The immuno-oncology (IO) field is becoming incredibly crowded and competitive. What factors should sponsors weigh up when planning a new IO trial in 2019 and beyond?
CL: Sponsors of IO trials should consider (1) the novelty of their agent in terms of mechanism of action as well as combination, (2) the feasibility of enrolling the patient population of interest (with determined focus on potential challenges and restrictions), (3) empirically established timelines to enrol populations that will satisfy the study’s primary objective(s), and (4) the competition (in all applicable forms) for the patient population to be enrolled over a given period of time. In order to ensure efficient spend and effort, these key criteria should be met positively and, most importantly, only those sites that have the capabilities to deliver IO trials, as well as the enthusiasm and available resources to dedicate to a study, should be selected.
ML: In addition, it is key in the combinatorial setting that there is adequate data or design of protocol to support the protocol hypothesis giving assurances to competent authorities, IRBs and physicians as to the validity of the protocol approach.
In particular, what approaches should be taken in regards to patient recruitment for these trials?
CL: To effectively recruit, sponsors must clearly know the limitations of both their IO protocol as well as the patient population to be recruited. Protocol review and commentary by regulatory agencies and patient advocacy helps to ensure the trial’s objectives are aligned from the outset with scientific merit as well as respect for the patient journey. Patient referral networks, recruitment materials and scientific/medical conferences provide foundational opportunities in planning for enrolment success through early engagement of the critical path stakeholders, ie Key Opinion Leaders, referral networks, advocacy groups, etc.
ML: There is a growing body of community healthcare facilities that are demonstrating an interest in and a capability of participating in IO trials. This provides access to a broader patient pool. However a focus on increased support for the community-based centres is paramount to achieve success. Finally the advent of precision medicine platforms that deploy natural language processing algorithms to interrogate Electronic Health Records in defined site networks is assisting sites to know their patient populations better with a view to identifying patients for particular clinical trials.
A number of IO companies are pioneering the use of new biomarkers, eg tumour mutation burden (TMB). How mainstream will these become, and how should trials adapt?
CL: For decades, oncologists have characterised tumours based on their supposed tissue of origin. With the advent of the –omics era in the mid- 90s, new perspectives were ushered in in terms of oncologic molecular characterisation rather than tissue origin. Research has shown that many tumours derived from different tissues are often more alike molecularly (or metabolically) than relative tumours originating from the same tissue. Thus, the continued search for new biomarkers is simply an evolution of the need to better understand and characterise neoplasias, and will invariably differentiate treatment schema going forward. IO trialling has historically leaned heavily upon exploratory endpoints for biomarker elaboration to drive understanding as well as to propose the next set of hypothetical objectives to be investigated. Trials will continue to use real- time information to inform treatment decisions and design, as well as spend, making near-term adaptation a must.
There has been a rapid evolution in clinical trial design in IO, eg basket trials, adaptive trials, etc. What do you see as the major industry and regulatory trends over the next five years?
CL: Evolution of trial design has benefited greatly in past decades, as the search for meaningful signals in patients has provided faster screening of larger populations with differentiated tumour burdens. The dual benefit of this approach is a shorter timeline to ‘picking a winner’, both in terms of sponsor spend and patient outcomes. Notably, basket and adaptive trials permit researchers to quickly pivot away from potential dead ends and back towards empirical signals. Given both the historical expense of trialling as well as the IO competitive landscape to improve care, the rapid evolution of trial design is not so much a characterisation of what has occurred to date as it is a competitive necessity. Regulatory oversight of interventional studies has been tasked with ensuring patient safety, while also helping to encourage cost containment through promoting expediency in discovery. Through these concerted efforts, meaningful progress in IO will have its best chance.
ML: The explosion in combinatorial approaches to potential treatment paradigms makes platform/ basket/adaptive designs all the more compelling and will accelerate over the next years.