Precision medicine in practice: Strategies for rare cancers

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Greater understanding of disease biology and revolutionary diagnostic and therapeutic technologies have unlocked increasingly effective treatments for people with cancer. Diseases for which the only recourse was palliative care now have treatment-response rates of more than 80 percent.1 Notwithstanding those encouraging improvements, there are a number of rare cancers, many of them genetically defined, for which there are still no effective treatments. For example, KRAS, an oncogene commonly mutated in non-small-cell lung cancer (NSCLC) and other diseases that affect thousands of people, has historically been considered an “undruggable” target.2 However, there have recently been successful clinical efforts to target such gene families in disease treatment.3 Ongoing research is likely to uncover more and more molecularly defined rare cancers in need of therapies.

Many biotech and pharmaceutical companies are working to develop drugs to fill the treatment gaps. They face the same basic challenge encountered by every company developing a treatment for a rare disease: a small population of people with the disease. That obstacle slows drug development because it can be hard to identify sufficient people to enroll in clinical trials. From a commercial perspective, efficient approaches are required to optimize drug access and adoption, while achieving the aspiration to leave no patient behind requires precision. Large-scale commercial tactics are unaffordable in the majority of rare-cancer indications, since the assets for their treatment will achieve peak revenues of no more than $250 million, on average (Exhibit 1).

A majority of rare-cancer therapies will have peak sales of less than $250 million.

Companies developing and launching treatments for rare cancers need to factor the small-population issue into their strategies. But they will also need to account for a set of challenges that are unique to oncology. Overcoming them will be crucial in ensuring that as many people as possible have access to innovative therapies for oncologic diseases.

Understanding rare cancers’ challenges

Recruitment for multiple ongoing trials in same populations

Several large pharma companies have invested in treatments for rare-cancer indications. Additionally, more than 60 biotech companies around the world are advancing therapies for rare-cancer indications, often targeting the same ones. For example, there are two approved therapies for cancers with NTRK mutations, which have an overall incidence in the United States several times lower than that of breast cancer (1,000 per year, compared with more than 280,000 per year), and there are at least two more in late-stage development. Even drugs targeting the rarest genetic mutations have competition (Exhibit 2).

Cancer treatments, even those targeting the rarest of genetic mutations, face competition.

That competition can make it very challenging to recruit people for trials of drugs for rare cancers (Exhibit 3). Take acute lymphocytic leukemia (ALL) as an example. More than 25 Phase III trials in ALL, requiring approximately 36,000 participants, are either under way or planned in the United States. Yet there are around 100,000 people with ALL in the country (around 6,000 diagnosed per year). To fill the requirements for all the trials, more than one-third of those people would have to be both interested in participating in a trial and eligible to do so.4

In many rare cancers, there are nearly as many clinical-trial slots as patients.

Engagement with dispersed groups of specialists

Although rare diseases tend to have a long tail of prescribers who might only treat one or two people, the majority of people with them are treated by a relatively concentrated group of specialists. The specialists are deeply involved in the research for the disease, and they interact with one another and with patient communities. Hence, there is a relatively small base of specialists with whom drug companies will need to work to build awareness of a treatment.

Expertise is less concentrated in oncology. Up to 85 percent of people with cancer are treated in community practices by oncologists who treat a wide range of indications across different types of cancers.5 As a result, biopharma companies with rare-cancer-related assets have a much bigger specialist base to engage with.

In addition, many rare-cancer indications are pan tumor, which means that eligibility for the treatment is based on molecular status, not histology. For example, NTRK mutations are present in multiple different types of cancer, including, but not limited to, NSCLC, thyroid cancer, and colorectal cancer.6 Although the mutations can span different cancer types, oncologists often specialize in only one. That can make pan-tumor education challenging and requires biopharma companies to engage with an even broader set of customers.

High requirements for diagnosis: Education and testing

Many rare diseases, by nature of their rarity, can be hard for nonspecialists to recognize and diagnose. But numerous rare cancers, which are molecular subsets of larger indications, have additional challenges. As with any rare, molecularly defined disease, diagnosis depends upon conducting a test.

In oncology, however, the symptoms of the rare disease are often no different from the larger indication of which they are a subset, and there are many different possible rare mutations. Take NSCLC as an example. Its incidence is quite high: there are around 78,000 people a year with stage IV NSCLC in the United States. Yet it also is associated with many rare genetic mutations, including in the ALK, EGFR, KRAS, NTRK, and RET proto-oncogenes—the latter two being among the rarest, present in around 0.1 percent to 1.0 percent of people with NSCLC.

Hence, while molecular tests conducted for many rare diseases tend to have relatively high positivity rates, single or even small gene panels are unlikely to detect the precise mutation connected to a particular rare-NSCLC population. Large genomic panel tests are required, yet they aren’t commonly requested by physicians or used by pathologists.

Awareness of rare cancers overshadowed by larger cancer indications

Awareness is critical to the success of any treatment for a rare disease: it can be the perseverance of the people with the diseases that secures access to the right care, given how few physicians have experience in rare diseases. Often, the awareness of those with the disease is quite high thanks to the work of support groups, foundations, and campaigners.

Awareness is critical to the success of any treatment for a rare disease: it can be the perseverance of the people with the diseases that secures access to the right care, given how few physicians have experience in rare diseases.

Rare cancers, however, can get overshadowed by the more prevalent forms of a particular cancer. For example, compared with common forms of lung cancer, the rarer one with an ALK mutation (ALK+ lung cancer) receives scant public attention. Often, people with the disease can remain unaware of the significance of the different molecular alterations. Even the nomenclature can be confusing.

The merging of the molecularly defined indication into the much more prevalent indication is true beyond just patients’ awareness. For example, the European Medicines Agency considers all molecularly defined tumors as part of the larger oncology indication. Such definitions can have important implications for access to and reimbursement for treatment, clinical trial design, and pricing, as therapies targeting those molecularly defined indications cannot receive orphan-drug status.

Distinct capabilities needed to reach every person with a rare cancer

Most companies that are developing treatments for rare diseases have strong strategic focuses on rare diseases and portfolios of unrelated assets. That structure allows them to build distinct clinical and commercial capabilities. In contrast, biopharma companies developing treatments for rare cancers tend to have broad portfolios of oncology assets. They might include various drugs for treating, say, NSCLC, with some focusing on narrow, molecularly defined indications and others having broader targets that include those indications. That structure can dilute focus on the smaller asset and prevent development and launch strategies from being sufficiently tailored for a rare-cancer therapy.

Overcoming rare cancers’ challenges

Companies involved with rare-cancer therapies require distinct development and commercialization strategies to overcome the challenges they face. Through our work across oncology, rare diseases, and rare cancers, we have identified three key elements of such a strategy: use of advanced analytics and real-word evidence (RWE), a robust biomarker strategy, and a tailored engagement plan based on biomarker status and market position.

Use of advanced analytics and real-world evidence

Advanced-analytics capabilities are table stakes for the successful development and launch of a rare-disease treatment. Analytics platforms help companies ingest data from various sources and translate them into insights that help the companies understand individual cases, educate healthcare providers, and distribute treatments rapidly. That said, it is important to rightsize the analytic approach for each launch. Companies with a single commercial product should be thoughtful about the trade-offs of building versus borrowing analytical capabilities.

The analytic capabilities enable companies to employ RWE in new ways. Used for decades to understand patient behavior and outcomes better, RWE is now helping move precision medicine from descriptive understanding of patient segments to predictive approaches to R&D, market access, and commercial and medical undertakings.

One of most important use cases of advanced analytics and RWE in rare cancers is the synthetic control arm in clinical trials. Such arms help overcome both the difficulty of finding enough people with a disease to run a traditional randomized controlled trials and the ethical concerns raised by offering a placebo to people who could benefit from a disease-modifying treatment. Even in traditional trials, synthetic control arms can reduce the number of people necessary for the control arms.

Regulators are looking more favorably on the role of RWE in approving new indications for approved drugs and in postmarket safety monitoring. In 2019, for example, the US Food and Drug Administration (FDA) expanded the label for IBRANCE to include male breast cancer on the basis of RWE. The drug is a treatment for breast cancer that tests positive for hormone receptor and negative for human epidermal growth factor receptor 2 (HR+ HER2 breast cancer), which is an extremely rare cancer in men, with an estimated patient population of 2,700 in the United States. Similarly, Amgen was able to secure an additional approval of BLINCYTO for a rare form of leukemia.

Real-world data and advanced analytics are clear enablers of RWE for drug development. So far, large biopharma companies have mainly been the ones to build the necessary capabilities, often through partnerships. However, as more data become readily available, biotech companies involved in therapy for rare cancers may also be able to use RWE to streamline development.

A robust biomarker strategy

The number of drug launches that have biomarkers in the label is rising, with more than 400 FDA-approved therapy and biomarker combinations on the market today at the indication level.7 And as discussed, many of the approved therapies target the same or similar mutations, leading to intense competition. Despite this, many companies struggle to include biomarker strategy from early enough in development to avoid challenges at launch. Thus, biomarker strategy should be an integral part of a company’s therapy development and commercial approach when it comes to treatment for rare cancers. For a successful biomarker strategy, companies need to consider three critical factors: the category of diagnostic, type of diagnostic technology, and role of the diagnostic partner.

Often, companies refer to a molecular diagnostic test that accompanies a therapy as a companion diagnostic (CDX). However, in strict terms, a CDX is an FDA-approved test that has been analytically and clinically validated with the therapy. Although that is typically done in tandem with therapy development, it can also be done after through a retrospective analysis, as in the case of Guardant360 CDx.8

If identification of the biomarker is not needed for exclusion or inclusion criteria for the therapy or if a diagnostic for the mutation is already available on the market, then some manufacturers will obtain therapy approval with the mutation listed but not a requirement around diagnostic testing. In that case, the diagnostic used in clinical trials may be made available as a complementary diagnostic at launch, when the manufacturer can rely on lab-developed tests (LDTs) that are already routinely used, as in the case of many of the therapies that inhibit programmed death-ligand 1 (PD-L1 inhibitors).

The choice of the category of diagnostic will partly depend on where the treatment will be approved and prescribed, as the related rules, regulations, and practices vary across geographies. For example, in most European countries, molecular diagnostics are commonly conducted as LDTs in government-affiliated facilities (such as the Institut National du Cancer in France), though that may change as regulation becomes stricter with the passage of In Vitro Diagnostic Regulation (IVDR) legislation.9 Other countries, like Japan, require a CDX for reimbursement. In the United States, both LDTs and CDXs are regularly used, with a large number of different commercial providers. If testing for a mutation is not commonplace, a CDX makes the most sense in ensuring awareness and access to the right molecular testing, as a CDX claim is generally required for drug reps to talk about the diagnostic and the importance of testing for the specific mutation.

Regardless of the category of diagnostic, another key decision is which molecular profiling technology to support. Common types of molecular diagnostics are based on polymerase chain reaction (PCR), which can test for a single gene alteration; immunohistochemistry (IHC), which can test for a limited number of proteins; and next-generation sequencing (NGS), which can analyze multiple genomic alterations at once. Some types of mutations are better detected by one technology versus another, but it’s also important to consider the overall landscape.

For cancers for which molecular testing is relatively routine, such as NSCLC, it’s important to ensure that the relevant biomarker is included on the frequently used NGS panels.10 A new CDX could be created for only the gene of interest, but oncologists focused on lung cancer are unlikely to order a test that will only identify a rare mutation in addition to a larger panel. Also, many of the larger panels may already include the mutation of interest, whether or not there is already a targeted therapy. Particularly for the indications for which testing is routine, it’s important to understand the current testing landscape and the current frequency of testing for the mutation in question.

However, in diseases for which molecular testing is less frequent, such as hematologic cancers, or in indications for which a single mutation drives most of the therapy decisions, a pathologist may prefer to do a simple PCR test or IHC stain, depending on the biomarker. As overall molecular testing becomes more frequent, oncologists are moving toward use of NGS and larger panels, but the trend isn’t universal. Often, pharma companies will invest in partnerships with multiple diagnostic companies that specialize in different testing types (for example, one company for NGS and another for PCR).

If the CDX route is chosen, the diagnostic company is responsible for clinical and analytical validation of the diagnostic test. Companies typically manage that concurrently with drug development so that they can be launched at the same time. However, there may be additional commercial advantages to consider as part of the partnership. For example, a pharma company discovered that insurance companies were often unwilling to fund the genomic test needed for diagnosis and therapeutic selection for its drug to treat a rare disease. The company offered the tests for free at the centers of excellence where patients with the indicated diseases were most likely to be seen. The strategy resulted in an excellent return on investment, with almost a quarter of free tests indicating that the person could benefit from the company’s rare-disease therapy. An appropriate biomarker strategy is critical to ensuring that people are receiving the most efficacious therapy for their disease states.

A differentiated customer-engagement strategy

Physician education is always important, but the strategy for engaging with payers and group purchasing organizations (GPOs) could prove even more so for rare-cancer therapies. Several considerations can help ensure that more people with rare cancers get treated with the most appropriate treatment.

Physicians: Education and awareness. The successful launch of a rare-cancer therapy—and the resulting ability to improve outcomes for the people who need it—depends upon a strategy to maximize the number of people with the disease reached. That approach typically hinges on engaging with healthcare providers both to raise awareness of the disease and to ensure that they run the tests capable of detecting it.

As we have pointed out, however, all oncologists could theoretically be treating people with rare cancers, and companies launching a rare cancer treatment can’t reach them all. They will need a more targeted strategy if they are to use limited resources efficiently. A distinction should therefore be drawn between the launches of differentiated therapies and those that are in competition with similar products.

Companies have a differentiated therapy if it targets a new biomarker; has superior clinical, safety, or dosing characteristics compared with peers; or offers more convenience. Those companies will need to invest in field resources and marketing campaigns to ensure awareness of their products’ clinical value to healthcare providers.

Companies can seek to reach the providers that are at the point in the treatment paradigm where the treatment can make a meaningful difference, typically starting with academic medical centers as the first adopters. For molecularly defined cancers, they will also need to engage with oncologists and pathologists about which tests to conduct. Some pharma companies have deployed precision-medicine liaisons to do exactly that. For example, several years before Bayer and Loxo Oncology launched VITRAKVI, a treatment for solid tumors with NTRK mutations, they hired a diagnostic-strategy leader. The leader managed regulatory issues, began building awareness with customers, and began educating key reference labs on how to test for NTRK mutations. Then, nine months before launch, the companies hired a diagnostic team with a mix of diagnostic-science liaisons to build awareness with oncologists and pathologists.

We have also seen pharma companies use reference labs and diagnostic reports to highlight their drugs. Ensuring that the drug is listed on the pathology report whenever a specific genetic alteration is identified allows them to raise awareness with physicians while minimizing field resources. And some partner with diagnostic companies that alert the pharma companies when a physician runs a diagnostic test that could potentially identify a person who might benefit from the company’s therapy. Although personal information must remain protected, the test can trigger outreach by the pharma company’s field force, providing the physician with targeted content.

However, companies that don’t have a differentiated offering might want to rethink their commercial models, potentially limiting their spending on field resources and marketing campaigns. With their more limited resources, those companies might find it more beneficial to engage the tail of community oncologists who may not have adopted targeted therapy, helping to ensure that more people have access to precision medicine. Time could also be spent engaging selectively with payers to share data and practices on managing risk and with GPOs that can offer a range of services efficiently.

Payers: Help in managing risk. Payer engagement is important for all oncology indications. But companies with rare-disease assets might consider selective payer engagement. For example, the majority of rare oncologic diseases are not uniformly distributed, occurring perhaps in specific ethic populations or geographies. As a result, a cluster of people with a rare disease could disproportionately affect certain small health plans or certain employers.

A potential way to mitigate risk for insurers is to offer outcome-based contracts, ensuring that the outcomes of the people being treated drives value for all parties. Stop-loss insurers are another possible segment on which to focus. They already play an important role in the cell- and gene-therapy market, in which a single claim can be for more than $200,000 and employers that self-insure their medical benefits are looking to protect themselves against unpredictable losses. Stop-loss insurers could come to play an equally important role in rare-cancer treatment as more niche therapeutics with price points higher than those of other therapies come to market.

GPOs: One-stop shop. Engagement with GPOs has long been important for oncologic products, especially those used in community-care settings, where patient services may not be as available as they would be in large academic medical centers. However, some specialty GPOs now provide a range of the services that are important to people suffering from rare cancers. They offer rapid distribution of drugs, patient services, contracting for access, and a single point of contact for physicians coordinating care.

Several large US drug distributors have made acquisitions over the past few years to offer such one-stop shops too. Working with companies that offer those kinds of combined offerings can be beneficial—particularly for biotech companies that would struggle to offer such a wide range of services in house.

Although there isn’t yet a gold-standard approach for developing and launching treatments for rare cancers, it’s clear that the approach must be guided by the recognition of the specific challenges such treatments face. Considerable investment in the analytics capabilities that support the use of RWE, a ready-to-go biomarker plan, and a differentiated customer-engagement plan that uses limited resources wisely: all are key elements of successful strategies for treating such cancers. That success will help prize open the door toward more treatments and better outcomes for people with rare cancers.


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