy number, amplifications, mutations and deletions. The frequency of genomic alterations in MET varies widely among solid tumors. The criteria for MET amplification and MET overexpression have not been established as well as the relationship between MET amplification, MET expression and additional genomic alterations known to be important in tumor biology. Previous and current phase 1 clinical trials have selected patients without matching MET criterion. Materials and Methods: From Dec/2012 to Dec/2014, 203 formalin fixed paraffin embedded tumor samples from 197 patients consented to undergo targeted MET analysis. Samples were 117 primary and 86 metastatic tumors. Tumor types included colorectal, gastric, lung, glioblastoma, and breast. Samples were analyzed by fluorescence in situ hybridization (FISH) for MET gene amplification (MET/CEN-7 FISH Zytolight SPEC assay Z-2087, Zytovision), and by immunohistochemistry (IHC) for MET protein expression [Met (D1C2) XP® Rabbit mAb #8198, Cell signaling]. Mutations in key oncogenes were determined using Sequenom (Mass Array) and Amplicon-Mi Seq (Illumina) Cancer Panel. Results: MET gene copy number variation (>5copies) was found in 11 of 203 samples (5%) and MET gene amplification (based on the definition of MET/CEN-7 ≥2.2) was found in 6 of 203 samples (3%). Eleven (5%) samples had ≥4 or ≤5 copies of MET gene. KRAS mutation was found in 28 of 167 samples (17%) and PIK3CA mutation in 6 of 167 samples (4%). Both mutations were observed in tumor samples with Conclusion: MET expression is higher in metastatic than primary tumor samples. There is a significant association between MET expression and gene copy number. High MET copy number was more frequent in tumors without KRAS and PIK3CA mutation. Quantitative MET protein expression data will be presented. Citation Format: Analia Azaro, Guillem Argiles, Maria Alsina, Elena Elez, Teresa Macarulla, Cristina Cruz, Donatella Marino, Cinta Hierro, Susana Cedres, Alejandro Navarro, Maria Ochoa de Olza, Irene Brana, Juan Martin-Liberal, Marta Vilaro, Debora Moreno, Paola Martinez, Maria Diaz, Ana Vivancos, Jordi Rodon, Josep Tabernero, Ludmila Prudkin, Paolo Nuciforo. Prevalence of MET copy number variation, MET expression and MET related genomic alterations in all solid tumors pre-screening program. VHIO experience. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B187.