The future of oncology therapeutics

KEYWORDS:

• Precision oncology
• clinical drug development
• immunotherapy
• targeted therapy
• healthcare sustainability

1. Introduction

In the past decade, we have witnessed several breakthrough events that changed our clinical practice in oncology. Precision medicine is now a reality. It was built upon the availability of an unprecedented massive amount of data regarding cancer molecular biology (driven by initiatives such as the Cancer Genome Atlas, the International Cancer Genome Consortium, or the 100,000 Genome Project) [1–3], along with a progressive transition toward a digital and global practice:

• the molecular and clinical databases are rapidly transforming raw data into useful applicable knowledge [4,5];

• there has been a gradual shift toward health-care systems now centered on involving the patient in clinical decisions.

All of this new knowledge allows the fostering of further learning opportunities and is giving place to an authentic historical revolution in oncology that is difficult to follow. For the first time, a proportional response to our patients’ therapeutic perspectives begins to be provided.

2. New standards in clinical drug development

We are living in an exciting era in which the gold standard in clinical development of antitumor drugs is changing at an astonishing pace, after roughly half century of stagnation and relative inefficacy in providing more and better drugs to our patients. New study designs have emerged, such as basket and umbrella clinical trials, as well as dynamically evolving multiple-arm phase 1b/2 trials with hundreds of recruited patients and specific exploratory cohorts of different tumor types and pivotal trials with associated sub-studies. These novel designs coupled with the recent awareness and sensitization of regulatory agencies in improving the current system inefficacy are changing the paradigm of clinical cancer research [6–9]. As opposed to a classically based succession of phase 1 trials for dose finding and administration schedule, followed by phase 2 trials to check for antitumor activity and, lastly, phase 3 trials in which the drug was compared against the standard therapy for superiority and drug approval, it is now becoming a reality that the typical objectives, in early- and late-phase investigation, are now obtained in a time continuum during the course of the initial trials that seek to be much more informative [7].

However, this revolution is insufficient. We cannot conform in our objective of developing new molecular entities with different mechanisms of action, which we aim to be better tolerated and more active, if we are not able to reduce costs, development time, and drug accessibility to our cancer patients. In what concerns the latter, we still have the need for a disruptive change, which would shift the current focus to the free, informed decision and choice of the patient from the hand of his oncology practitioner, through a more libertarian clinical drug development system that is nowadays frankly intervened [10]. In this sense, some initiatives of globalization and clinical data sharing, as Targeted Agent and Profiling Utilization Registry (TAPUR) and CancerLinQ, are heading in the right direction [11,12].

3. New paradigm in treating cancer patients

With the arrival of two new waves of drug classes, which have come to complement and improve the classical cytotoxic arsenal, we are now observing the treatment and the perspectives of our patients with advanced solid tumors, until now relatively untreatable, change in a very significant way. On the one hand, drugs aiming at inhibiting specific tumor targets, the theoretical ‘Achilles tendons’ of each cancer, such as the monoclonal antibodies, the so-called small molecules or the new generation of antibody–drug conjugates, have improved both efficacy and safety when compared to classical cytotoxics [13]. On the other hand, the more recent and modern immunotherapy agents, aimed at modulating immune system checkpoints, while also being targeted therapies, are no longer tumor oriented. Yet, they potentiate the cells of our own immune system so that these cells can have a large-spectrum antitumor effect, as shown by their spectacular efficacy in the treatment of patients across different tumor types (melanoma; kidney, lung, urothelial, head, and neck cancers, lymphomas, as well as many others) [14]. The evolution of both therapeutic modalities has also brought us new molecules and concepts, such as the ones based on the chimeric antigen receptors, which are engineered receptors that graft the specificity of a monoclonal antibody onto an immune effector T cell (CAR T-cells) [15] or as synergistic combinations of different targeted agents.

Thanks to these novel agents, we are starting to see a small, but real, percentage of patients who can become cured of their metastatic disease or that can have their disease controlled without the need of periodically receiving new doses of treatment, especially with immunotherapy. With our current therapeutic repertoire, once we are able to improve our knowledge in optimizing the administration of these drugs, along with their potential predictive biomarkers of response across different tumor types (and, in this sense, clustered regularly interspaced short palindromic repeats (CRISPR) technology will be an authentic revolution) [16,17], we will significantly improve our patient’s perspectives regarding disease control and quality of life.

4. Future perspectives

Will we see the cure for cancer? Once we are able to master liquid biopsies and incorporate them in daily clinical practice, we will have easy-to-obtain real-time information of the molecular and functional status of each patient’s tumor [18]. There has been a significant improvement in the technology applied in early detection of otherwise clinically silent diseases. Furthermore, we are now learning how to optimize the selection and use of currently available treatments and new drugs that will come short term, either in synergistic combinations or in sequential use. Taken this into account, we will go from ‘only’ curing additional patients to being able to cure most patients over the coming decade. If we combine this with the importance of cancer prevention, using increasingly efficient campaigns of awareness, we could potentially halve the number of new cases. If corrective and preventive measures were adequately applied [19], one could perfectly and unequivocally say that cancer would no longer be the overwhelming problem without valid solutions, which it is today.

In order to put this into practice, it is necessary to create a sustainable system so that these new advances and knowledge in oncology can be applied globally. Otherwise, we will not have a significant impact on global cancer mortality and morbidity, but only on a minority among the wealthiest countries and citizens. In this regard, we do not refer solely to prices, but to the value of new therapies (as investor Warren Buffet, known as the ‘Oracle of Omaha’ said, ‘Price is what you pay. Value is what you get.’). The goal is not a less expensive health but a better global cancer health: to improve the experience and expectations of the cancer patient in a true way, giving him/her control of his/her own malignant disease. We need to improve worldwide oncologic health and, for all purposes, provide the cancer patient authentic added value, of many carats, with our diagnostic and therapeutic interventions.

Also in favor of maintaining the sustainability of the system, we must be able to channel this knowledge and adequately train the next generation of oncology specialists (medical oncologists, radiation oncologists, surgeons, pathologists, etc.), as the current model of training and its content has changed substantially. While the knowledge, attitude, and skills necessary to fight this terrible disease are similar in its essence (the doctor–patient concept), they are now substantially different in many nuances and aspects compared to what they were a decade ago. This responsibility lies in us, present oncologists, to make the bridge and serve as an umbilical cord to the transition between the old and new oncology.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper has not been funded.