Merck’s Keytruda Receives FDA Priority Review for Second Tumor-Agnostic Indication Based on High Tumor Mutational Burden

On the 8th, MSD announced that the U.S. FDA had accepted its second “tumor-agnostic” supplemental Biologics License Application (sBLA) for the blockbuster PD-1 inhibitor Keytruda. This application seeks accelerated approval of Keytruda for the treatment of patients with previously treated, unresectable or metastatic solid tumors exhibiting high tumor mutational burden (TMB-H). The FDA has also granted Priority Review designation to this application, with a decision expected by June 18 of this year.

Previously, the FDA had already approved Keytruda as a “tumor-agnostic” therapy for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors. However, MSI-H represents only a small subset of patients with high tumor mutational burden (TMB). If this application is approved, it would not only significantly expand the patient population eligible for Keytruda monotherapy but also mark the FDA’s recognition of TMB as a molecular biomarker for patient selection.

What Is Tumor Mutational Burden? How Does It Impact Patient Selection for Cancer Immunotherapy? In this article, the WuXi AppTec Content Team will help readers answer these questions.

Identifying Patients Suitable for Immune Checkpoint Inhibitor Therapy

The emergence of immune checkpoint inhibitors, represented by PD-1/PD-L1 inhibitors, marks a major breakthrough in the history of cancer treatment. These cancer immunotherapies enhance the ability of T lymphocytes to effectively kill tumor cells by blocking the inhibitory signals acting on T lymphocytes within the patient’s body. Since the approval of the first checkpoint inhibitor, this class of drugs has demonstrated significant efficacy across multiple cancer types.

However, not all cancer patients respond to checkpoint inhibitor therapy. Without patient screening, only about 20% of patients respond to checkpoint inhibitor monotherapy. The mechanism of checkpoint inhibitors is often described as “releasing the brakes on the immune system”; however, for the immune system to attack tumors, it must first mount an immune response against the tumor. Some tumors have a limited capacity to elicit an immune response (i.e., low immunogenicity) and are referred to as “cold” tumors. Checkpoint inhibitors demonstrate limited efficacy against these “cold” tumors.

Therefore, in addition to expanding the indications for checkpoint inhibitors, it is also crucial to identify more effectively those patients who are likely to respond to checkpoint inhibitor therapy. After all, in the race against cancer progression, the use of ineffective therapies not only imposes an unnecessary burden on patients but also delays their access to effective treatments. Currently, the primary method for screening patients who may respond to PD-1/PD-L1 inhibitor therapy is to assess the level of PD-L1 expression on tumor cells. However, this assay does not measure tumor immunogenicity; rather, it determines whether the tumor utilizes PD-L1 to evade immune system attack. Continuing with the metaphor of "releasing the brakes on the immune system," testing PD-L1 levels essentially assesses whether the tumor is employing PD-L1 as a "brake."

Researchers still need an assay to determine tumor immunogenicity, and tumor mutational burden is one of the key factors determining immunogenicity.

The Relationship Between Tumor Mutational Burden and Immunogenicity

It is well established that cancer arises from the continuous accumulation of genetic mutations in the genome of cancer cells, ultimately leading to malignant transformation. These genetic mutations not only impair the mechanisms regulating cell division, thereby triggering uncontrolled cellular proliferation, but also result in the production of proteins that differ from those in healthy cells. Such proteins are recognized by the human immune system, eliciting an immune response. Antigens that emerge on tumor cells due to genetic mutations and differ from those on healthy cells are termed “neoantigens.” They are among the key determinants of tumor immunogenicity. Furthermore, a higher burden of genetic mutations in the protein-coding regions (exons) of tumor cells increases the likelihood of neoantigen generation, potentially enhancing the tumor’s immunogenicity.

▲Relationship between Tumor Mutational Burden and Immunogenicity (Image source: Reference [5])

In 2017, Keytruda received its first FDA approval for the treatment of patients with solid tumors exhibiting high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). MSI results from mismatch repair deficiency, leading to a high burden of genetic mutations in specific regions of DNA. Patients with MSI-H show a significantly higher response rate to PD-1/PD-L1 inhibitors, reaching approximately 50%. However, aside from colorectal cancer and endometrial cancer, the prevalence of MSI-H in other cancer types is low; therefore, patient screening based on MSI-H status impacts a relatively small number of individuals.

Previous studies have shown that the proportion of patients with high tumor mutational burden (TMB-H) who also exhibit high microsatellite instability (MSI-H) ranges from 15% to 40% (the definition of TMB-H significantly influences this value). Therefore, if TMB-H can be used as a molecular biomarker for screening cancer patients, checkpoint inhibitors may benefit a larger patient population.

Predictive Value of Tumor Mutational Burden for the Efficacy of Immune Checkpoint Inhibitors

The impact of tumor mutational burden (TMB) status on the efficacy of checkpoint inhibitor therapy in cancer patients has been evaluated in multiple studies. Overall, patients with high TMB (TMB-H) exhibit improved response rates to checkpoint inhibitors and prolonged progression-free survival (PFS) (see table below). However, some clinical trials have found that the influence of TMB status on the efficacy of checkpoint inhibitor therapy is not significant, with suboptimal outcomes observed for the overall survival (OS) endpoint.

Taking the KEYNOTE-158 clinical trial, on which MSD based its submission, as an example, patients with various types of previously treated metastatic solid tumors received Keytruda monotherapy in this trial. The overall response rate (ORR) in patients with high tumor mutational burden (TMB-H) was 30.3%, including a 4% complete response rate and a 26.3% partial response rate. In contrast, the ORR in non-TMB-H patients was 6.7%. At one year, the progression-free survival rate was 26.4% in TMB-H patients, compared to 14.1% in non-TMB-H patients.

In terms of overall survival (OS), the median OS for patients with high tumor mutational burden (TMB-H) was shorter (11.7 months) than that for non-TMB-H patients (13.0 months). Notably, tumors in TMB-H patients, harboring a higher number of genetic mutations, may progress more rapidly or exhibit greater aggressiveness, thereby leading to a poorer prognosis compared to non-TMB-H patients.

Establishing Standards for TMB Testing

Tumor Mutational Burden (TMB) testing is typically performed using next-generation sequencing (NGS) technology. Initially, TMB assessment relied on whole-exome sequencing (WES) of cancer cells. Although this approach provides a comprehensive measurement of the mutational load in cancer cells, its relatively high cost has somewhat limited its widespread adoption. An alternative method involves sequencing a representative panel of specific genes within the cancer cell genome, using their mutational burden as a surrogate marker for the whole exome. For example, the application submitted by Merck Sharp & Dohme (MSD) utilizes the FoundationOne CDx molecular test developed by Foundation Medicine. This test performs ultra-deep NGS to detect variants in only 324 genes. However, the gene panels selected for molecular tests vary among different manufacturers, and determining which gene combination best reflects the TMB of the cancer cell genome remains an unresolved issue for researchers.

Image source: Foundation Medicine official website

Another critical factor is the determination of the threshold for tumor mutational burden-high (TMB-H). In this application, MSD defines TMB-H as a tumor mutational burden exceeding 10 mutations per megabase (>10/megabase). However, other companies have adopted inconsistent definitions of TMB-H in their clinical trials (see table above), which may hinder the broader clinical adoption of TMB as a molecular biomarker.

From this perspective, MSD’s application is expected to facilitate the establishment of TMB testing methodologies and TMB-H criteria. If the FDA endorses the TMB testing methods and TMB-H standards outlined in MSD’s application, it will set a significant benchmark for other pharmaceutical companies developing TMB-based therapies.

In the era of personalized therapy, physicians aim to identify the most suitable treatments for patients through more in-depth analysis. The priority review granted for Keytruda’s “tumor-agnostic” indication represents a significant step forward in establishing tumor mutational burden (TMB) as a biomarker for personalized therapy. We look forward to further refinement and standardization of TMB testing by the industry, enabling more patients to find the most appropriate treatments through pre-screening.

References:

[1] Merck Receives Priority Review from FDA for Second Application for KEYTRUDA® (pembrolizumab) Based on Biomarker, Regardless of Tumor Type. Retrieved April 7, 2020, from https://www.businesswire.com/news/home/20200407005141/en

[2] FDA Grants Pembrolizumab Priority Review for TMB-High Tumors. Retrieved April 7, 2020, from https://www.targetedonc.com/news/fda-grants-pembrolizumab-priority-review-for-tmbhigh-tumors

[3] FoundationOne®CDx Technical Information. Retrieved April 7, 2020, from https://assets.ctfassets.net/vhribv12lmne/6Rt6csmCPuaguuqmgi2iY8/629ba4e5c7d9a3bd1f1f666085e1e4b1/FoundationOne_CDx_Label_Technical_Info.pdf

[4] Chan et al., (2019). Development of Tumor Mutation Burden as an Immunotherapy Biomarker: Utility for the Oncology Clinic. Annals of Oncology, DOI: 10.1093/annonc/mdy495

[5] Galuppini et al., (2019). Tumor mutation burden: from comprehensive mutational screening to the clinic. Cancer Cell International, https://doi.org/10.1186/s12935-019-0929-4

[6] FDA's new Keytruda review is step for genetic medicine, immunotherapy. Retrieved April 7, 2020, from https://www.biopharmadive.com/news/fda-keytruda-tissue-agnostic-genetic-medicine/575623/

Original Title: Another Breakthrough in Personalized Therapy: In-Depth Analysis of FDA’s Priority Review for Keytruda’s “Tissue-Agnostic” Application

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