A New Paradigm for Cancer Drug Development

Reading time: 4 minutes

Brittany Avin McKelvey

We are in a hayday for cancer therapies, as research has surpassed traditional chemotherapeutics. New drugs, new treatment regimens, and even new drug classes are approved each day, broadening the horizons of oncology. The newest types of drugs to recently gain FDA approval are tissue agnostic drugs. (See here for a refresher on how a drug gets approved by the FDA).

Tissue agnostic drugs are developed to treat a tumor, regardless of tumor location, if the tumor tests positive for a specific genetic alteration that the drug is designed to molecularly target. This type of treatment varies vastly from other classes of treatments. Some cancer treatments are designed for a specific cancer type that harbor a specific alteration or biomarker. For example, anti-estrogen therapy for estrogen receptor-positive breast cancers. The treatment is specifically for breast cancer, and further, is for a subset of breast cancers that have a certain molecular signature. But now, with tissue agnostic drug development, drugs are approved not for a single cancer type, but for a specific biomarker in multiple cancer types.

The first tissue agnostic drug approved was the immunotherapy drug pembrolizumab (Keytruda), approved in May 2017.  Keytruda and other checkpoint inhibitors like it are tissue agnostic because they are approved for many different cancer types; however, they do not target a specific molecular biomarker. Alternatively, two anti-cancer drugs have been approved by the FDA that are tissue agnostic and target a specific molecular driver. Both drugs target  NTRK gene fusion, which is known to drive cancer growth in up to 1% of all solid tumors. The drugs were approved based upon data collected by a basket trial. A basket trial is a type of clinical trial in which patients are enrolled regardless of their cancer type, but all patients have the same genomic alteration. These genomic alterations, like the NTRK gene fusion, are usually rare events in rare cancer types or advanced cancers that have no standard of care, creating the need for more inventive clinical trials.

The first drug approved was larotrectinib (Vitrakvi), approved by the FDA in November 2018. The drug was given accelerated approval for both adults and children with solid tumors that tested positive for the NTRK gene fusion. Approval of larotrectinib was based on a basket trial of 55 patients. Three-quarters of patients in the trial showed either full or partial shrinkage of their tumors. The basket trial encompassed 17 different types of cancers, including melanoma, thyroid cancer, colon cancer, lung cancer, and cholangiocarcinomas.

Recently, the FDA approved a second tissue agnostic molecularly targeted drug. In August 2019, entrectinib (Rozlytrek) was given accelerated approval. Like larotrectinib, entrectinib is also approved for adults and children 12 years of age and older with solid tumors testing positive for the NTRK gene fusion. The initial pooled phase I and phase II clinical trials were compiled from 54 patients with a variety of tumor types, including breast cancer, colorectal cancer, mammary analogue secretory carcinoma, non-small cell lung cancer, pancreatic cancer, sarcomas, and thyroid cancer. Over half of the patients treated exhibited tumors that at least partially shrunk after treatment.

Further, at the end of January, it was announced that the FDA granted priority review for loxo-292 (selpercatinib). This tissue agnostic drug targets RET, which has been linked to RET-mutant medullary thyroid cancer, RET-fusion positive thyroid cancer, and RET fusion positive non-small cell lung cancer. Further study is ongoing for several other tissue agnostic drug developments.

The future of tissue agnostic drug development seems bright, with a few caveats. A major benefit of tissue agnostic drug development is that it provides patients with novel potential therapies when previous therapies were not successful. This broadens the available existing therapies, especially for cancers that are relatively rare. For example, entrectinib is approved for treatment in patients in which there is no standard therapy, or the patient’s tumor has progressed after treatment and surgery is not an option.

However, one potential downside is the dependency on a companion diagnostic test. Without knowing if the patient has the genetic alteration, there is no way to know if the patient could benefit from these tissue agnostic drugs. In the cases for larotrectinib and entrectinib, at the time of FDA approval there was no FDA approved test for the detection of the NTRK fusion events. This may hinder the effective use of the drugs by not effectively identifying the patient population, and is dependent on the patient’s access to molecular and genetic testing. Tissue agnostic drug development may also not work for all drivers of cancers. For example, there were greatly varied responses to BRAF inhibitors in patients with BRAF mutant melanoma and BRAF mutant colorectal cancer. Therefore, just because tumors share a common driver, they may not respond to a tissue agnostic drug the same. Lastly, as these drugs are targeting specific molecules that are found in only a subset of all cancer patients, tissue agnostic drugs have the potential to be expensive as they serve rare cancers.

The FDA’s accelerated approval for tissue agnostic drugs signals support of this class of cancer treatment, and time will tell if tissue agnostic drug development becomes a predominant path for cancer treatment. 

Work Discussed: 

Blumenthal, G. and Pazdur, R. Approvals in 2018: a histology-agnostic new molecular entity, novel end points and real-time review. Nat Rev Clin Oncol 16, 139-141 (2019) doi: 10.1038/s41571-019-0170-z

Edited by Sara Musetti

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