Path toward Precision Oncology: Review of Targeted Therapy ... molecular targets in cancer therapeutics

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    Path toward Precision Oncology: Review of Targeted Therapy Studies and Tools to Aid in Defining "Actionability" of a Molecular Lesion and Patient Management Support Young Kwang Chae1,2, Alan P. Pan2, Andrew A. Davis2, Sandip P. Patel3, Benedito A. Carneiro1,2, Razelle Kurzrock3, and Francis J. Giles1,2


    Precision medicine trials and targeted therapies have shifted to the forefront of oncology. Although targeted ther- apies have shown initial promise, implementation across the broad landscape of oncology has many challenges. These limitations include an incomplete understanding of the func- tional significance of variant alleles as well as the need for clinical research and practice models that are more patient- centered and account for the complexity of individual patient tumors. Furthermore, successful implementation of targeted therapies will also be predicated on efforts to standardize the framework for patient management support. Here, we

    review current implementations of targeted therapies in pre- cision oncology and discuss how "actionability" is defined for molecular targets in cancer therapeutics. We also comment on the growing need for bioinformatics tools and data plat- forms to complement advances in precision oncology. Final- ly, we discuss current frameworks for integrating precision oncology into patient management and propose an integrated model that combines features of molecular tumor boards and decision support systems. Mol Cancer Ther; 16(12); 2645–55. �2017 AACR.

    See related article by Pili�e et al., p. 2641

    Introduction With the evolving landscape of medical oncology, focus has

    shifted away from nonspecific cytotoxic treatment strategies toward therapeutic paradigms more characteristic of precision medicine, whereby therapy is delivered to patients on the basis of unique patient clinical and molecular features. When applying precision medicine, the goal is to tailor diagnosis and treatment to each patient's individual biologic profile, while minimizing exposure to unnecessary or ineffective therapies. Technological advances in accessibility of patient and tumor genomics have improved understanding of tumor biology and led to enhance- ments in the ability to identify and target major molecular drivers of cancer. These developments have shifted precision oncology to the forefront of cancer treatment strategies.

    Despite early successes of targeted cancer therapies, complex- ities in therapeutic development and application have been revealed, in many cases due to considerable genomic heteroge-

    neity among tumor histology subtypes. Some of these complex- ities will need to be addressed by customized combination therapy or bymoving targeted therapeutics fromend-stage disease to earlier stages,when thediseasehas evolved to a lesser extent (1). Although significant advances in targeted therapeutics have been observed in some areas in medical oncology—notably in late- stage melanoma (2) and non–small cell lung cancer (3)—there are many areas that have not experienced similar progress, at least in part due to the paucity of biomarker-driven trials (4–6).

    Limitations also exist with respect to clinical trial design, avail- ability of biomarker data, and challenges in understanding how to use existing, yet un-annotated data in clinical practice. These obstacles have limited the application of targeted therapies and highlight the need for validated bioinformatics tools and data platforms that can help guide clinicians in patient management.

    Here, we review the implementation of precision oncology trials to study targeted therapies.We also discuss considerations in describing the "actionability" of amolecular target, with respect to the biomarker–response association. Lastly, we comment on important topics relevant to the development of a standardized framework for integrating precision oncology trials and targeted therapies into patient management.

    Clinical development pathway of targeted therapies Targets of precision therapeuticsmay include aberrant products

    of altered genes, cell surface molecules differentially expressed in cancer, andmolecules that regulate immune cell activity. Support for targeted therapies in oncology has been driven by several factors. First, the advent of next-generation sequencing (NGS) and the emergence of increasingly cost- and time-efficient genomic profiling methods have advanced our capability to develop novel

    1Developmental Therapeutics Program, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 2Depart- ment of Medicine, Northwestern University Feinberg School of Medicine, Chi- cago, Illinois. 3Center for Personalized Cancer Therapy, Moores Cancer Center at the University of California San Diego, La Jolla, California.

    Y.K. Chae and A.P. Pan contributed equally to this article.

    Corresponding Author: Young Kwang Chae, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 1006, Chicago, IL 60611. Phone: 312-926-4248; Fax: 312-695-0370; E-mail:

    doi: 10.1158/1535-7163.MCT-17-0597

    �2017 American Association for Cancer Research.

    Molecular Cancer Therapeutics 2645

    on September 20, 2020. © 2017 American Association for Cancer Research. Downloaded from

  • clinical trial designs (7–9), and current turnaround times of three to four weeks (half of which is generally attributed to specimen collection) have made tumor molecular profiling clinically fea- sible in patient management (10).

    Second, improved understanding of the molecular pathology of disease has aided in the capacity to develop therapeutics targeting oncogenic drivers. Initial efforts using matched ther- apeutic agents were driven by the perspective that molecular alterations were specific to tumor location and histopathology, and early clinical development of targeted therapies often followed that of standard-of-care cytotoxic chemotherapies. However, lack of evidence supporting this approach led to trial designs that match specific molecular alterations to therapeutic agents, independent of tumor cell origin (11–14). These con- siderations contributed to the birth of precision oncology trials. Nonetheless, adaptations have been necessary to address lim- itations of classical trial designs. These challenges include technical and practical concerns hindering patient selection and biomarker discovery (11).

    Precision oncology trials Several factors provided the impetus for precision oncology

    trials. First, while traditional cytotoxic chemotherapy targets common, generic disease mechanisms shared among tumors, tumor heterogeneity beyond random variation has been repeat- edly demonstrated (11). Second, the use of a biomarker approach to tailor treatments to subsets of patients with the same tumor type became more common, particularly in programs that aimed to show a significant therapeutic effect in unselected patients where the prevalence of the biomarker was low (11). This created challenges in advancing a drug's development, especially if ther- apeutic effects were detectable in only a small patient population. As a result, early phase trials now feature selected patient popula- tions tominimize the inclusion of patients unlikely to respond to novel treatments.

    The evolution of the clinical drug development pathway has resulted in flexible trial designs, including "umbrella" and "bas- ket" trials (5, 11, 15, 16). "Umbrella" trials, such as BATTLE-2 (NCT01248247), Lung-MAP (NCT02154490), and I-SPY (NCT01042379), assign patients with particular tumor histolo- gies to treatment regimens specifically developed to target the tumor's oncogenic molecular pathway. The Leukemia & Lympho- ma Society's (LLS) Beat AMLCore Study is particularly unique as it will be the first-ever precision oncology trial for a blood cancer (NCT02927106). Newly diagnosed acute myeloid leukemia (AML) patients will be assigned to receive investigational thera- pies targeting particular hematologic malignancies based on genomic profiling.

    Alternative approaches to "umbrella" trials are "basket" and "hybrid" trials. "Basket" trials, such as CUSTOM (NCT01306045) and SHIVA (NCT01771458) treat patients with specific agents targeting aberrant molecular pathways, independent of tumor origin. In this way, therapeutic agents may be considered effective across tumor types. Lastly, "hybrid" trials incorporate aspects of both "umbrella" and "basket" trials into one protocol and feature subtrials that target different molecular drivers within the same histology or the samemolecular driver across different histologies (16). Several of these trials have been published, and trials such as UCSD PREDICT and the MD Anderson Phase I initiative dem- onstrate that approximately 25% to 30% of patients can be matched to therapy when larger NGS panels are used, as well as

    improved outcomes inmatched versus unmatched patients, albe- it in a nonrandomized setting (13, 14, 17).

    Nonetheless, limitations do exist with flexible trial designs. The majority of trials feature monotherapies, yet treatment strategies incorporating drug combinations have provided benefit to patients with multiple genomic aberrations or advanced cancers (10). Approval of targeted drug combinations remains a challenge because of the potential for overlapping drug toxicities. Further- more, the SHIVA trial notably concluded that off-label use of molecularly guided targeted therapies did not show improvement in pr