MARKET BRIEF - Navigating the Evolving Landscape of Rare Cancer Trials


Rare cancers account for 27% of all new cancer diagnoses in the US and 22% of all new cancer diagnoses in the EU.1 With the shift toward grouping cancer based on molecular subtypes rather than by location and tissue type, some common cancers are now categorized as groups of rare cancers. For example, melanoma as a whole is not considered a rare cancer, but when divided into molecular subtypes, it can be viewed as a collection of rare cancers. When grouped as families, the most common rare cancer types are hematological, female genital tract, gastrointestinal, and head and neck malignancies.2

Grouping cancer based on molecular subtypes has changed not only how tumors are categorized, but also how novel thera­peutics are studied in clinical trials. In this discussion, we explore the landscape of rare cancer clinical trials, from key considerations for study design and the value of biomarkers to the importance of the patient perspective and the options for speeding much-needed therapies to mar­ket.

Distribution of families of rare cancers.3

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There is no universally accepted defi­nition for a rare cancer. In the US, rare cancers are defined as those with fewer than 15 cases per 100,000 per year. In the EU, however, cancers are considered to be rare if they occur in six cases per 100,000 per year.

While rare cancers are sometimes called the rare diseases of oncology, the terms are not synonymous. From a clinical trial perspective, there is some overlap be­tween rare cancers and rare diseases — namely small and geographically dis­persed patient populations, diagnostic challenges, poorly understood natural his­tories, and statistical hurdles stemming from small sample sizes. There are, how­ever, some key differences:

How they are defined – Rare diseases are defined by prevalence, while rare cancers are defined by incidence.

The role of genetics – 80% of rare disease have a genetic basis, whereas few rare cancers have a well-defined genetic com­ponent.

How they affect children – 75% of rare diseases affect children, and while child­hood cancers are less common than adult cancers, every pediatric cancer is consid­ered rare.

The approach to target discovery – Rare diseases comprise a heterogeneous collection of diseases with unique targets, while rare cancers fall under the larger cancer umbrella and may benefit from dis­coveries in common cancers.


Surgery, radiation, and chemotherapy were the mainstays of cancer treatment for many decades, but precision medicine has transformed the oncology landscape. With advances in genetics and technology, it is now possible to offer customized care based on the molecular characteristics of a particular tumor. In recent years, there have been breakthrough developments of tumor- or tissue-agnostic therapeutics. Three such therapies have received regu­latory approval to date:

Pembrolizumab – for tumors with mi­crosatellite instability-high (MSI-H) or defi­cient mismatch repair (dMMR).

Larotrectinib – for tumors with neu­rotrophic tyrosine receptor kinase (NTRK) gene fusions, which are found in approxi­mately 0.3% of patients across various cancer histologies.

Entrectinib – also for tumors with NTRK gene fusions.

Larotrectinib is the first drug devel­oped entirely using an agnostic approach. Its approval was based on efficacy data derived from three separate open-label, single-arm trials. Designed as basket stud­ies, these trials included patients with 12 different solid tumor indications, all with the same NTRK gene fusion and all of whom were treated with larotrectinib. The overall response rate was 75% across all three trials. Approval was based on pooled data from only 55 patients and the time from Phase 1 to accelerated approval was only 3 years, highlighting the potential efficiency of adopting a biomarker-driven approach to innovative drug development.


An increasing number of rare oncol­ogy programs have transitioned from a traditional, sequential drug development pathway to a seamless one. In seamless drug development, pharmacology, thera­peutic exploratory, and therapeutic confir­matory studies are combined, with the goal of achieving accelerated approval.

Cross-functional alignment across clinical, regulatory, manufacturing, and marketing is essential for meeting the shortened timelines of seamless drug de­velopment. Rare oncology sponsors who are considering this approach will need to account for the following:

Population size – The number of patients in the final dataset will be low, so innova­tive trial designs and statistical methods for data analysis may be required.

Recruitment strategy – For successful en­rollment, broad geographic reach will likely be necessary, increasing study cost and complexity.

Study design – It is critical to define the study population and subgroups, method­ology for response assessment, and end­points. Biomarkers may be more sensitive than tumor measurements for gauging re­sponse, especially with targeted therapies and immunotherapies. If overall survival is an endpoint, it is also important to deter­mine how to manage patients who progress after initial treatment.

Genetic or biomarker testing – Sponsors will need to identify an appropriate testing kit and testing methodology early in the program. The kit and methodology should be fit for purpose based on the develop­ment phase, but also scalable for late-stage studies and commercialization.

Manufacturing – With an accelerated program, manufacturing will need to scale quickly while remaining compliant with regulatory requirements.

Traditional versus seamless drug development.4

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Adaptive designs are study designs that allow for prospectively planned, pre-defined modifications to be made based on analysis of accumulating data at pre­determined points in the trial. These de­signs can be used to optimize rare cancer trials, allowing for additional flexibility, in­creased efficiency, and more targeted study populations. Adaptive designs com­monly used in rare oncology trials include:

Seamless Phase 1/2 – where a Phase 1 study focused on dose-finding transitions directly into a Phase 2 expansion study fo­cused on efficacy.

Biomarker enrichment – which uses bio­markers as inclusion/exclusion criteria, with the goal of identifying patients who are most likely to respond. An alternative to this approach is biomarker stratification, where biomarkers are measured on all patients and are used as stratification vari­ables.

Umbrella – which evaluates multiple tar­geted therapies for a single disease by stratifying patients into subgroups based on tumor molecular characteristics.

Basket – where a single targeted therapy or therapy combination is investigated in a variety of cancer types that share com­mon underlying molecular alterations.

Notably, adaptive designs are not mutually exclusive, and multiple methods may be used in a single trial.


Use of biomarkers for patient selec­tion and treatment response monitoring has increased significantly. Research has shown that studies using biomarkers for patient selection are both more likely to advance at every stage of development and more likely to gain regulatory ap­proval. In Phase 3 trials, studies employing biomarkers are nearly twice as likely to succeed as those that do not.5

Biomarker testing methodologies are myriad. Next-generation sequencing (NGS), which enables a broad spectrum of genomic alterations to be analyzed simul­taneously, has been a driver of precision medicine in oncology. NGS can be ap­plied to specific genes, off-the-shelf or cus­tom gene panels, whole exomes, or even the entire genome. Coupled with de­creases in sequencing costs and increases in efficiency, NGS has fueled a paradigm shift in biomarker discovery and targeted drug development.

NGS generates a massive amount of data, but not all genomic information is clinically relevant. It is, therefore, impor­tant for sponsors to develop a strategy for sifting through and interpreting the data to assess its clinical significance. In addition to leveraging online genomic knowledge bases, sponsors may find it useful to create precision medicine teams or molecular tumor boards to assist in data interpreta­tion. Liquid biopsies — which may be blood, plasma, or other bodily fluids — are also poised to be indispensable bio­marker tools. Traditional tissue biopsies are associated with certain limitations such as availability, invasiveness, cost, and in­ability to perform multiple assessments. With liquid biopsies, it is possible to per­form cost-effective serial sampling for lon­gitudinal assessment and downstream analysis.


Successful rare cancer studies require strong patient advocacy and engagement. Imatinib, a type of chemotherapy, is a classic example of how the internet can in­spire patient activism and impact drug de­velopment. When reports of remission with imatinib treatment in a Phase 1 study cir­culated in the early 2000s, patients clam­ored for increased clinical trial activity and drug production, spurring a Phase 2 trial and, ultimately, approval.

Technology has been a powerful en­abler of patient involvement in drug devel­opment. Social media platforms facilitate knowledge sharing at scale and offer op­portunities for sponsors to learn more about the patient perspective. This is espe­cially important in rare cancer research, in which patients are searching for options and might be willing to accept different levels of treatment-related risk. Facebook groups and other online forums bring to­gether patients with rare cancers, allowing sponsors to reach out to patients for feed­back. An increasing number of nonprofit organizations such as Count Me In are seeking to connect patients with re­searchers to accelerate discovery and de­velopment of novel treatments. The ability to interact with geographically dispersed patients not only facilitates recruitment but also broadens access.


Given the limited arsenal of treatment options available for most rare cancers, time is of the essence in drug develop­ment. The 2020 approvals of tazmetostat for advanced epithelioid sarcoma and selumetinib for neurofibromatosis type 1 signal the FDA’s commitment to prioritizing the unique needs of rare cancers. Recog­nizing that certain aspects of drug devel­opment for common diseases may not be feasible for rare cancers, the agency has demonstrated a willingness to offer addi­tional flexibility.

In the US, there are a number of reg­ulatory mechanisms available to help ex­pedite rare oncology program, including:

Fast track designation – To qualify for fast track designation, a therapeutic must be intended to treat a serious condition, and there must be nonclinical or clinical data demonstrating its potential to address an unmet medical need. Alternatively, the therapeutic must be designated as a qual­ified infectious disease product. This des­ignation can be rescinded if the therapy no longer meets the qualifying criteria.

Breakthrough therapy designation – Like the fast track designation, the breakthrough therapy designation ap­plies to therapeutics intended to treat a serious condition and can be re­scinded. To qualify as a breakthrough therapy, however, there must be prelim­inary clinical evidence indicating that the product may demonstrate substan­tial improvement on at least one clini­cally significant endpoint over available therapies.

Accelerated approval – This pathway is intended for therapeutics that treat a serious condition, provide a meaning­ful advantage over available therapies, and demonstrate an effect on a surro­gate endpoint that is reasonably likely to predict clinical benefit or on an in­termediate clinical endpoint. Sponsors who are interested in pursuing acceler­ated approval should discuss their plans with the FDA review division early on in development. In general, the FDA will request that confirmatory studies be underway at the time of accelerated approval.

Priority review designation – The pri­ority review designation requires that a drug is intended to treat a serious con­dition and, if approved, provide a sig­nificant improvement in safety or effectiveness. Other submissions that might qualify for priority review include supplements that propose a labeling change pursuant to a pediatric study, applications for drugs designated as qualified infectious disease products, and submissions accompanied by a priority review voucher.

PRIME – In the EU, PRIME is the main mechanism for expediting development of medicines targeting unmet medical needs. PRIME provides enhanced inter­action and early dialogue with regula­tors to help ensure generation of robust data and enable accelerated assess­ment of marketing authorization appli­cations. Key benefits of PRIME include appointment of a rapporteur for con­tinuous support, organization of a kick-off meeting for guidance on the regulatory strategy and overall devel­opment plan, assignment of a dedi­cated contact point, and provision of scientific advice at key development milestones.


Rare cancers represent a signifi­cant unmet need in oncology. Globally, more than one in five cancer patients is living with a rare cancer and faced with limited treatment options. With ad­vances in genomic testing, im­munotherapy, and precision medicine, progress is being made, bringing new treatment alternatives to the patients who need them.


  1. Greenlee RT, et al. The occurrence of rare cancers in U.S. adults, 1995-2004. Public Health Rep. 2010;125(1):28-43.
  2. Based on data from RARECARENet. Available at
  3. Rare Cancers Europe. “Families” and List of Rare Cancers. Avail­able at
  4. Theoret MR, et al. Clin Cancer Res. 2015;21:4545-4551.
  5. Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics 2019;20(2):273-286.

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Dr. Rupa Doshi is Vice President, Program Strategy, Oncology at Premier Research. With more than 23 years in the industry, she is an experienced professional with demonstrated leadership skills in clinical operations, global project/program management, customer management, and strategy development. Her experience spans the clinical development spectrum from pre-IND to NDA. She has also led global teams to execute full-service complex clinical trials across all phases. She brings drug discovery and clinical development experience with biologics and small molecules as well as cell and gene therapy products over a range of indications. Her doctoral research focus was on breast cancer, while her post-doctoral research was in site-directed mutagenesis. She holds patents in angiogenesis and has also supported three products resulting in agency approval.

Dr. Sameena Sharif is President, Regulatory Professionals, A Division of Premier Research. She is a strategic thought leader in drug development, alliance, project, and portfolio management. She has broad experience in managing projects at all stages of drug development — from the target selection and pre-investigational new drug stages through new drug application/marketing authorization application submissions and commercial planning. She has led large, cross-functional teams in global alliances with Amgen, Otsuka, Genentech, Novartis, Onyx, and AstraZeneca, with a particular interest in optimization of the drug development and alliance management process in small and midsize companies. She earned her Bachelor of Pharmacy from the University of Bradford and her PhD in Pharmaceutics from the University of Nottingham.