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BioCentury – Patient access pitfalls, regulatory inconsistencies hamper tissue agnostic drugs

BioCentury – Patient access pitfalls, regulatory inconsistencies hamper tissue agnostic drugs

At a Friday meeting FDA co-hosted with ASCO and Friends of Cancer Research, patient advocates expressed concern over their ability to access newly approved tissue-agnostic medicines, as well as clinical trials assessing up-and-coming treatments based on molecular markers rather than tissue of origin. Stakeholders also raised concerns about the lack of access to tumor-profiling technologies and inconsistent approaches among regulators to tissue-agnostic drug development.


At the workshop on the development of therapies for tissue agnostic, biomarker-based indications, patients talked about the difficulty of finding studies enrolling patients based on mutations and/or tumor molecular markers rather than tumor type.


Ann Ramer, a patient advocate with family members who harbor p53 mutations, cited challenges in searching by tumor type or for rare tumors that may be studied as part of a tissue-agnostic trial. With children who have cancer, Ramer said it can be daunting to find new treatment options, including investigational agents.


Other advocates also said the way patient groups are organized can present another hurdle to connecting patients with clinical trials because most groups are organized around a specific tissue type.


FDA has approved two drugs for tissue-agnostic indications: anti-PD-1 mAb Keytruda pembrolizumab from Merck & Co. Inc. (NYSE:MRK) to treat MSI-high cancers, and Vitrakvi larotrectinib from the Loxo Oncology unit of Eli Lilly and Co. (NYSE:LLY) to treat cancers with NTRK gene fusions. Neither drug was approved with a companion diagnostic.


Loxo CEO Joshua Bilenker lamented the fragmented state of tumor profiling, which the biotech used via various sources to identify NTRK mutations in the clinical trials.


“Only 15% of patients are getting access to tumor profiling but it needs to be standard of care,” he said, adding that “Medicare has led the way, but private payers have not followed suit.”


Last year, CMS issued a National Coverage Determination that backed coverage of multiple next-generation sequencing-based tumor-profiling technologies, including the Foundation One test from the Foundation Medicine Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY).


Several attendees, including oncologists from academic medical centers and industry representatives, said most community oncologists don’t use tumor profiling until patients have progressed on multiple therapies, if at all. Many said the results from tumor-profiling tests are difficult to interpret with regard to the recommended targeted treatments or potential clinical trials for patients.


Another challenge raised by Merck’s Eric Rubin was inconsistency among international regulators. Keytruda gained a tissue-agnostic approval in Japan and is approved for the MSI-high indication in 22 countries. “One of the areas it hasn’t occurred yet is Europe,” said Rubin, who is medical oncologist and VP of global clinical oncology.


Pierre Demolis, chairman of the oncology working party of EMA’s CHMP, highlighted some of the issues that have come up as EMA continues to review two undisclosed applications seeking tissue-agnostic indications. For example, he pointed to instances where patients harbor a biomarker that could be associated with multiple different tumor types but do not respond to the targeted treatment used in a tissue-agnostic approach. Demolis also noted the potential for marker heterogeneity in the tumor or metastases.


“You have a marker but the marker isn’t explaining everything,” Demolis said, “you could have alternative drivers.”


EMA also doesn’t often approve agents based on single-arm studies, which Merck and Loxo both used to support approval of their agents.


Demolis did say that EMA’s forthcoming fifth update to its oncology product guidelines will address some issues related to tissue-agnostic drug development. He did not give a time frame for its release.…