Background

Immunotherapy has shifted the treatment paradigm for many malignancies, but not all cancer types have enjoyed a clinically meaningful response from checkpoint blockade. Therefore combination therapies that allow enhancement of the antitumor immune response are needed. Poly(ADP-ribose) polymerase (PARP) inhibitors may stimulate antigen presentation via increased T cell cytotoxic activity. In preclinical models, the combination of PARP inhibition with anti-PD-L1 therapy compared with each agent alone has been shown to significantly increase the therapeutic efficacy. PARP inhibitors when combined with anti-CTLA-4 therapy in BRCA1-deficient ovarian tumor models have also been found in vitro to induce long-term survival. One group that may benefit from this approach are tumors with germline or somatic mutations in the homologous recombination (HR) DNA damage repair pathway – including BRCA1/2, PALB2, ATM, and the FANC family of genes among others. It is unclear whether this benefit can be extended to HR proficient tumors. This presentation overviews these data and ongoing clinical trials designed to answer these questions.

Legal entity responsible for the study

N/A

Disclosure

The author has declared no conflicts of interest.

Funding

Has not received any funding

Background

The ‘Methodology for the Development of Innovative Cancer Therapies’ (MDICT) task force was originally established in 2006 to provide practical guidance on the development of anticancer targeted agents. The task force published a number of recommendations. [1] [2] [3] [4] Although originally focused on targeted agents, for 2018, it was decided to convene the task force to examine issues in the development of immune based therapies. [1] Booth CM, Calvert AH, Giaccone G, Lobbezoo MW, Seymour LK, Eisenhauer EA. Endpoints and other considerations in phase I studies of targeted anticancer therapy: Recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT). EJC 2008;44(1):19–24. [2] Booth CM, Calvert AH, Giaccone G, Lobbezoo MW, Eisenhauer EA, Seymour LK. Design and conduct of phase II studies of targeted anticancer therapy: Recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). EJC 2008;44:125–9. [3] Goodwin R, Giaccone G, Calvert H, Lobbezoo M, Eisenhauer EA. Targeted agents: How to select the winners in preclinical and early clinical studies? Eur J Cancer 2012;48:2170–8. [4] Seymour LK, Calvert AH, Lobbezoo MW, Eisenhauer EA, Giaccone G. Design and conduct of early clinical studies of two or more targeted anticancer therapies: Recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

Methods

Participants included experts from academic centres as well as from industry and regulatory authorities. The mandate of the meeting was to review current knowledge and discuss and make recommendations regarding the design and conduct of early clinical studies of combinations of immune based anticancer agents.

Results

Response patterns and current criteria were reviewed. Critical issues were identified regarding capacity, trial design, optimal endpoints, data sharing and the publication of results. A structured discussion was conducted to allow recommendations on data needed to justify a proposed combination, optimal endpoints and design.

Conclusions

Clinical trial identification

Not applicable

Conclusions

At the end of the MDICT meeting, agreed recommendations were summarized and then presented for feedback to the audience attending TAT2018.

Legal entity responsible for the study

Queens University

Funding

Has not received any funding

Disclosure

J. Tabernero: Has served on advisory boards for Bayer, Boehringer Ingelheim, Genentech/Roche, Lilly, MSD, Merck Serono, Novartis, Roche, Sanofi, Symphogen and Taiho. All other authors have declared no conflicts of interest.

Background

DNA topoisomerases are validated targets for a broad range of widely used anticancer drugs. They include the topoisomerase II (TOP2) inhibitors, etoposide, teniposide, doxorubicin, daunorubicin and mitoxantrone, and the topoisomerase I (TOP1) inhibitors, topotecan and irinotecan. Both topotecan and irinotecan are derivatives of the plant alkaloid camptothecin. To overcome the limitations of these camptothecin derivatives (chemical instability, short half-life, resistance of cancer cells overexpressing multidrug-resistance efflux pumps and rapid reversibility of the TOP1 cleavage complexes), we have developed a different chemical series of TOP1 inhibitors, the indenoisoquinolines, which overcome the camptothecin limitations. Three indenoisoquinolines are in early clinical trials at the Center for Cancer Research of the US National Cancer Institute, LMP400 (indotecan), LMP776 (imidotecan) and LMP744. We will report on these new drugs, which are now transitioning to Phase 2 clinical trials. We also report on the determinants of response to the TOP1 inhibitors (“signature”), which include homologous recombination deficiency (HRD prominently represented by BRCA inactivation), overexpression of TOP1 and overexpression of a gene newly linked with response, SLFN11 (Schlafen 11), and could be used for patient selection and improving precision medicine. We will also report the burgeoning field of tumor-targeted delivery TOP1 inhibitors in clinical trials, which includes liposomal formulations (Onivyde), PEG conjugates (CRLX101; NKTR-102; PLX038, NK012), ADC (antibody drug conjugates: IMMU-132; IMMU-130; DS-8201a). These tumor-targeted TOP1 inhibitors aim to target tumors while sparing the bone marrow without having the dose-limiting toxicity of alternative payloads.

Methods

This section does not apply

Results

This section does not apply.

Conclusions

In conclusion, TOP1 inhibitors are targeted therapies that are being improved by introducing novel chemical inhibitors, novel tumor-targeted delivery and predictive biomarkers (TOP1, SLFN11, HRD).

Background

Deoxyribonucleic acid-dependent protein kinase (DNA-PK) plays a critical role in the repair of DNA double strand break (DSBs). DNA double stranded breaks are the most lethal type of DNA lesion, and cells have developed two distinct repair pathways to protect the cell genome from the deleterious effect of DSBs. While homologous recombination occurs mainly during S and G2 phase and requires a homologous DNA template, non-homologous end-joining, (NEJH) uses direct ligation of DNA ends without a homologous DNA template and can therefore take place anytime during the cell cycle.

DNA-PK is a key enzyme in NHEJ-mediated repair of DSBs and, therefore, represents an attractive pharmacological target. Selective inhibition of DNA-PK could synergistically enhance the activity of many commonly used DSB inducing treatment modalities, such as radiotherapy and certain chemotherapeutic agents.

The presentation will provide an overview of the biological role of DNA-PK in normal and cancer cells, available pre-clinical data that explore the effect of DNA-PK inhibition in vitro and in vivo, and early data from DNA-PK inhibitors currently in clinical development.

Legal entity responsible for the study

Merck

Disclosure

F.T. Zenke: Employee and stockholder of Merck KGaA.

Funding

Has not received any funding

Background

In cancer the presence of T cell immune infiltration has been recognised as a prognostic factor, however the mechanisms underpinning this response are not clearly defined. Our group and others have identified a relationship between type I Interferon immune signalling and loss of DNA repair, particularly the Fanconi Anemia pathway, in several different types of cancer. We therefore investigated the mechanism activating this immune response in the context of abnormal DNA repair.

Methods

Preclinical isogenic cell line systems and human tumours were used to identify the relationship between loss of function of DNA repair genes and activation of immune signalling. A panel of Chemotherapeutic agents were studied for their effect on immune activation.

Results

IHC analysis demonstrated that both intra-tumoral and stromal CD8+ and CD4+ T cell infiltration were associated with DNA repair deficient breast tumors. The CXCL10 and CCL5 cytokines as well as the immune checkpoint target PD-L1 were shown to be significantly up-regulated in DNA repair deficient tumours and in tissue culture models when compared to DNA proficent tumours. Furthermore, conditioned media from DNA repair deficient cell lines stimulated inward migration of peripheral blood mononuclear cells, when compared to media from proficient cells, indicating the presence of active cytokines. We identified constitutive activation of the innate immune pathway STING/TBK1/IRF3 specifically in DNA repair deficient tumour cells when compared to proficient cells and found that binding of the DNA sensor cGAS to cytosolic DNA fragments was required for this immune response. In addition, we identified several chemotherapeutic agents that were able to activate the immune response in DNA repair proficient cell lines through DNA damage, the development of cytoplasmic DNA fragments and the consequent activation of the STING/TBK1/IRF3 immune pathway.

Conclusions

We have identified that the STING/TBK1/IRF3 immune pathway is constitutively activated by cytoplasmic DNA in DNA repair deficient cancers and may explain lymphocytic infiltration and the response to immune checkpoint based therapy. Some conventional chemotherapy agents such as doxorubicin are able to active this pathway in DNA repair proficient cancers and may represent a logical combination with immune checkpoint targeted drugs in clinical trials.

Legal entity responsible for the study

Queen\'s University of Belfast

Disclosure

R. Kennedy: I receive payment as the Global VP and Medical Director for Almac Diagnostics.

Funding

McClay Foundation

Background

Immunotherapy with immune checkpoint inhibitors (ICIs) is modifying the standard of care for several solid tumours. Nevertheless, the results in terms of efficacy are still limited to a minority of patients even if the percentage of response differed among tumours type. The evaluation of response with ICI has been improved by the definition of new immune-related Response Criteria (irRC) that identified pseudo-progression followed by delayed tumour shrinkage in up to 10% of patients treated with anti CTLA-4 or anti PD1/PDL-1 agents. Afterward, hyper-progression (HP) after ICI administration has been recently reported but a mechanicistic explanation of the relationship with the ICI administration has not yet clearly identified. For this presentation, the obvious difficulty is to distinguish between resistance and consequent progression due to the tumour biology and a truly progression primed by ICI treatment.

Methods

A total of 132 patients with solid tumors treated from 2014 to 2017 with antiPD1 (n = 15), anti PDL1 (n = 47), antiPD1 plus antiCTLA4 (n = 41) or plus antiGITR (n = 14), or IDO inhibitor (n = 6) or antiOX40 (n = 2), and bifunctional anti PDL1/antiTGFbeta monoclonal antibody (n = 7) in phase I/II trial at Istituto Nazionale Tumori were retrospectively evaluated for their tumor growth rate (TGR) before treatment and upon treatment. We defined the HP as: 1. progression at first restaging on ICI; 2. increase in tumor size >50%; 3. >2-fold increase in TGR, as reported by Champiat et coll.

Results

Of 132 patients analyzed, 34 patients stopped the treatment before the first tumor evaluation (21 for clinical progression and 13 for drug-related adverse events), 42 patients exhibited disease progression at the first RECIST evaluation. Based on the criteria for the definition of HP, we excluded 14 pts without a previous imaging, 4 pts without target lesions and only 3 out of 24 pts (ovarian, gastric and squamous lung cancers) can be defined as HP (2.3%).

Conclusions

In our experience, the occurrence of HP is limited to a small amount of patients treated with ICI in early phase clinical trials. In our analysis most of the patients have been treated with combo of ICIs, which could be a possible explanation for the lower incidence of HP as compared to what is reported. Nevertheless, the most important bias of underestimation for the evaluation of truly HP can be due to the very stringent criteria used for their definition that exclude patients with progression of non-target lesions and patients with early clinical progressions. As matter of fact, early clinical progression related to tumor biology and not to treatment is a major issue and the criteria reported by Champiat are not adequate to assess HP in patients receiving ICIs as first line of treatment, where we should probably concentrate our effort to investigate HP. Despite the fact that prospective trials are necessary to obtain more accurate data about the true incidence of HP and its etiology, we are evaluating a wider number of cases from disease treated in clinical trials and/or with standard of care to assess if incidence is related to histology.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale Tumori Milano

Funding

Has not received any funding

Disclosure

F. de Braud: Advisor for BMS, Ignyta, MSD, Novartis, Pfizer, Amgen, Roche, Merck Serono, Servier. All other authors have declared no conflicts of interest.