Developing Companion Diagnostics for Innovative Therapies: Strategic Challenges and Opportunities for Genetic Testing Companies

The application of genetic testing technology in companion diagnostics is becoming increasingly clear. The core business model has shifted from a primary focus on comprehensive, large-panel testing to a dual approach that combines both large and small panels. In-depth large-panel testing remains recommended for complex cases (such as rare cancers or advanced, metastatic tumors); whereas for relatively typical patients (such as those with newly diagnosed non-small cell lung cancer), assessment usually only needs to target a few key genes (as recommended by NCCN guidelines). In such scenarios, relevant testing can be performed using approved companion diagnostic products.

The key change in the business model lies in the growing number of approved companion diagnostic kits. In particular, the wave of tumor immunotherapy sparked by PD-1 monoclonal antibodies has led pharmaceutical companies to gradually recognize the importance of companion diagnostics tailored to their drugs. As a drug product with a relatively low response rate on its own, PD-1 monoclonal antibodies use PD-L1 companion diagnostics to screen patients, thereby focusing more precisely on the target patient population and effectively improving the response rate of PD-1 monoclonal antibodies in certain indications.

Therefore, in the current era, the development of companion diagnostics for targeted therapies has become a standard component of pharmaceutical R&D. Both well-funded pharmaceutical giants and biotech companies with maturing product pipelines are collaborating with genetic testing firms to develop drug-specific companion diagnostic products.

However, this has also brought new challenges to the genetic testing industry. Pharmaceutical services are more intricate than the research and clinical services that genetic testing companies excel in, and they have higher compliance requirements.How can we “tailor” solutions for innovative drugs to develop companion diagnostic products with genuine clinical value, and even provide feedback to guide drug development?

This article takes the “Human PDGFRA Gene D842V Mutation Detection Kit (PCR-Fluorescent Probe Method),” which recently entered priority review, as an example to explore the key considerations in developing a companion diagnostic kit specifically for an innovative drug.

Drug targets are highly diverse, and their corresponding companion diagnostic kits are equally complex. Each drug with a distinct target must be used in conjunction with its specific companion diagnostic kit to truly achieve precision therapy. For certain well-developed biomarkers, such as EGFR, ALK, and PD-L1, multiple companion diagnostic products have already been launched on the market, which is gradually shifting from a blue ocean to a red ocean state.Meanwhile, some more innovative targets remain entirely in a blue-ocean space, representing the focal point of collaboration between pharmaceutical companies and companion diagnostic firms.

The collaboration between Genetron Health and CStone Pharmaceuticals centers on the innovative targeted therapy Taygita® (generic name: avapritinib). Avapritinib was approved by China’s National Medical Products Administration (NMPA) in March 2021 for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations, including the PDGFRA D842V mutation. It had previously received approval from the U.S. Food and Drug Administration (FDA) in January 2020, becoming the world’s first precision targeted therapy approved for GIST patients with PDGFRA exon 18 mutations.

At first glance, “GIST patients with PDGFRA D842V mutation” may seem like too small an indication, but upon closer examination, it becomes clear that this is actually a very important population of patients with refractory disease.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, are commonly used targeted therapies for GIST. However, clinical practice has revealed that a subset of GIST patients frequently exhibits primary resistance to TKIs. A significant proportion of these patients harbor the PDGFRA D842V mutation. Historically, there has been a lack of effective therapeutic options for this patient population. Avapritinib is currently the only approved drug that precisely targets the PDGFRA D842V mutation in GIST.

This is precisely where the clinical significance of avapritinib lies. Although the currently approved indications for avapritinib appear limited, they fill a critical gap left by conventional therapeutic approaches.

However, the approval of avapritinib has not fully resolved the issue.. New problems have emerged once again,How to Precisely Identify Patients Harboring the PDGFRA D842V Mutation Prior to Treatment?If a “trial-and-error” approach is adopted—initiating treatment with tyrosine kinase inhibitors and reserving avapritinib for patients who develop resistance—the treatment duration for resistant patients will be significantly prolonged, inevitably compromising the quality of care they receive. The integration of companion diagnostics can effectively bridge the gap between pharmaceuticals and their appropriate patient populations, thereby avoiding delays in treatment or inappropriate therapeutic interventions.

At this point, the critical importance of a tailored companion diagnostic for avapritinib becomes evident. The rationale behind developing a companion diagnostic product for avapritinib is also one of the key reasons why numerous innovative drug products today are opting to develop companion diagnostics.Innovative therapies currently target indications primarily in patient populations for whom standard of care fails to provide adequate solutions. The critical role of companion diagnostics is to precisely identify this subset of patients, enabling earlier intervention with innovative therapies rather than waiting for the “trial-and-error” approach of standard treatments, which may delay optimal therapeutic timing.

With the development of the companion diagnostics industry, national regulatory guidelines are gradually becoming more defined. Last month, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) released the Technical Guidelines for the Application of Biomarkers in the Clinical Development of Antineoplastic Drugs (Draft for Comments), clearly highlighting the increasingly prominent value of biomarkers in antineoplastic drug development. Biomarkers have progressively become a critical tool in this process. In the research and development of new drugs for precision medicine, where biomarkers are used to select patients, pharmaceutical companies must communicate with the drug approval authorities to determine whether companion diagnostics are required before initiating pivotal clinical trials. When formulating drug development strategies, companies should also consider the development strategy for companion diagnostics.However, as the number of products currently approved is still limited, many specific details in the research and development process require case-by-case discussion. Therefore, continuous communication with regulatory authorities is crucial throughout the entire product development lifecycle.

While communication with regulatory authorities is one aspect, collaboration with the clinical side is equally important in the development of companion diagnostic products.An industry practitioner told VCBeat that the most complex aspect of co-developing companion diagnostics lies in synchronizing and aligning with drug clinical trials. This requires coordination among multiple agencies, including the Human Genetic Resources Administration of China, the Center for Drug Evaluation and Inspection, the Center for Drug Evaluation, and the Center for Medical Device Evaluation, making the barrier to entry notably high.

Currently in China, an increasing number of diagnostic companies are attempting to establish collaborations with pharmaceutical enterprises. Their platform operational capabilities and accumulated testing experience are crucial for managing risks in new drug clinical trials. However, compared to the scientific research services and clinical services that these companies excel in, pharmaceutical enterprise services are more intricate and subject to stricter compliance requirements. Beyond technical prowess, this also poses new challenges to the end-to-end management capabilities of testing companies.

Taking the collaboration between Genor Biopharma and CStone Pharmaceuticals as a case study.During communications with regulatory authorities, due to the lack of relevant regulations governing clinical trials for companion diagnostic reagents at the project initiation stage, the Genetron Health team conducted multiple pre-clinical consultations with regulators to facilitate smooth project progress, jointly developing a feasible clinical trial protocol.

Regarding integration with clinical practice, due to the relatively low incidence of gastrointestinal stromal tumors (GIST) and the rarity of PDGFRA exon 18 mutations—particularly the D842V mutation, which results in prolonged sample collection periods—the clinical studies for this original companion diagnostic product (i.e., whose clinical validity studies were linked to clinical efficacy data from new drug development) were conducted simultaneously at three hospitals: Beijing Cancer Hospital, Harbin Medical University Cancer Hospital, and Shanghai Tenth People’s Hospital. By ensuring that the data submitted to the Center for Medical Device Technical Evaluation was fully consistent with the efficacy data provided by the pharmaceutical manufacturer to the Center for Drug Evaluation, the clinical validation period was shortened, thereby accelerating the product’s market launch process.

It is precisely by maintaining continuous information alignment with regulatory authorities and clinical practices that Genetron Health’s companion diagnostic product has been able to advance its compliance process at the fastest pace.In June 2021, just nine months after the collaboration was established, the marketing application for the “Human PDGFRA Gene D842V Mutation Detection Kit” was accepted by the National Medical Products Administration (NMPA), and it subsequently received priority review status in July.

During the drug development cycle, when is it appropriate to begin developing companion diagnostics? GenePharma and CStone Pharmaceuticals offer the same answer: in parallel with the submission of the drug for marketing approval.In September 2020, a collaboration was reached with CStone Pharmaceuticals for the development and commercialization of companion diagnostic tests for avapritinib in the Greater China region. Just over a month prior to the announcement of this partnership, avapritinib had been included in the priority review and approval process.

Collaborations between pharmaceutical companies and companion diagnostic developers are progressively shifting earlier along the drug development timeline. Many drugs in clinical stages have initiated the development of accompanying companion diagnostics, which are being integrated into clinical trials concurrently.

In fact, integrating companion diagnostics with new drug development not only optimizes the efficiency of companion diagnostic reagent development but also reduces the risks associated with new drug clinical trials to a certain extent. In clinical trials for new drugs, companion diagnostics enable precise identification of target populations and indications by stratifying or enriching patient cohorts, thereby helping achieve more favorable clinical outcomes. This approach shortens the new drug development cycle, controls the scale of clinical trials, and improves the success rate of clinical studies.

In certain specific scenarios, the inclusion or exclusion of companion diagnostics can even have a critical impact on the outcomes of new drug clinical trials. For instance, when the efficacy difference between the investigational drug and the comparator is not substantial, the support of companion diagnostics becomes crucial for enhancing clinical success rates. Furthermore, when the proportion of patients who benefit from the treatment is low within the general population—such as in studies targeting fusion variants associated with rare targets—clinical trials are likely to fail unless enrolled patients are precisely screened.

However, the early integration of companion diagnostics also presents greater challenges. In the intricate landscape of new drug development, simultaneously optimizing the development of companion diagnostic products and the efficiency of clinical trials for new drugs is no easy task. There are three key points in this regard.

First, select companion diagnostic products with sufficiently high sensitivity and specificity.For the development of companion diagnostic kits, performance validation is a core component, requiring comprehensive consideration of four aspects: accuracy, limit of detection (LOD), precision, and specificity. When the proportion of benefiting patients in the population is low, the specificity of the companion diagnostic test has a significant impact on the objective response rate (ORR) in clinical trials. For example, assume that biomarker-positive patients account for 1% of the patient population, the sensitivity of the companion diagnostic test is 100%, the ORR for positive patients is 100%, and the ORR for negative patients is 0%. In this scenario, if the specificity of the companion diagnostic test is 99%, approximately one false positive occurs for every two enrolled patients, reducing the observed clinical efficacy of the drug to 1/2. If the specificity further decreases to 98%, approximately two false positives occur for every three enrolled patients, reducing the observed clinical efficacy to 1/3.

Secondly, diagnostic companies developing companion diagnostics need to possess considerable technical reliability and stability.Over the past decade, companion diagnostic technologies have undergone significant differentiation. For instance, in biomarker selection, there has been a shift from single-target to multi-target approaches; sample types have expanded from predominantly tissue-based samples to diverse options including liquid biopsy specimens; and detection technologies have continuously evolved, transitioning from earlier methods primarily focused on single targets—such as qPCR, IHC, and FISH—to various next-generation sequencing (NGS) panels characterized by biomarker enrichment.In other words, the R&D team for companion diagnostic products must possess robust technical capabilities and extensive testing experience to deliver genuine value in optimizing clinical trials for new drugs.

Third, genetic testing companies need to have extensive registration experience and a capable registration team,Collaborate with relevant teams at innovative pharmaceutical companies to formulate and execute appropriate regulatory strategies, while maintaining close communication with regulatory authorities. The integration of companion diagnostic development into new drug clinical trials requires concerted efforts and joint promotion by both pharmaceutical companies and testing companies. Each party’s team is responsible for the regulatory approval of its respective product, ensuring synchronized and expedited market launch processes. In particular, as many new drugs now adopt a dual filing strategy in both China and the United States, it is even more critical for genetic testing companies to possess the capability for dual regulatory submissions in both countries to facilitate joint registration.

Overall, the companion diagnostics industry for precision drug matching is just emerging in China. This wave represents a cross-sectoral product of the flourishing domestic innovative drug industry and the gene testing sector, aligning with the broader trend toward precision medicine. The increasing number of outstanding cases indicates that this continuously focused interdisciplinary field is gradually establishing a development model suited to its industry characteristics. During this period, the guiding role of successful cases is undeniable. We also look forward to seeing more collaborations like that between Genetron Health and CStone Pharmaceuticals, ensuring that all targeted therapies are truly evidence-based.