Power of targeted, personalized and combined therapies - TAT 2018
9 March 2018, Yuva Oz
The home of Phase I oncology conference a.k.a. the Targeted Anticancer Therapies (TAT) conference took place this week in the beautiful city of Paris. The program is dedicated to early-phase development and translational research, and attracts a growing number of professionals including basic scientists, physicians and translational researchers from academic settings, industry and regulatory agencies interested in pre-clinical and early clinical development of targeted pathways since 2002.
The conference kicked-off with the Honorary Award Lecture by Professor Jean-Charles Soria giving an excellent overview of the changing landscape of the early drug development with its advantages and the new challenges we face. Classical drug development - consisting of Phase I (safety), Phase II (activity) and Phase III (efficacy over SoC) with increasing number of patients - is on the shift with the precision medicine and better understanding of the molecular mechanisms. Contrary to the classical paradigm in which the Phase III trials carries the highest registration value, the new design weighs heavily on the early phase trials with its new nature and end goals. Based on molecular enrichment and holistic screening, the new combined Phase I/II trials recruit up to 1000 people with the emphasis on safety and activity together by using biomarkers. This new design reduces the global costs and duration of the drug development. Examples include Pfizer, its ALK and ROS1 antagonist crizotinib (Xalkori) and Merck’s anti-PD1 inhibitor pembroluzimab (Keytruda). Crizotinib was registered based on Phase I and II single arm data in a record time of 4 years from the enrollment of the first patient to accelerated approval by FDA. The Phase I study with pembrolizumab started in 2011, initially planned to recruit only 36 patients, however eventually enrolled more than 1260 patients becoming the basis of breakthrough therapy with its marketing authorization gained in 2014 for advanced melanoma patients who carry a BRAF mutation. Both trials highlight the profound registration value of early phase studies as well as the increased pressure on Phase I centers, which are required to adapt and expand their clinical operations and regulatory work load. A tsunami of immunotherapies and precision medicines in development based on comprehensive molecular profiling was also discussed, with the emphasis on the challenges they bring amongst which hyperprogressed disease, the unknown mechanism of action of monoclonal antibodies and the lack of concrete biomarkers.
The presentations on the first day focused on the most exciting novel targets and undiscovered pathways for cancer therapies. Covering a broad range of novel immune targets, epigenetic targets and new concepts in drug development, the newest approaches aim to overcome the limits of currently existing treatments. One of the biggest challenges in immuno-oncology (IO) is the heterogeneity in tumor immunogenicity, resulting in unresponsive treatments. Non-immunogenic tumor micro environment (TME), also coined as “cold tumors”, mediate tumor escape and insensitivity to immunotherapy. Novel immune targets aim to convert “cold” to “hot” with targeting pathways lying underneath the immunosuppressive TME. Two enzymes were discussed targeting this issue: IDO1 and Arginase inhibitors as the inducer and amplifier of regulatory T cells. Studies targeting TREX1/STING pathway and CD137 as mono and combination therapy with anti-CTLA4, anti-PD1 were presented showing synergies for inducing Tumor Infiltrating Lymphocytes (TILs) in TME.
Novel epigenetic targets were also the point of interest. Several studies were carried out with positive outcomes on the synthetic lethality with EZH2 inhibitors in INI1-negative tumors, BET domain inhibitor activity in lymphomas, acute leukemia and NUT-midline carcinoma as well as in combination with HDAC inhibitors and hormonal therapies such as fulvestrant and enzalutamide.
With the storm of novel concepts and new targets in haematologic drug development, the last session covered the ‘a la cart menu’ of treatment options for personalized medicine. Elias Jabbour from MD Anderson Cancer Center presented the use of the patient specific mutational tumor biomarkers for the choice of therapy. CAR-T was recommended in early phases for high-risk patients; therapy with blinatumomab; inotuzumab for MRD positive patients, and finally HCVD + inotuzumab + blinatumomab combinations in relapsed/refractory ALL.
Day two was dedicated to the IO and the trend for combinations with targeted therapies (such as VEGFRi), metabolic targets (arginine, glutamate, IDH, cholestrol), DNA and DNA repair pathways (PARPi, topoisomerase-i, DDR-i) as well with chemo and radiotherapy. There is growing evidence that combination of checkpoint inhibitors (CPIs) with other therapies will result in the increased response rate with selection of indicative biomarkers. CPIs were compared to chocolate by Ruth Plummer: addition of them to any therapy cocktail makes the therapy better.
The recent report from the Methodology for the Development of Innovative Cancer Therapies (MDICT) 2018 was also presented. 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. 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. Additionally, the issues related to the rising trends such as growing number of IO trials was discussed. More than 2000 agents are in development (940 in clinical stages, 1,064 in preclinical) targeting the same usual suspects with similar combinations PD/PDL1 with α-CTLA4, chemotherapy, radiotherapy and α-VEGFA. Sharing data and especially the negative data was encouraged in all online platforms to avoid overlaps and inefficiencies. Describing better endpoints for immunotherapy was highlighted as RECIST1.1 might underestimate the response, and go/no decisions should be made on better clarity with the use of volumetric imaging, and novel statistical analysis for tumor kinetics. Definition of clear biomarkers for IO is vital for overcoming the challenges. Using preemptive strategies with pre-selection of defined patients was encouraged over predictive trial design, where the right patient population is selected in the interim analysis. Hyper progression – as seen in many patients in IO trials – was one of the highlight topics. These phenomena need to be better defined and coupled with relevant biomarkers and a genomic profile.
The third day covered a broad range of topics including the role of microbiome, cell cycle targets (CDK4/6), PI13 kinases and Antibody Drug Conjugate (ADC) payloads. Giorgio Trinchieri discussed the impact of the microbiome on the efficacy of CPI. Microbiota is certainly involved in immune regulation and genomic identification of microbiome subtypes in cancer patients might predict the responders versus non-responders in α-CTLA4 and α-PDL1 treatments. However, it will be important to pay attention to variability of the genomic analysis that can be affected by geography, disease and sequencing technology. Progressively, intratumoral (IT) drug delivery is used in many clinical trials. This method is preferred to overcome systemic toxicities and to achieve local efficacy allowing multiple combinations. Locally injected combination of CpG nucleotides with α-CTLA4 and α-OX40 have shown to increase survival in mice studies. However, determining the dose of injection and the injection site remains a challenge in IT administration of IO drugs. Palbociclib resistance was also discussed and promising results were shown on how CDK4/6 inhibition, allowing palbociclib to induce senescence in non-responders. Another session focused on the PI3K inhibitors. Toxicities associated with this type of treatment and combinations (paclitaxel, olaparib, letrozol-fulvestrant, PARP inhibitors) were presented with conclusion of addition of the PI3K inhibitors to select treatment cocktails can be tolerated (in terms of toxicities) and may alter outcomes. ADCs with EGFRi payload were introduced, matching the target to the indication and matching the indication to the payload as key for achieving a better response. Targeted alpha therapeutics and radioimmunoconjugates were introduced as novel potent payloads. Studies with the use of alpha emitting nuclides for AML and castrate resistant prostate cancer (CRPC) were shown to hold promise.
The quality of scientific knowledge and exchange at this edition of TAT 2018 was quite exceptional. A special focus was given to the tsunami of IO combinations. The very promising but also complicating nature of personalized cocktail therapy design is likely to dominate the medical landscape of 2018. Physicians will be enabled to choose the right-fit-treatment for patients by the availability of many combinations in an a la carte menu. The science driven cocktail design and distinguishing the synergistic effect from additive effect in combination trials should be addressed with understanding the underlying molecular mechanisms. The biomarker selection and preemptive study design will be prerequisite in successful trial outcomes.