Beyond Tumor Type: New Milestones on a Long Road

Anita T. Shaffer @Shaffer1 | July 16, 2017
Luis A. Diaz, MD

Luis A. Diaz, MD

After years of efforts to steer clinical trials toward molecularly defined therapeutic targets, oncology researchers recently notched 2 key successes in changing the paradigm of how patients with advanced cancers are diagnosed and treated:

On May 23, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, marking the first time a drug gained an indication based on its efficacy against a molecular target rather than on the primary tumor site.1

On June 3, investigators reported that 78% of patients with TRK fusion–positive cancers responded to treatment with larotrectinib (LOXO-101), potentially making the drug the first targeted therapy developed in a “tumor agnostic” manner.2

Oncology experts have described these developments as important milestones on the road to personalized medicine. At the same time, the complexities involved with translating such molecular breakthroughs into broader research protocols and clinical practice have quickly become a matter of discussion.

Although most somatic genetic aberrations can be found in multiple tumor types, preclinical models are not adequately constructed to reflect sensitivity to potential new agents in tumor microenvironments across histologies, Flaherty and colleagues cautioned in an article in the 2017 ASCO Educational Book.3

Moreover, laboratory experience has shown that primary tumors may respond differently to a targeted therapy even if they share a molecular defect, the researchers noted. “Every drug presents unique circumstances in regard to the population of patients who might benefit from it,” they wrote. “Furthermore, development agnostic of tumor type could actually slow drug development if there are differential effects across tumor types by diverting resources from enrolling patients in a predominant population or in the tumor type most like to respond.”

A notable example of disparate results from targeting the same mutation in multiple tumor types is the BRAF mutation. “The BRAF inhibitor works in 100% of the histiocytosis patients who have BRAF mutations, but it only works in about 60% of the melanoma patients, and about 40% of lung cancer patients, and it never works alone in colorectal cancers,” said David B. Solit, MD, in an in interview with OncologyLive®.

“So it’s the same drug and the same exact BRAF V600E mutation, but that drug works differentially depending upon what cancer type you have because each of those cancers has co-mutation patterns and other lineage-specific factors that are true because of the development of those cell contexts,” said Solit, who is the Geoffrey Beene Chair and director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering (MSK) Cancer Center in New York City.

Nevertheless, Solit said he believes the evidence for the utility of targeted therapies across tumor types has made broad genomic sequencing of patients’ tumors a necessity. “The pembrolizumab data in particular with the MSI status makes genomic analysis of every patient’s tumor now important to do just from a standard-of-care perspective,” he said. “If you don’t do it, you’re going to miss something that that patient could have responded to.”

The major barrier to conducting such testing for every patient is that payers are balking at covering the cost of next-generation sequencing (NGS), as opposed to single-gene testing, without an approved targeted agent linked to the assays, according to Solit and other experts.

Gordon B. Mills, MD, PhD, a pioneer in the field of molecularly targeted anticancer therapies, said a “culture shift” is necessary to build support for covering such testing.

“I think we’ve known for quite a while that many drugs work beyond the original tumor that they were identified in,” said Mills, who is chair of the Department of Systems Biology and head of the Kleberg Center for Molecular Markers at The University of Texas MD Anderson Cancer Center in Houston, in an interview. “The question is whether we’re going to able to leverage the MSI approval and the [larotrectinib data], and some of the other ones that will come down the pipeline soon across diseases, to justify broad testing of all patients, or at least all patients likely to benefit.”

Mills said sequencing can cost $2000 to $3000 per patient at MD Anderson, but the reimbursement from CMS can be as low as $50. “How does one balance the need to do the testing to acquire the information to say that this really does benefit patients and should be paid for versus the pushback from industry and CMS saying until you know exactly how to use it we find it is far too expensive and not sustainable?”


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Online CME Activities
TitleExpiration DateCME Credits
Cancer Summaries and Commentaries™: Update from Chicago: Advances in the Treatment and Management of CINVJul 26, 20171.5
Cancer Summaries and Commentaries™: Update from Chicago: Advances in the Treatment of Genitourinary CancersJul 28, 20171.5
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