Genetic Testing Considerations and Questions Persist Surrounding Tumor-Agnostic Approvals

Pedro Barata, MD

As more agents receive tumor- and tissue-agnostic approvals, several crucial points have been raised surrounding nuances with genetic testing, according to Pedro Barata, MD.

“There are considerations and changes that need to occur within the different practices to accommodate [the changing field]; we want universal genetic testing provided to patients because for most tumors it’s becoming the exception of the rule to see guidelines that are not including biomarker-based approaches,” Barata said in an interview with OncLive®. “That speaks to the significantly increasing importance that these therapies [are] playing in the management of patients with advanced solid tumors.”

Among the 8 drugs that hold tumor-agnostic FDA approvals as of January 2025,¹ the April 2024 indication granted to fam-trastuzumab deruxtecan-nxki (Enhertu) represented a critical approval for adults with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.² Repotrectinib (Augtyro) also joined the pan-tumor approval group in June 2024 with it’s indication for those with NTRK-positive solid tumors.³

In the interview, Barata detailed considerations in determining treatments when biomarker-based approvals are available options and highlighted key questions regarding genetic testing. Barata is director of the Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, the Miggo Family Chair in Cancer Research at University Hospitals, and an associate professor of medicine at Case Western Reserve University School of Medicine in Beachwood, Ohio.

OncLive: What are the most important considerations for community oncologists determining a treatment plan for a patient when a biomarker-based approval is an available option?

Barata: We’re getting to an era where, at least in the US, we’re able to sequence all the patients with unresectable or metastatic malignancies who come to see us, specifically those with solid tumors. It opens the door to precision oncology, whether you talk about specific markers to predict response to immunotherapy or specific targets to predict the efficacy of targeted approaches; that has revolutionized treatment with the care we’re providing to patients. For the most part, [these therapies] are still being used in the refractory setting beyond frontline regimens. There are a few exceptions to that, I’m thinking of lung cancer for example where you go after EGFR, ROS, or ALK [targets]. But [when] you start talking beyond that, you start seeing [that] biomarker-based approaches [are] moving early on and sparing the patient from the toxicity of chemotherapy and sometimes the lack of efficacy of chemotherapy with [a] far more effective therapy.

This revolution has been amazing to see, including [in] tumors that are very difficult to treat such as sarcomas, and that has been a significant change. How does that work out in the community [setting]? It depends because community colleagues are very busy and have to be on top of ordering those tests, sending them out, [and] getting the results back usually few weeks later. You have reflex testing that pathology can do on your behalf and get done automatically, [so] you don’t need to wait to see the patient in clinic to get that testing going.

What is important to note about the logistics of biomarker testing?

The question around genetic testing is a complicated one because it has a lot of factors that we need to consider. First, I talk about tumor testing or germline testing—somatic vs germline. With somatic testing you go after the tumor [and] the question then becomes are you testing the tissue or are you testing the circulating free DNA, which you hope will have a 100% representation with circulating tumor DNA, but [they] are not necessarily the same. From that point of view, the timing of collection, the wait time, and what tissue you are using are relevant. Is it very old tissue? Does it represent the tumor that’s now progressing on 1, 2, or 3 lines of therapy? Those questions are very important. What do you do with the allele fraction [variant] of 1% vs 20%, does that matter? Where does that come from when you are testing circulating free DNA, is that driving the tumor? What assay are you going to use? Are you doing a test, a panel of just 15 genes, are you sequencing the DNA, or are you going to go after RNA and IHC?

We are trying to figure out the answers to these questions, a lot of times we don’t know them, and so it is a complex story. Even thinking about how we adapt the teams to provide that service to patients in a timely manner and saving time [in] your visits with them to explain what that means [is important]. For germline [testing], do you have a genetic counselor, or do you have to do the pretest counseling, and then what do you do with the positive results? Do you have a genetic counselor there or do you have to provide a remote genetic counseling service? All those are relevant, important questions that the care teams are struggling to figure out the right answer to, and my guess is the right answer is not the same for all the care teams out there.

What works for some doesn’t work for others, and that’s becoming even more challenging because you need to figure out what works for you and your team, which might not be necessarily what works for the team across the street from you. From that point of view, we’re not there yet and have to do better. We need to put a lot of effort into the care teams and the structure [of them], so that we can provide sequencing testing to patients who come to see us with metastatic solid tumors.

What do clinicians do when there is a biomarker approval but not a lot of data in a particular tumor type? How would you treat a patient who could qualify for the approval?

As an academic doctor, my easy answer is we’ll have to develop those data. That happened with immunotherapy—when pembrolizumab [Keytruda] was approved based on microsatellite instability–high [status] initially we had microsatellite instability being tested in tissue even before it was able to be tested in liquid biopsy. We didn’t have that in prostate cancer, so we had to develop those data. When we don’t have much data usually those therapies are not prioritized over the standard-of-care and are saved [for] the settings where there are more limited options. Once you clarify what the role of that specific biomarker-based approach is in that specific tumor, usually there’s good awareness around it where it either works as much as you think it would, as much as it [does] in other tumor types, [or it doesn’t].

The thought process around prioritizing that specific therapy depends a lot on the data coming from that specific tumor type. People were using more immunotherapy after data [in] prostate cancer came out, for example, because we know for [certain] patients with prostate cancer, immunotherapy is not helpful—for the most part, that’s the case. We also have insurance considerations [as well]; you have to have a good reason why you’re going to offer a drug [that] is a targeted therapy to a patient, and you usually must have a marker there and must quote data supporting your choice. The system balances out, if you will. The more data you have in your tumor type, the more likely you are going to use [a targeted therapy], and the more likely you know what you’re doing.

References

1. Tumor-agnostic drugs. American Cancer Society. Updated June 20, 2024. Accessed January 13, 2025. https://www.cancer.org/cancer/managing-cancer/treatment-types/tumor-agnostic-drugs.html
2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed January 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
3. FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. FDA. June 13, 2024. Accessed January 13, 2025.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-repotrectinib-adult-and-pediatric-patients-ntrk-gene-fusion-positive