 Dr Patel, you I think said early on that you had a handful of these patients with 

 fusion-positive lung cancer. I wonder if you could tell us about your experience.

 Primarily, I am prescribing more larotrectinib, but that is primarily because of my familiarity with the trial. I am also using a lot of entrectinib to treat patients with 

 fusions. There are different types, but I am looking at the toxicity profile. These drugs are well tolerated, as Ben mentioned. There is perhaps a little more fluid retention for patients who take entrectinib, but generally our patients have done really well. One thing that is interesting is how quickly we have understood resistance in these patients; researchers identified where resistance would develop even before it was clinically detected for larotrectinib. It may be that most patients have a good duration of response, but for patients who do develop resistance, it will be interesting in the long run to see if there are any differences in the mutational profiles of patients taking larotrectinib and those taking entrectinib.

 Going back to Jonathan, I think Jonathan raised some of those issues regarding resistance. I wonder if you could give us your comments on what you have seen in the sarcoma population, in terms of the acquired resistance to these agents.

 I have really only found 1 patient so far who has acquired resistance, and that seemed to be the result of a mutation in the ATP [adenosine triphosphate] binding pocket of the kinase. This is similar to what we have seen in patients with 

 mutations and patients with GISTs [gastrointestinal stromal tumors] who become resistant to imatinib. That is the only patient with acquired resistance I have seen. It is going to be interesting to see whether newer agents, newer generations of TRK inhibitors can overcome this type of resistance. 

 I will open it up to the panel. Is there anything we have not discussed in the NTRK space that we should mention to our audience? I cannot think of anything off the top of my head, but I will give people a moment. If something comes to mind before we transition to our next session, please say so. I think it is important for our audience to remember that this should be on our list of biomarkers that are routinely tested. It is seen across a broad base of solid tumors. We talked about many of them here today, but again, they should be on the list, and you should know the 

status of all your patients. Remember it is the fusions we want to identify and not necessarily the mutations.

 I would add one thing. Ben mentioned that many of these patients have a proclivity for developing CNS [central nervous system] metastasis. Certainly, 

, when it was first presented, was presented with CNS data. Larotrectinib also has CNS data available. Many of these patients will do well for a long time, and so when I am able, I always prioritize a TKI [tyrosine kinase inhibitor] before brain-directed therapy. I think with radiation, the cognitive and quality-of-life deficits, over time, can certainly add up for these patients. Again, understanding the mutation status is important; if you have the time to wait a little longer until you have that firmed up, I think that has implications for how they do.

 When treating lung cancer historically, we have had the reflex of pursuing radiotherapy initially. I think we now know that in many of these oncogenic driver subsets, these TKIs can be highly effective. Is the issue of brain metastases a lung cancer issue? I’ll ask Lori and Jonathan to weigh in. Is there something specific about 

 across all tumors? We in the lung cancer field are used to having a high incidence, particularly in many driver situations, 

 is like the poster child, for the most part, of brain metastases. Is it true? Are you seeing that in other populations with these drivers, or is it mostly more of a lung cancer phenomenon?

 We see brain metastases in patients with advanced thyroid cancers. Anaplastic thyroid cancer goes anywhere, including the brain, and so we routinely rule out brain metastases in all patients with newly diagnosed anaplastic thyroid cancer. For patients with other advanced thyroid cancers—differentiated thyroid cancer or poorly differentiated thyroid cancer, medullary thyroid cancer—we see about 10% of patients harboring brain metastases. I do not know that we see them more commonly with the 

fusion driven cancers. But I think it is an underappreciated phenomenon. I now, knowing that, routinely rule out brain metastases in all patients with advanced thyroid cancer who need systemic therapy.

 It is an important topic. If you consider sarcomas in general, we rarely see brain metastases. Less than a fraction of a percentage of patients will ever get brain metastases. However, each subset is different; for instance, when considering patients with 

translocated alveolar soft part sarcoma, some people would say 100% of patients will eventually develop brain metastases. It is very common in that entity. Every patient gets an MRI of the brain at diagnosis. With the other sarcomas, it is so rare that we do not generally do a brain scan. It is not surprising that, in the presentation at the CTOS [Connective Tissue Oncology Society] conference in 2020 given by Sant P. Chawla, MD, which addressed the sarcoma subset from the larotrectinib trial, there were not any patients who had brain metastases in that study.

Videos

Experts discuss their personal experiences when treating patients with NRTK fusions and solid tumors. 

TRK Fusion Inhibitors in Clinical Practice

 I’ve found plasma-based testing for markers to be incredibly helpful clinically. Jyoti, what is your view on looking at tissue versus liquid or both in this setting, particularly when examining lung cancer?

 Sure, in lung cancer, unlike some other cancers, we have a multitude of different targetable mutations. Our field has shifted in the past decade or so to support broad testing of multiple markers, as part of tissue stewardship as well as getting and answering appropriate coverage early on. I think as Ben mentioned, RNA adds another layer to that. RNA can add onto a DNA-based platform in cases in which there may be low cellularity or a large number of repetitive introns. We know, particularly with fusions, and particularly with 

There can be other complex genetic events; there are different fusion partners, for example, that you can only assess with RNA. Our take is that all patients with advanced diseases should undergo full NGS [next-generation sequencing] that is both DNA and RNA based. Certainly, where we stand with patients with squamous tumors has evolved. Many might say that this requires a bit of a research effort because those determinations are quite infrequent. Currently, for all patients with advanced nonsquamous tumors, we sequence; we sequence for patients with squamous tumors who have no history of smoking, or low cellularity. We sequence in cases where there are admixtures or things are just poorly differentiated. Now, within our institution, Lurie Cancer Center at Northwestern Medicine, as part of a research effort, we are sequencing all patients with squamous tumors, so that pie keeps getting a little larger. At the same time, when we meet a patient, we are testing blood, and we know there is great concordance. We know that the concordance is upward of 80%, but a lot of things can change. You know that you can have insufficient tissue. You know that sometimes you will find something because of tumor heterogeneity in the blood that may not happen in the area that you biopsy, and so you make decisions based on both of them.

The real impact of this, and it’s a question that Lori and Mark touched on before, was what do you do when patients progress? You have had 1 targeted therapy, but that is really a role for rebiopsy, and often blood can be very helpful there. It can show patterns of progression as well as capture tumor heterogeneity if there is a transformation. The one piece that has changed in the treatment of lung cancer that I think we also need to acknowledge is that we now have a great TKI [tyrosine kinase inhibitor] in the adjuvant setting, so we are testing earlier and earlier. Certainly, with 

, we have had the approval of osimertinib for 3 years. That testing paradigm is moving up to being an option for patients with even stage I disease now.

 Ben kind of touched on this before; patients for whom you identify a molecular target who receive targeted therapy do so much better than those treated with standard chemotherapy approaches. This tends, at least in patients with lung cancer, not to be a group of patients who get particular benefit from immunotherapy in this setting. Like you, I bought into the idea of testing both tissue and blood at the time of diagnosis. I think that the greatest thing we can do is to identify an oncogenic driver because all those targeted agents are not available to the patient unless you make the molecular diagnosis. I think it is incredibly important to do that. I must say, the NILE trial that was published 2 years ago was very influential in convincing us that you can find things in plasma that you do not find in tissue and vice versa. No matter where you find it, you can believe it and act on it.

Jyoti Patel, MD, FASCO, discusses the pros and cons of tissue versus blood for molecular testing of solid tumors.

Key Considerations for Biomarker Testing

, “Updates on Biomarker-Directed Therapy for Solid Tumors With a Focus on 

.” I am Dr Mark Socinski from the AdventHealth Cancer Institute in Orlando, Florida. Joining me today in this discussion are my colleagues: Dr Jonathan Trent from the Sylvester Comprehensive Cancer Center, University of Miami, Florida; Dr Lori Wirth from the Massachusetts General Hospital in Boston; Dr Jyoti Patel from the Lurie Cancer Center at Northwestern Medicine in Chicago, Illinois; and Dr Benjamin Levy from the Johns Hopkins Kimmel Cancer Center in Washington, DC. Today we are going to discuss how we measure and use specific pan-tumor biomarkers to optimize therapy for our patients. Let’s get started with our first topic; I am going to ask Dr Ben Levy to lead us and underscore the importance of biomarker testing in general.

 Thanks, Mark. We have come a long way from the model of chemotherapy for all, at least concerning patients with lung cancer, and for other tumor types as well. Of course, this model has now been supplanted appropriately with targeted therapies, genotype-directed therapies. This underscores the importance of biomarker testing. Biomarker testing is, of course, testing for specific genetic alterations or even protein expressions in tumors that will help inform a treatment decision.

The nice thing about that is that there are now many biomarkers in lung cancer and for other tumor types. If you have that particular biomarker, gene of interest, or protein expression, if you want to think about PD-L1, you can leverage that information and use it to make treatment decisions, oftentimes with targeted therapy. Just briefly, I think what we know, at least when considering patients with lung cancer, is that patients who have an identifiable target who receive targeted therapy, do better. They have improved response rates, progression-free survival, oftentimes improved overall survival, and an improved quality of life, which is perhaps underrepresented in the literature. I know we are going to talk about how to test and how important it is, but that is my high-level overview of why biomarker testing is so important in solid tumor oncology, specifically in lung cancer.

 That is a good point, I like to say to my patients that I view cancer as a disease of your DNA, and we should interrogate the DNA to see if it gives up any secrets; that is the crux of biomarker testing. I'll ask Dr Wirth: in terms of the timing of biomarker testing, when are you doing it in your patients? Is biomarker testing done at diagnosis only, or is there a role for it at the time of disease progression? What are your thoughts there?

 Mark, as you know, I take care of patients with head, neck, and advanced thyroid cancers. Many patients who are diagnosed with and treated for thyroid cancer do not need any systemic therapy beyond the scalpel except for, perhaps, radioactive iodine, which was the very first targeted therapy, I might point out. Many patients with thyroid cancer, and also patients with head and neck cancer, are cured with their initial therapy that involves standard treatments without any targeted therapy necessary. In my clinic at Massachusetts General Hospital, we test patients who will be in need of systemic therapy in the foreseeable future. We do not want to wait too long, or until the patient needs to start therapy tomorrow. Often, we are going back and looking for old tissue in the archives that may not be good for testing, and so we need to definitely plan ahead. I think, in our clinics, when considering all of our patients with systemic disease who need therapy, there is definitely a very strong rationale behind testing for biomarkers that will direct our treatment options.

 Are you using broad-based platforms like NGS [next-generation sequencing]? Is there any role for spot testing for particular mutations or alterations? What are your thoughts?

 When considering thyroid cancer, for example, the most common mutation is 

 V600E in patients with papillary thyroid cancer. It is also not uncommon in cases where we are treating anaplastic thyroid cancer with dabrafenib and trametinib, and you can easily test for 

 V600E mutations utilizing immunohistochemistry. You can very quickly get the answer. Many institutions do 

immunohistochemistry during a first pass, and when that testing is positive, these institutions do not do further testing for cost savings and practical purposes. At our institution, we have our own in-house NGS assays that are very robust and are the easiest for us to use for most of our patients. We go straight to broad panel testing for most of our patients, looking not only for point mutations and amplifications, but also all of the oncogenic fusions and their multiple fusion partners, which are so important to find.

 Let me go back to Ben. Obviously, lung cancer is the poster child for targeted therapies, and we have a number of biomarkers to consider. In your opinion, is a next-generation platform the standard of care? Comment on the DNA- or RNA-based testing issue.

 Yes, if you would have asked me this question 2 years ago, I may have had a different answer. I think what we have learned recently is the importance of both DNA- and RNA-based sequencing platforms, and an NGS platform that examines both. I think that the identification of fusions is critical—

 are ones that we can miss on a DNA-only NGS. This is a call for DNA and RNA testing for patients with advanced lung cancer, and I will—maybe we will talk about this, maybe we won’t—throw in the liquid [biopsy] piece here too. It is important to do tissue sequencing when treating lung cancer, but Mark and Jyoti can attest to this as well, we know now that layering in the liquid may help us identify additional alterations that may have been missed in tissue. I think tissue NGS is important in all patients, a DNA and RNA platform, and then also a consideration for liquid biopsies for patients as well.

Benjamin Levy, MD, and a multispecialty panel of experts discuss the importance of biomarker-directed therapy for appropriate solid tumors.

Jonathan C. Trent, MD, Sylvester Comprehensive Cancer Center

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