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Funda Meric-Bernstam, MD, highlights considerations with pan-tumor approvals and where testing and reporting should be improved for clarity/ease.
As more agents and regimens receive tumor agnostic approvals from the FDA, further defining expression level cutoffs and refining genomic/immunohistochemistry (IHC) testing and reporting techniques will result in improved care, according to Funda Meric-Bernstam, MD.
Eight regimens have received tumor-agnostic FDA approvals as of February 2025, and last year’s regulatory decisions on fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and repotrectinib (Augtyro) have further provided pan-tumor options for select patients.1-3 These regulatory decisions are accompanied by questions about genetic testing for the biomarker-based approvals and considerations in tumor types where data are lacking.
“This is an exciting time to think about how we [can] do things better. Currently, a lot of our tumor-agnostic approvals have focused on a single-gene treatment algorithm. With time, we’ll be looking at rational combinations and have a lot more momentum in that space,” Meric-Bernstam said. “As for antibody-drug conjugates [ADCs], HER2 is a great example of showing how we’ve leveraged expression for selection of patients who are most likely to benefit. As we have more ADCs coming down the pike that have activity, we need to start looking at expression [levels] and try to identify the best treatment for each individual patient, and better study the best way to sequence different therapies.”
In an interview with OncLive®, Meric-Bernstam highlighted considerations with pan-tumor approvals and where testing and reporting should be improved. Meric-Bernstam is the department chair of the Department of Investigational Cancer Therapeutics, medical director of the Department of Khalifa Institute for Personalized Cancer Therapy, the Nellie B. Connally Chair in Breast Cancer, and a professor in the Department of Breast Surgical Oncology, all at the University of Texas MD Anderson Cancer Center in Houston.
Meric-Bernstam: This is a very exciting time because there’s increasing recognition [regarding] the value of looking at tumor-agnostic investigations of drugs as a registrational path. However, this raises a few things that are important for oncologists to remember. First, in the context of advanced solid tumors we consider genomic testing standard of care and there were already several genomic targets that led to disease-specific FDA approvals.
Over the past several years, we’ve seen pan-tumor approvals, starting with pembrolizumab [Keytruda] for microsatellite instability-high or mismatch repair deficient [tumors] which requires IHC testing or genomic testing with a specific polymerase chain reaction test. Then, the tumor mutation burden-based immunotherapy approval [of pembrolizumab occurred]. From the context of genomics, [the 2024 approval of repotrectinib—which] is now the third NTRK gene fusion [approval]—emphasized how important of a target [NTRK] is.
But tumor-agnostic approvals [such as the one] with BRAF V600E—[dabrafenib (Tafinlar) plus trametinib (Mekinist) received an indication in this context]— raise the important question of are we able to adequately make oncologists who take care of multiple different disease types aware that this got approved? For example, [oncologists treating] a patient with melanoma who has a BRAF mutation or an endocrine specialist who sees a BRAF mutation in a patient with anaplastic thyroid cancer are well aware of these alterations, but are all oncologists aware of the importance of looking for [BRAF mutations or] NTRK fusions? Making sure that a fusion assay has been done and being able to appropriately act with NTRK inhibitors as a potential option [is key].
This is an area that we need to investigate to increase awareness about these tumor-agnostic targets, especially in the context of fusions we’re seeing such strong activity [with these agents targeting]. It’s very exciting to see these approvals.
T-DXd is a different scenario because it’s [approval] is based on HER2 IHC [status] and it is the first HER2-targeted therapy that’s pan-tumor [FDA-approved]. It’s also the first ADC that received approval in a pan-tumor fashion. That also opens the window of looking at ADCs in a tumor-agnostic fashion. There has been great interest in ADCs recently, and a lot of drug development in that space [is ongoing], but often the drugs are developed in a disease-specific fashion. We’ll see if this leads to greater interest in better assessment of the target.
HER2 testing can be done with genomics as well, but there isn’t a direct concordance of genomics and HER2 IHC and if we just rely on amplification testing with next-generation sequencing, we will be missing patients who have HER2 overexpression. It’s important to think about genomics that capture all tumor-agnostic targets, as well as IHC testing to make sure we’re not missing patients who have IHC 3+ disease.
HER2 is unique in some ways because it’s expressed more frequently in some tumor types, which led to the early approvals in breast cancer and gastric cancer, but it is also expressed at meaningful levels across a variety of tumor types. The current approval is for patients with IHC 3+ [expression]. But we saw in [the phase 2] DESTINY-PanTumor02 trial [NCT04482309] that there was already an activity signal in those with IHC 2+ [disease]. We’ll start seeing a bit more information about whether patients with lower expression will be able to benefit from this agent.
There has been a lot of excitement in the breast cancer field because we not only saw the approval of T-DXd for patients with HER2-low breast cancer, but now there’s the [2025] approval for patients with HER2-ultra low disease. However, with that excitement comes additional complexity because we also need to be able to harmonize our pathology reads about how we define these different categories. How do we make sure that everybody is getting tested appropriately [and] scored appropriately and treating physicians are aware [of what that means]? It’ll be interesting to see whether the activity we’ve seen in breast cancer is extrapolatable to other diseases.
There are some nuances in efficacy with T-DXd in lower-expressing tumors because we’ve seen activity with T-DXd in multiple tumor types among patients who have IHC 3+ [disease], but a bit more variability in patients who have lower expression. But there has been remarkable activity in gynecological tumors so it’s understandable that the gynecological community is excited about this treatment option.
If you don’t order HER2 testing, you won’t get the results. It’s not a reflex test done in pathology and this is something that a treating physician would need to put an order in for [with] most disease types. In breast cancer and gastric cancer, HER2 is often reflexively tested, but for other tumor types we need to deliberately be asking for HER2 testing if we think patients are eligible for HER2-targeted therapy. T-DXd is a very active agent, but patient selection is also very important in its use.
[Additionally], both the testing and the reporting have not been completely harmonized at this time, and there is still room for improvement in how we decide as a community how we’re going to test and how we’re going to report. For example, it’s quite common for patients to be reported to have a HER2-negative test if they have HER2 IHC 2+ [disease]. Therefore, it’s important to read the actual report and not just the summary of a report because that earlier classification that led to patients being called HER2-negative [included those who] were IHC 1+/2+ expressors [which] has still carried on into the current nomenclature. As we have more clinical trials for these patients, and as more activity is seen in lower expression in some tumor types, it’s important to read the granular reports and improve our reporting as well so we can give more details about percent similarity and intensity but also make oncologists aware of some of the nuances of the testing and reporting.
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