Tumor-Agnostic Therapy Assessment: Following Regulatory Approval, What Challenges Exist for HTAs?

By Xcenda

Historically, despite progress in understanding tumor biology, cancer drug approvals of “one-size-fits-all” medicine were based on a single anatomical location, regardless of the type of therapy. However, recent substantial advances in molecular diagnosis and testing of cancer, along with exponential growth in data-mining capabilities, have led to the development of targeted classes of therapeutic agents expected to confer benefit to patients whose cancer displays specific genetic molecular features. This article examines the challenges HTA bodies face in evaluating these novel therapies.


Tumor-Agnostic Therapy Assessment: Following Regulatory Approval, What Challenges Exist for HTAs?

By Isabell Kang, PharmD; Kristin Hennenfent, PharmD, MBA, BCOP, BCPS; Chelsey Campbell, PharmD, MBA, MS; Keith Tolley, MPhil; Kasia Shields, PharmD, MBA, BCOP, BCPS

Date last updated: August 8, 2019

Novel Therapies Bring New Terminology

Historically, despite progress in understanding tumor biology, cancer drug approvals of “one-size-fits-all” medicine were based on a single anatomical location, regardless of the type of therapy. However, recent substantial advances in molecular diagnosis and testing of cancer, along with exponential growth in data-mining capabilities, have led to the development of targeted classes of therapeutic agents expected to confer benefit to patients whose cancer displays specific genetic molecular features. These molecularly tailored therapies are broadly termed precision or personalized medicine, and they facilitate the delivery of “the right medicine, at the right time, to the right patient.” 
Distinctively, tumor-agnostic or tissue-agnostic therapies are cancer therapies that target a specific genetic or molecular alteration but do not focus on the anatomical location. As such, the same drug has potential to be used to treat various unique types of cancer, including very rare (ie, orphan) tumors, as long as the common biomarker targeted by the drug is present. The targets of tumor-agnostic therapies are identified through genetic and molecular profiling of tumor tissue. Improved availability of comprehensive, clinical-grade, next-generation genomic sequencing techniques has led to an increase in the identification of such alterations across tumor types. Collectively, advances in identifying cancers with specific genetic or molecular alterations and developing tumor-agnostic therapies to treat these niche patient populations have been incorporated into treatment paradigms for various cancers, establishing a new era of precision medicine. For further information about this topic, please also see the article on next-generation sequencing in this issue of HTA Quarterly.

Tumor-Agnostic Therapy Trials Differ From “Traditional” Anti-Cancer Trials

In a departure from the traditional clinical trial structure, trials evaluating tumor-agnostic therapies enroll patients with particular genetic markers to establish efficacy in phase 1 expansion cohorts and phase 2 studies. These studies, termed basket trials, are biomarker based and designed to evaluate a drug targeting a specific molecular aberration with a reasonable likelihood of predicting therapeutic response—regardless of the cancer type—among biomarker-selected patients. In general, basket trials aim to support regulatory approval for drugs with tumor-agnostic, biomarker-specific indications vs traditional anti-cancer trials that are used to seek approval for indications based on the anatomic origin of the cancer. 
Basket trials can also be valuable for investigation of outcomes for patients with very rare cancers, for which prospective trials involving specific biomarkers have been logistically difficult due to small numbers of patients. Considerable clinical efficacy (eg, overall response rate) associated with anti-cancer activity reported in basket trials has led to United States (US) Food and Drug Administration (FDA)’s Breakthrough Therapy Designations (BTDs) and approvals of drugs for rare cancers (eg, vemurafenib for Erdheim-Chester disease) as well as incorporation of therapies into national guidelines (eg, trastuzumab emtansine for ERBB2-mutant lung cancer).

How Are Regulatory and HTA Agencies Approaching Decisions on Tumor-Agnostic Therapies?

Since both regulatory and health technology assessment (HTA) agencies play a key role in the successful widespread adoption of and access to a new therapy, but have differing needs in terms of evidence, it is important to consider both perspectives while selecting trial design and endpoints to evaluate tumor-agnostic therapies.


Regulatory Agencies
Regulatory agencies base their authorization decisions on objective scientific criteria as they relate to efficacy and safety; economic considerations are usually not included. Three tumor-agnostic therapies have been submitted for approval to regulatory bodies, 2 of which are now approved by the FDA. On May 23, 2017, the FDA granted accelerated approval to expand the use of pembrolizumab (Keytruda®) for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR) solid tumors based on 5 uncontrolled, open-label, multicohort, multicenter, single-arm trials. The approval of pembrolizumab represents the first time a cancer treatment was approved based on a common biomarker rather than the anatomical location of tumor origin, and the results from a confirmatory, open-label, phase 3 trial (KEYNOTE-177) will form the basis for the full approval in the future. Keytruda’s use in MSI-H or dMMR solid tumors is not yet approved by the European Medicines Agency (EMA). 
On November 26, 2018, larotrectinib (Vitrakvi®) became the second tumor-agnostic therapy to receive accelerated approval by the FDA; a marketing authorization application (MAA) has also been submitted to the EMA. In the US, larotrectinib is indicated for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic tropomyosin receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. The clinical development program evaluated larotrectinib in 17 different tumor types (eg, non-small cell lung cancer, colorectal cancer, melanoma, thyroid carcinoma, various soft tissue sarcomas, gastrointestinal stromal tumor, infantile fibrosarcoma, and salivary gland cancer) in 3 multicenter, open-label, single-arm clinical trials conducted in adult and pediatric populations with NTRK gene fusions. Larotrectinib represents the first time a cancer treatment was developed with a tumor-agnostic indication in mind. Initially, the 2 phase 1 clinical studies included any patient with an advanced solid tumor. However, patients without an NTRK gene fusion did not respond to larotrectinib, while patients with NTRK gene fusions had near-universal response rates. Subsequently, the phase 2 study, which was a basket trial, was limited to patients with NTRK gene fusion tumors. 
Furthermore, from the manufacturer perspective, it is imperative to consider the differing regulatory requirements across global markets and learn from the success (and failure) of recent submissions of tumor-agnostic therapies, including any precedents or new standards set. As previously mentioned, larotrectinib, which had BTD and Priority Review status, filed and gained approval from the FDA and also submitted an MAA to the EMA. Entrectinib has obtained BTD by the FDA and was granted Priority Review, as well as priority medicines (PRIME) designation by the EMA, and also has Sakigake (innovative pharmaceutical product) designation by the Japanese Ministry of Health, Labour, and Welfare. The Japanese government just recently approved entrectinib, and the FDA is expected to have a decision by August 2019. These regulatory approvals established a precedent for tumor type-agnostic therapy for several tumor-agnostic therapies now in various stages of clinical development (Table 1). 


Table 1. Select Tumor-Agnostic Therapies in Development (Adapted From Garber 2018 and Clinicaltrials.gov)

Table 1. Select Tumor-Agnostic Therapies in Development (Adapted From Garber 2018 and Clinicaltrials.gov) 

Key: ALK – anaplastic lymphoma kinase; DNA – deoxyribonuclease acid; MSI-H – microsatellite instability high; NTRK – Neurotrophic tropomyosin receptor tyrosine kinase; PDL1 – programmed death ligand 1; RET – rearranged during transfection proto-oncogene; TRK – tyrosine receptor kinase.

HTA Agencies

With a growing pipeline of tumor-agnostic therapies, it is also important to consider how HTA agencies may evaluate the value of these therapies as they reach the global markets. Across various markets, each HTA places a differing emphasis on the relative consideration of clinical effectiveness, safety, and cost-effectiveness for new therapies. A particular consideration for the evaluation of new tumor-agnostic therapies is that current HTA systems still apply an organ-specific evaluation approach in the field of cancer drugs. The existing process for HTA evaluation will likely need to evolve further; in a tumor-agnostic scenario, new “rare” diseases are essentially created out of many individual conditions by combining biomarker or genomic subsets into 1 larger population (eg, TRK fusion cancer for larotrectinib). HTA bodies are still relatively early on in preparing for the appraisal process, though there are developments in hand (eg, the National Institute for Health and Care Excellence [NICE] in the United Kingdom [UK] is prioritizing the determination and evaluation of genetic testing for tumor-agnostic therapies). However, as no formal evaluations of tumor-agnostic therapies have been carried out, no precedents have been set. As more tumor-agnostic therapies receive regulatory approval, it is possible that disparate HTA requirements across key markets could emerge and add intricacies to an already complex scenario. In this section, we provide some further potential challenges likely to be faced by HTA bodies evaluating tumor-agnostic therapies.

Evaluation of Clinical Trial Data

Regulatory bodies still require that tumor-agnostic trial data be separated by tumor site in the product’s label, to identify tumors where the therapy may work best. This type of reporting can create challenges in the evidence package for HTAs, since there can be many clinical and economic differences for each individual tumor. For example, a 2-month improvement in progression-free survival has a different meaning in pancreatic cancer vs prostate cancer.

Additionally, determining the optimal approach to evaluating the clinical effectiveness and cost-effectiveness for reimbursement purposes of tumor-agnostic therapies is going to be challenging, especially when the conventional model of HTA is based on assessing value for single-indication cancer patient populations. Given how clinical data obtained from basket trials are reported, it may be difficult for HTAs to assess the overall economic value. As a fundamental example, in a basket trial, confidence intervals may differ for key outcomes across tumor sites, which may subsequently make estimates around quality-adjusted life-years (QALYs) and the resulting incremental cost-effectiveness ratio less precise. This issue could be even further compounded by the small trial subpopulations often seen in rare individual tumor sites. Moreover, HTA bodies are additionally challenged to identify the appropriate comparators for use in their evaluations given that, thus far, basket trials are single-arm and further complicated by the wide range of relevant interventions, comparators, and populations for multiple diseases that may be concurrently included in a single assessment of a tumor-agnostic therapy. Additionally, within current HTA frameworks, the basket trial efficacy data by which regulators may be willing to accept for approval or marketing authorization are unlikely to fit the purpose of assessing drugs for site-specific indication reimbursement. 

Diagnostic Testing Is Still in Early Development

Though there are companion diagnostic tests that have been evaluated by several HTAs (eg, the Canadian Agency for Drugs and Technologies in Health [CADTH], the Centers for Medicare & Medicaid Services [CMS], and NICE) alongside therapies indicated for populations with a specific genetic mutation, the genetic testing landscape remains convoluted. The availability of multiple molecular diagnostic tests from hospital and commercial labs makes it difficult for clinicians to identify an appropriate test for their patients in a timely fashion. Moreover, there is uncertainty around the best methodology to test for these genetic and molecular targets. Providers may be left with an abundance of unnecessary information, as some genetic tests may include extra biomarker information, or the chosen test may lack information on a key molecular target, making it difficult to interpret test results. Furthermore, the coverage for multigene panel testing is limited. Payers are more likely to cover a test if it is clearly linked to a drug response or is a regulatory agency-approved companion diagnostic. In a multinational survey, 895 clinicians from Argentina, Brazil, China, France, Germany, Italy, Japan, Russia, Saudi Arabia, Spain, Turkey, and the UK were queried about their use of genomic testing, and results identified cost and lack of insurance reimbursement as the primary reasons for avoiding genomic testing. Uncertainties around appropriate use of diagnostics for tumor-agnostic therapies may make it difficult for HTAs to effectively evaluate these treatments.

Key Considerations for Manufacturers Around Strategies to Overcome HTA Challenges With Tumor-Agnostic Therapies

As evidenced above, these novel therapies will require a departure from the traditional mindset and a shift in perspective when it comes to HTA agency consideration. Below, we outline further considerations for manufacturers developing tumor-agnostic therapies.

Obtain Early Scientific Advice

Given the complexity of the trial design used for tumor-agnostic therapies, early scientific advice from regulatory agencies (eg, FDA), HTAs (eg, NICE in the UK or the Institute for Quality and Efficiency in Health Care [IQWiG] in Germany), and payers will facilitate early alignment and appropriate evidence generation to assist in gaining approval for relevant markets. Specifically, manufacturers would be well served to collaborate with both regulatory and HTA bodies on trial designs that will ultimately meet evidence generation needs both within and supplemental to the clinical development program. Earlier engagement than what is considered typical may prove beneficial as innovative therapies differ substantially from traditional medicines (eg, a novel mechanism of action, indicated for rare conditions, etc) and will require additional dialog to reach a place of consensus.

Improve Genetic Testing

Given that tumor-agnostic therapies are based on tumor biomarkers, genetic testing plays a key role. However, there is a lack of direction around coverage of genetic testing. For example, in the US, CMS recently made a National Coverage Decision for a next-generation sequencing test, which may minimize prior authorization requirements for Medicare beneficiaries. However, few other HTA agencies have made decisions in this space. Manufacturers are encouraged to meet with regulatory agencies to facilitate companion diagnostic test development to accompany tumor-agnostic therapies. 

Establish Innovative Payment Models

As is the case with many of the new therapies coming to market, economic impact is a significant consideration. Tumor-agnostic therapies can show a significant clinical benefit across numerous unique tumor types but may be accompanied by a hefty price tag; the expected price considerations with these therapies will be an issue for HTA bodies. Thus, it may be helpful for manufacturers to initiate conversations about the economic challenges with new therapies and work with agencies to come up with solutions around coverage. For example, through the Vitrakvi® Commitment Program™ in the US, patients who do not show clinical benefit within the first 90 days after initiating treatment will be refunded the cost of larotrectinib. Additionally, NICE has an updated appraisal process where therapies under review are available to patients through the Cancer Drugs Fund while additional evidence to address clinical uncertainty is generated. In consideration of the need for additional data and innovative payment models for tumor-agnostic therapies, real-world evidence (eg, post-approval prospective studies) might be used to provide additional support for reimbursement. A high level of collaboration between payers and manufacturers will likely be required to develop innovative, market-specific payment models that incorporate cost-effectiveness and successfully ensure all patients can obtain these life-saving therapies.

Conduct Frequent Landscape Assessments

Since this is a new, complex landscape and things will continue to rapidly evolve, manufacturers with an interest in tumor-agnostic therapies should monitor new drug approvals and HTA evaluations in this field in key markets in order to learn from early entrants about evidence generation and innovative pricing agreements. It would be prudent to consider tracking approvals, reimbursement, and market share of products approved across a broad range of tumor types and evaluate the need for additional services like personalized genetic marker maps and decision support tools. It is likely that a multistakeholder approach with global representation will be needed to determine meaningful HTA evaluation frameworks for tumor-agnostic therapies so that appropriate value assessments and reimbursements can be determined. 




The article should be referenced as follows: 

Kang I, Hennenfent K, Campbell C, Tolley K, Shields K. Tumor-Agnostic Therapy Assessment: Following Regulatory Approval, What Challenges Exist for HTAs? HTA Quarterly. Summer 2019. August 27, 2019.



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