Authored by Yoshinori Imamura, MD, PhD, Kobe University Hospital, Kobe, Japan

Dr. Bruce Chabner provided a great talk on targeted therapeutic drug development. At first, he defined the main concept of precision cancer therapy: matching the treatment to the precise phenotype or genotype of the tumor. It is optimized when the target, driver mutation, pathway, or antigen is tumor specific, or without off-target effects. Therefore, to identify biomarker is critical issue, as he stressed.

Next, he summarized the history of the targeted therapies. In 1976, ontogenetic drivers were discovered in viral tumors. In 1977, V-sarc was found in avian sarcoma. In 1979, C-sarc presented in the human genome. In 1995, Warner-Lambert showed that many oncogens were kinases, and then monoclonal antibodies or small molecule inhibitors were provided from the late 1990s (e.g. rituximab in 1997, bevacizumab in 1998, imatinib in 2000). The first antibody-drug conjugate, gemtuzumab ozogamicin, was developed in 2006. It is safe to say that we can develop new drugs much faster than before.

In addition, he presented the developing history of EGFR inhibitors as a favorable example. On the other hand, he pointed out that other potential targets involved in tyrosine kinase receptors, DNA repair genes, and epigenetic targets are still in straggled. Through these comparisons, he described the problems in developing a precision drug. One is concern about preclinical evaluation: lacking of specificity for tumor, resulting in normal tissue toxicity; lacking specificity for target, involving off-target effects; variability in PK; and limited effectiveness by toxicity. Another is concern about clinical evaluation: patient selection strategy, biomarker assay, and approval path and trial design. Again, biomarker is the key issue.

Finally, he articulated our challenges; 1) finding the perfect inhibitors with specificity and potency; 2) designing the right trial with patient selection by biomarkers; 3) determining the right dose and schedule through PK variability; 4) understanding molecular changes leading to drug resistance; and 5) tumor heterogeneity.

Scholar Summary

Authored by Tristan Knight, MD Children’s Hospital of Michigan, Detroit, Michigan, USA

At its simplest level, precision medicine implies the use of therapeutic modalities which are in some way matched to the target or desired outcome. In the realm of oncology, this means specifically using a key driver mutation, antigen, or other expression of the malignant genotype/phenotype as a target and exploiting it via a treatment modality, be it immunologic, biologic, or pharmaceutical. The key principles underlying precision oncology are (1) specificity, e.g. a target is tumor specific (and not found on non-oncogenic tissue), (2) target-specificity, e.g. the agent does not exert an impact upon other antigens/pathways other than the desired target, (3) adequate engagement and inhibition e.g. the agent adequately inhibits or otherwise interferes with its target so as to exert some therapeutic impact, and (4) biomarker existence, e.g. a specific and sensitive measure is available to allow ascertainment of the effectiveness of therapy.

The advances in the field of precision oncology have been breathtaking and are highly encouraging. Progress in survival as well as in quality of life have been achieved via the use of therapies that target specific molecular markers in specific cancer subtypes, including breast cancers which express HER2, BRAF V600E-mutated melanoma and, more recently, RET-altered cancers. In the latter realm, LOXO-292 is presently undergoing evaluation and has demonstrated encouraging results and an acceptable toxicity profile.

Key challenges include the need to blend potency and specificity; many agents exist which are quite potent but of limited specificity and therefore demonstrate a host of off-target side effects. Dosing schedule and determination of dose itself is a key area as well; inter-patient variability may complicate pharmacokinetics and introduce an element of variability. Tumor heterogeneity is also a key obstacle; evolution or development of new mutations, or selection for such a mutation, is a documented factor in treatment failure with precision agents. In the work toward eliminating this obstacle, continuing to monitor and understand the clonal evolution of a malignancy, both within a primary site and at distant metastases, is crucial to therapeutic success. The existence of circulating, cell-free tumor DNA offers a useful and highly precise missing a noun here of real-time surveillance – and one that, while not yet fully realized, will only grow in importance.

As the field continues to evolve, we will likely continue to gain insights into the mechanisms and sites of action of those agents already in the therapeutic armamentarium and those constantly being added to it – and shall likely discover, as we have in the past, that the ‘precise’ drugs are not as precise as we might hope. As new generations of agents become available, their spectrum of action will likely narrow and thereby reduce off-target and unintended side effects.