1. Kumar Das, Dibash PhD

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Genome-driven cancer treatment (precision medicine) has been suggested as the future standard-of-cancer management. Precision medicine employs omics techniques and platforms to profile genomic, transcriptomic, and proteomic abnormalities of cancers (Cancer Treat Rev 2020; doi: 10.1016/j.ctrv.2020.102019). The strategy is becoming increasingly attractive to clinicians and investigators, offering a progressive understanding of cancers based on their genetic alterations instead of their primary locations. This molecular profiling information can lead to the development of targeted therapies designed to be more effective for the specific tumoral molecular alterations found in each individual tumor.

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Nevertheless, precision medicine still presents several limitations, including poor-quality biopsies, as well as lack of off-label use of drugs and clinical trials (Ecancermedicalscience 2018; doi: 10.3332/ecancer.2018.ed86). Other limitations include intrinsic features such as the complexity of the tumor microenvironment, cancer heterogeneity, and clonal evolution as mechanisms of individual treatment resistance.


Recently, the MAST Study evaluated the improvement in clinical outcomes of patients with advanced solid tumors by applying a molecular-based approach using a customized next-generation sequencing panel (Br J Cancer 2021; The single-center retrospective analysis had three goals within their early clinical trial program: 1) investigate the efficacy of a comprehensive molecular profiling for patients with advanced solid tumors; 2) evaluate the impact of those targeted therapies versus standard therapies in subsequent treatment options for advanced cancer patients; and 3) determine the primary predictive factors for possible treatment benefit using a Bayesian model method.


In the study, 98 eligible patients aged >=18 years with advanced solid tumors were molecularly chosen to be given a molecular-matched treatment into early (Phases I and II) clinical trials (n=32) versus best investigator choice (n=66), according to the evaluation of a multidisciplinary molecular tumor board. The primary outcome was progression-free survival (PFS) measured by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1).


The findings revealed that, compared to those who received standard therapy (2.76 months; 95% CI, 2.14-3.91), patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24-14.43) (log-rank P=.022). Notably, no significant differences were detected comparing median PFS1 with their immediately previous therapies between patients treated with targeted versus non-targeted therapy (PFS1) (P=0.56). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the molecular-matched group compared with those who did not qualify for such therapies (0.33 vs. 0.08; P=0.008). Additionally, disease control was observed in 68.7 percent of patients treated with targeted therapy, while it was only seen in 36.4 percent of those designated to standard care.


Oncology Times connected with study authors Desamparados Roda Perez, MD, PhD, and Valentina Gambardella, PhD, to further discuss their work. They are both medical oncologists at the INCLIVA Biomedical Research Institute in Spain.


Oncology Times: What is the benefit of a molecular profiling selection approach for early trial candidates in the context of targeted agents?


Perez & Gambardella: "We observed that an early detection of molecular druggable alterations was able to improve the therapeutic plan of advanced cancer patients that could help in improving the clinical outcomes as observed in our investigation. Patients with actionable molecular aberrations may benefit more from specific targeted therapies than from standard treatments. Precise selection of targeted agents matched to molecular alterations in advanced cancer patients may play a significant role in improving treatment decisions and management."


Oncology Times: What findings did you find most compelling regarding the utility of your customized molecular screening approach? Can you also speak to the potential plasticity of this panel?


Perez & Gambardella: "We designed a customized panel in order to actualize the molecular study according to the novel drivers identified. It helps in opening novel possibilities for our patients. This is a key characteristic of our molecular team approach, especially relevant in early trials development."


Oncology Times: Molecular profiling is an attractive approach to make a treatment decision for a patient. What concerns need to be addressed before such an oncotarget-based strategy can be widely accepted?


Perez & Gambardella: "There is an important need for the presence of a critical discussion in the molecular tumor board for a correct interpretation of the molecular data. At the same time, it is important to understand the rational and the proof of concept for the selection. To improve the decision based on the molecular alterations, the use of qualified scale and tolls (such as the ESMO Scale for Clinical Actionability of Molecular Targets) could help us in treatment selection. As an example of the continuously developing field, Tamborero, et al, have published in Nature Medicine an interesting article describing a new molecular tumor board portal that could support clinical decisions and automated reporting (2020;"


Oncology Times: When it comes to molecular profiling-based precision medicine in cancer, what recently reported or soon-to-be reported data excite you?


Perez & Gambardella: "The improvement of the high-throughput tools and the RNA sequencing development has led to the identification of novel gene fusions which are considered drivers and once drugged could improve clinical outcome. These new alterations have offered a challenging opportunity to precision medicine in cancer, full of new necessities and difficulties. Most of these new alterations occur only in a low percentage of patients, so massive sequencing and fast referral to Phase I development centers could become a key part of the process."


Dibash Kumar Das is a contributing writer.