Moving forward, how do you see these patients, Dr Rodriguez, in your practice? How do you approach these patients, really, in everyday practice?

I think the No. 1 thing is to recognize [whether] they have something actionable because I think they have gone unnoticed. And if you look at when osimertinib came into use and [individuals] started moving away from afatinib—they also moved away from using it in the right patients, which are these patients with uncommon mutations. I think we see these patients and if you test everyone, you will find these patients. These are the mutations that sometimes get lost because they don’t come at the top of the report because they’re uncommon, and they don’t have a strong FDA approval. But this is why we discuss it in our molecular tumor boards—is there an option? [Are] there data? And I think with this large database, you’re correct. Afatinib has the longest, more robust data set to look at the effectiveness of treating these atypical mutations.I think I have used that database to see if this mutation could potentially respond to this agent. Because of these patients, we know in general, for biomarker-driven actionable mutations, really having a targeted therapy—patients will do best. So, I have seen it. It depends on where you practice. In our practice probably 15% to 20% of our patients have

 mutations, but these uncommon mutations are less. So I include the exon 20 insertions, which are about 6%. Then you have all the other ones uncommon that you mentioned, the L861Q, which is about 1%. So, these are not the patients you’re going to see every day. But if you do lung cancer only, which you and I do, we will see these patients, and you will have them in your practice. And you will see that they will get benefit from being treated with a targeted treatment instead of selecting chemotherapy and immunotherapy for them. I think I have learned that and recognize that these are not as uncommon. If you keep testing, you’ll find them.

: How do we approach treating these patients? Right now, I will, if I find an uncommon mutation, and I know that afatinib also does a great job of penetrating the CNS [central nervous system], the brain—I will treat these patients up front, with an uncommon 

 mutation. I think that you will give them the benefit of seeing if there’s a response to a targeted option up front. If I found mutations later after the patients have had chemotherapy, I switched them to afatinib as an option. And the experience has been that it’s a different drug. I think that if we are not using afatinib as much, you don’t get as good as you used to be at managing rash and diarrhea, which are some of the main adverse effects of this drug. But we, for a long time, did a great job of managing that on patients who were on erlotinib and afatinib. And I think it’s all about patient education, having the team be very proactive about managing rash and diarrhea. And we’re able to have patients [who] have stayed on these drugs for a long time if you can dose-reduce and manage appropriately. I think right now, if I find these mutations early, I will treat the patients up front. In the second line, I will either find clinical trials, although many clinical trials exclude them. That’s a problem. But they will get chemotherapy second line. I would ask you, Dr Levy, [whether] the use of immunotherapy on some of these atypical mutations is controversial because the series doesn’t really show great responses. And it depends on which one you’re looking at. But if you include an 

exon 20 insertions, we know the responses to immunotherapy, they are not great. And those patients now have their own drugs that we can offer them. But for the other uncommon mutations, have you used immunotherapy with chemo[therapy]?

[T]his is a tough question. I have some exon 20s for sure [who] are former smokers that have a high PD-L1, which I’ll use it. We learned obviously from ASCO [the American Society of Clinical Oncology Annual Meeting] in KEYNOTE-789 [NCT03515837], post targeted therapy for 

-mutant lung cancer, the addition of immunotherapy to chemo[therapy] doesn’t do anything. That said, there are some subtypes of 

mutations if you integrate other things. Like PD-L1 in heavy smoking history, then I will. I will use it. Will I use it alone? No. But I will use it with chemo[therapy]. I think the lesson here is, for 

 mutations, immunotherapy is not a good choice. We have too many good drugs and too many drugs that are coming down the pike that are important. I think for patients, you really must pump the brakes and tell them, “Look”—because they want immunotherapy. You must tell them that immunotherapy may not be the best for them.

: Thank you. Now, in terms of afatinib, I was mentioning my experience, but what are some of the adverse events that you have seen, and what kind of strategies have you learned to put into place so patients can tolerate treatment well?

My strategies are predicated on a wealth of experience. And the thing I say about any drug that you give, anyone, is the juice worth the squeeze?

Because drugs have toxicity and they have efficacy. And in some drugs, the balance is a little bit off. In some drugs, there’s no question at all. I think the nice thing about my use of afatinib is we’ve learned very well how to mitigate some of the toxicities. The toxicities are your common toxicities: rash, diarrhea, and paronychia. But I think you can get patients through this quite well. One of the things we do have is that we have a low threshold to go down to 30 mg. We actually know that 30 mg is probably as good as 40 mg. Some data [were] presented by Balazs Halmos [MD] many, many years ago showing that’s the case. But I think being proactive with rash, being proactive with diarrhea, educating patients on this, educating them to talk to us about them, and also understanding the algorithm of how [to] do this—certainly, clindamycin gels and hydrocortisone creams can be used for rash, but I have a low threshold to go to doxycycline sometimes. And the diarrhea is Imodium [loperamide] and educating. And then the paronychia; everyone’s got their special sauce for paronychia. Every institution has its own creative ways to treat it. I’ve been partnering with my podiatrist for paronychia that exists on the toes, and I’ve had a really good experience with these types of things. And there’s a special sauce. We use tea tree oil. I’ve heard, “Put vinegar and water.” I mean, it’s interesting to see how this is done. But you gain experience with this drug and you’re able to really mitigate these strategies. And I do think for our uncommon mutations, afatinib is the right choice for most patients. I’m not just saying that because we’re here to talk about afatinib. This is my clinical experience. And the juice is worth the squeeze.

Videos

Benjamin Levy, MD, and Estelamari Rodriguez, MD, MPH, reflect on their experience managing real-world patients with uncommon EGFR mutations in non–small cell lung cancer. 

Uncommon EGFR Mutations in NSCLC: Real-World Selection and Use of Novel Agents 

Dr Rodriguez, what are the currently approved treatment options for patients with uncommon 

 mutations in non–small cell lung cancer?

: So, what’s great is we are really seeing an explosion of options. I think the importance of doing NGS [next-generation sequencing]—because one thing we lose when we do single-gene analysis—is sometimes you don’t get the complexity of these changes within all these exons in 

. One thing that I tell myself is that we call these uncommon, atypical mutations, but they’re not that uncommon. If you look at a pie chart of all the 

 mutations, the classical mutations—they combined, [exon 19 deletion], L858R, comprised about 67% to 70%. But everything else is uncommon, atypical, [and] compound mutations. So, it’s a big chunk of patients [who] I think have these changes that are being left untreated. Now, we do have data. Afatinib is really the one drug that has FDA approval for atypical mutations because they did the work of including those patients in their LUX-Lung trials. So, we saw data, and they have done a great job of collecting case reports of patients [whom] we wouldn’t expect them to respond to afatinib where they did. So, they have a large registry that you can access. It’s called uncommon 

 mutations, and you can see this mutation because there are so many, how patients have responded to their drug. So, I think we have at least one FDA-approved agent that you can go to for atypical mutations. I was involved in also an international series looking at the use of osimertinib in some of these uncommon mutations. And although that was a retrospective review, not a formalized clinical trial, there is a signal of activity in uncommon mutations also with osimertinib. So, it is something that we need to discuss with patients. And I think as we get more knowledge about the structure of each of these uncommon mutations and this drug will be better, I think we’ll be able to decide what’s the next plan for these patients. But again, these mutations are not as uncommon as you may think. We are seeing them in the reports. And they sometimes go to the bottom unnoticed because they don’t have an attached treatment option. But afatinib is an option that should be included. If you find an atypical mutation, they did have data that [were] reviewed by the FDA where they have activity. And they saw activity. You can probably, Dr Levy, really describe to us what efficacy outcomes they saw in these trials supporting the use of afatinib as a second-generation TKI in these patients with uncommon 

First, kudos to you for looking at osimertinib in these uncommon mutations. The thing is we can talk about osimertinib and all the ways that it works, and it’s a beautiful drug, but I will tell you, based on the data that I’ll share with you, that I am more inclined to use afatinib for my uncommon mutations. I’ve been an early adopter, or at least stuck with afatinib even when osimertinib came around. That’s not to say that osimertinib doesn’t have activity. I think your group has shown this in an international effort. And you still must think about it. But the data perhaps that sort of support this [involves] this pooled analysis from the LUX-Lung 2, 3, and 6 trials [NCT00525148, NCT00949650, NCT01121393]. These were trials exploring afatinib in all

 mutations. LUX-Lung 2 was a phase 2 trial. LUX-Lung 3 and 6 were phase 3 trials, comparing afatinib to chemotherapy, which led to the approval of afatinib for all 

mutations. And the importance of these studies is that they did include uncommon mutations, and perhaps because of that, we have the most data with afatinib in uncommon mutations. When they looked at the data in the pooled analysis, I think, they separated the groups into 3 cohorts. The first were the most common uncommon mutations, these point mutations and duplications, andexon 18 and 21. They looked at de novo T790M mutations, and they looked at exon 20 insertions. And the takeaway from this is essentially when you looked at the most common uncommon 

 mutations, they found a very high objective response rate that was north of 60% based on survival times that approach 2 years. So because of that, I think the data would suggest that afatinib is a little bit better by cross-trial comparisons in osimertinib. Again, [this is] an apples-to-oranges comparison here. But I would say, because we always do this, we say we don’t want to do it, but we do. I have really leaned on afatinib for my uncommon mutations. That’s not to say that there’s not some efficacy with osimertinib. And it’s always a decision. We must balance out efficacy and toxicity. But again, [these are] the data that I think [are] so important.

Focused discussion on uncommon EGFR mutations in non–small cell lung cancer and concurrent treatment options in this setting.

Treatment Options for Patients with Uncommon EGFR Mutations in NSCLC

We are going to transition to our next topic; we will be talking about 

 in this setting. I am going to ask her to set the stage for the role of 

 in oncology, why don’t I start out by discussing the identification of 

rearranged in transfection? This was first discovered, I believe, in 1986 by Masahide Takahashi, MD, PhD, in an NIH3T3 cell line. Then 1 year later, Alfredo Fusco, MD, in Italy identified 

 fusions in papillary thyroid cancer. Then shortly after that, the 

 gene was cloned in patients with familial MEN2A and MEN2B [multiple endocrine neoplasia type 2A and 2B] syndromes, causing as we know medullary thyroid cancer, as well as the other endocrine neoplasias associated with those syndromes. It was not until 

 was identified as a fusion driving non–small cell lung cancer that the pharmaceutical industry really got interested in potently inhibiting RET. We did have the multikinase inhibitors like vandetanib, cabozantinib, and others that do have anti-RET activity along with VEGFR2, KDR, EGFR, and so forth.

I think it took the identification of KIF5B 

 fusions in non–small cell lung cancer to really turn the spotlight specifically on RET. RET is a juicy target because it is a receptor tyrosine kinase. Interestingly, it does not homodimerize exactly with itself with ligand binding, but there is a GDNF [glial cell line-derived neurotrophic factor] coreceptor that the ligand binds to, and then that coreceptor leads to homodimerization, forming a complex of activated 

. There is signaling, as a result of that, through multiple signaling pathways. 

 fusions are, of course, seen in papillary thyroid cancer and other thyroid cancers in the subset of patients with non–small cell lung cancer. They can be rarely identified in other cancers, including pancreatic adenocarcinoma. Then we see 

 point mutations, deletions, and a couple of other alterations in the majority of patients with medullary thyroid cancer, whether it’s a germline mutation in MEN2A or MEN2B, or a somatic mutation arising in a sporadic cancer.

In that situation I’m under the impression, Lori, that you might see 

 mutations in other tumors, but it is really felt to be a driver only in the setting of medullary thyroid cancer. Is that a fair statement?

I do think it is a fair statement. Again, I think it is because 

 is not necessarily expressed in other tissues. A point mutation is not going to have any sort of oncogenic effect if it is not expressed to begin with.

Let’s discuss the impact of fusions and mutations on clinical outcomes. Before we had the real potent, modern-day RET inhibitors, how effective were those drugs, like sunitinib, vandetanib, and cabozantinib, and those other “dirty kinase” treatments, as we call them? What was your experience prior to the modern era?

There are MKIs [multikinase inhibitors] that are approved for iodine-refractory differentiated thyroid cancer that have anti-RET activity. There are also MKIs approved for medullary thyroid cancer. There is activity in cases of DTC [differentiated thyroid cancer] whether or not 

 fusions are present. There is also good activity in cases of MTC [medullary thyroid cancer] whether or not 

 mutations are present. However, at least regarding patients taking cabozantinib who are being treated for medullary thyroid cancer, a subset analysis correlating activity with a specific 

 mutation did show that it looked like cabozantinib is more effective in patients who harbor a 

 M918T mutation, which is in the tyrosine kinase domain. There is even a survival benefit that was seen in that particular patient population.

It is not too surprising, because in MTC, there is a really interesting genotype-phenotype correlation. The various 

 mutations do cause various degrees of aggressiveness of the cancer. In the familial syndromes, we see not just aggressiveness in terms of the age of onset of medullary thyroid cancer, but also in the risk of developing the other endocrine neoplasias like hyperparathyroidism and pheochromocytomas.

I’m under the impression that, at least in thyroid cancer, the germline issues are more commonly seen than the somatic mutations. Is that fair?

Not quite; about 25% of medullary thyroid cancers will be seen in patients who have MEN2A or MEN2B. They all have germline 

 mutations; MEN2A germline mutations are more common because MEN2B is just very aggressive. Of the 75% of patients who do not have the hereditary MEN2A or 2B syndromes, approximately 60% will have somatic 

 mutations driving their MTC. Overall, the somatic 

 mutations are more common in MTC because sporadic MTC is more common. Getting back to tumor testing and so forth, this germline versus somatic mutation adds a whole other level of confusion regarding how to test. One thing to point out is that we are talking mostly about NGS [next-generation sequencing] testing in today’s program, but for patients with medullary thyroid cancer, we absolutely have to make sure that those patients do not have a germline 

 mutation. It has implications not only for their individual health and care, but it also has implications for all of their first-degree family members.

Thank you. Ben, I want to give you the microphone for a second here, but I am going to limit your comments. When I first went to UPMC [University of Pittsburgh Medical Center], in 2011, or shortly thereafter, we were testing for 

. Occasionally we did find it in patients with lung cancer. In my experience with the drugs we mentioned before, like cabozantinib and sunitinib, the multikinase inhibitors have a lot of off-target effects and were not particularly active in the 

 fusion-positive lung cancer population. I am wondering if you had a similar experience. I do not want you to talk about the newer agents selpercatinib or pralsetinib because I want to give Lori the stage for that in a second. But there has been such a change in our ability to target this alteration that I want to give people a sense of what it was like prior to the modern era.

These drugs have already been bounced around during the discussion, and we have tried them in a lot of these tumors where we have identified some sort of 

 alteration. Vandetanib, cabozantinib, sorafenib, sunitinib—these were all drugs that may have had some RET activity. Now that we have these drugs, they do not elicit the meaningful activity that we are now seeing with these newer drugs, and they are not as well tolerated. I think this has been a win to have these new drugs, but certainly, dirty TKIs [tyrosine kinase inhibitors] are just that. They are not that selective; the depth of response and meaningful response are not as common, and there is more toxicity to deal with. I can recall several experiences with some of these drugs where you are just not getting a lot of activity out of what you think may work. It is an oral therapy. A lot of patients may think, “I am not getting chemotherapy, so maybe it will work,” but my experience with these treatments has not been as favorable as with the newer drugs.

Expert oncologists discuss RET-driven therapy for select solid tumors.

RET as a Therapeutic Target for Solid Tumors

 In terms of the current unmet needs, 1 of the important questions, that we deal with in advanced thyroid cancer is when we should initiate therapy. Advanced thyroid cancers are a wide array of different diseases, but even in the same histologies or histologic subtypes we can still see a very wide array of natural histories. Not every patient who has a RET-mutant MTC [medullary thyroid cancer] has the same exact disease. There are patients who can have metastatic disease and be relatively asymptomatic even for years whereas other patients may progress much more rapidly than that.

One of the important questions is when we should initiate therapy. When patients do have slow growing asymptomatic disease in general there isn’t an urgent need to initiate therapy. However, in the era of the multikinase inhibitors when there was perhaps a slightly higher price to pay, our general tendency was to delay the initiation of therapy for as long as possible to avoid the patients having to deal with the adverse effect profile. Now I wonder if in the era of more specific gene, specific targeted therapy that’s very potent and has a tolerable adverse effect profile will patients do better if we initiate therapy earlier in the course of their disease rather than waiting as long as possible. That’s a question of the pendulum swinging 1 way in the era of multikinase inhibitors, and now in the era of precision medicine maybe it’s more appropriate for the pendulum to swing back to earlier therapy. We don’t have any clinical trial data to answer that question, but it is an important question.

Another important question is what is the best sequence of therapies? We now have 3 FDA-approved drugs for the treatment of medullary thyroid cancer, and that question really has not yet been answered. We do have a randomized phase 3 trial underway internationally randomizing patients with RET mutant MTC to selpercatinib versus either vandetanib or cabozantinib as the physician’s choice. I think that this is an important phase 3 study that is now enrolling patients across the world.

Another important question is the question of acquired resistance. We have now, unfortunately, seen in a small handful of patients treated on the LIBRETTO-001 NCT03157128 trial as well as in patients on the pralsetinib studies the emergence of acquired resistance. Of course, we must expect that we will be seeing more of this arise in the future. We need to understand better what the mechanisms of acquired resistance are to RET-specific inhibitors and then, of course, have new therapies to target the acquired resistance mechanisms in those patients.

One other setting in which we have an opportunity to act perhaps earlier in the course of the disease is in patients who postoperatively have no known metastatic disease but have rather rapidly rising calcitonin and CEA [carcinoembryonic antigen] levels so that we know that they are destined to develop metastatic or locally recurrent disease in the future. Can we act early in the course of those patients with rising calcitonin and CEA? We don’t have any data at all, I wouldn’t consider using a drug like selpercatinib in that setting but it’s an important clinical research question that hopefully we’ll have a chance to think about in the future.

Next Steps for RET-Mutated Medullary Thyroid Cancer 

The FDA approval of selpercatinib is a landmark approval for patients with RET-driven cancers. It’s not an insignificant number of patients with non–small cell lung cancer that harbor RET fusions, and for those patients that is a significant improvement in treatment options. In patients with medullary thyroid cancer we now have a RET-specific agent that has good activity and a tolerable adverse effect profile overall. While we already do have 2 FDA approved drugs and selpercatinib is not just another FDA-approved drug for patients with medullary thyroid cancer but a new drug that has very good activity and a fairly tolerable adverse effect profile.

LIBRETTO-001 NCT03157128 was a phase 1/2 first in human trial investigating selpercatinib in patients with RET fusion non–small cell lung cancer and then RET-altered thyroid cancers, namely medullary thyroid cancer with RET mutations and then other thyroid cancers with RET fusions. We did see in patients with RET-mutant MTC whether it was germline mutation or a somatic mutation in patients who had been previously treated with either vandetanib and/or cabozantinib there was an overall response rate of 69% in those patients.

When patients were cabozantinib and/or vandetanib naïve, there was an overall response rate in MTC of 73%. Now, we did see good responses across all of the RET mutations that were seen in the patients enrolled including in several patients that did have the gatekeeper resistance mutation at RET V804. We also saw a good duration of response and PFS [progression-free survival] as well in both of the groups, both the previously treated group and the cabozantinib vandetanib–naïve patient population. In the previously treated group the duration of response had not yet been reached at a median follow-up of 14.1 months, and in the cabozantinib- and vandetanib-naïve patients also, again, the duration of response had not yet been reached with a median follow-up of almost 8 months.

In terms of progression-free survival, the medians also had not yet been reached for these patients. For example, in the patients who were previously treated the median progression-free survival had not yet been reached at a median follow-up of 16.7 months. We also saw in this study in the smaller subset of patients with advanced RET fusion thyroid cancer similar response rates, similar durations of response and long PFS—median progression-free survivals as well.

in terms of the tolerability there, of course, there are adverse effects. It’s a cancer drug. Most of the treatment-related adverse events were, however, grade 1 and grade 2. There were some grade 3 and grade 4 treatment-related adverse events. The most common one was hypertension, which was seen in 12% of patients. I’m talking about grade 3 and grade 4. We did see transaminitis as well, grade 3 and grade IV4 in approximately 10% of patients. Diarrhea, grade 3 and grade 4 was seen in 3% of patients. There was a small rate of grade 3 or 4 QTC prolongation in two percent of patients as well.

One of the other markers was tolerability is in the dose reductions. Thirty percent of patients did have dose reductions. However, only 2% of patients had to have dose discontinuation because of treatment-related adverse events.

Recent Approval of Selpercatinib in RET-Mutated MTC

 In the US, there are 2 multikinase inhibitors [MKIs] that are already FDA approved for medullary thyroid cancer [MTC], namely vandetanib and cabozantinib. Both these drugs have good activity in MTC. They are both multikinase inhibitors that do inhibit RET as well as VEGFR2 and other kinases. For example, vandetanib also inhibits EGFR whereas cabozantinib also inhibits MET. The response rates with both of the drugs are good, and both were studied in randomized trials compared with placebo and both drugs had improvement in terms of progression-free survival compared with placebo in the studies that were performed.

I don’t know that we know why these MKIs seem to work better in medullary thyroid cancer as compared to other cancers that are driven by RET such as RET fusion non–small cell lung cancer. It may be more related to the tumor type rather than the RET alteration itself, and because we do know that these MKIs or similar MKIs also have activity in iodine-refractory differentiated thyroid cancer when those cancers harbor RET fusions. It probably has something to do with the differences between medullary thyroid cancer and non–small cell lung cancer.

In medullary thyroid cancer with vandetanib we see an overall response rate of 45%, and in terms of the progression-free survival benefit the median progression-free survival had not yet been reached but it was estimated to be 30.5 months with vandetanib compared with 19.3 months with placebo. The vandetanib overall is fairly well-tolerated, but it does cause adverse effects that have to be reckoned with. Fatigue is fairly common. Patients can develop diarrhea, some anorexia and weight loss With vandetanib we also tend to see a lot of photosensitization, patients have to be careful about sun exposure in order to avoid getting a rash. Then, there is an uncommon but potentially significant increase in the QTC interval. Patients starting vandetanib and then on vandetanib do need to have careful EKG monitoring for QTC prolongation.

With cabozantinib the overall response rate in the EXAM trial NCT00704730 in MTC was 28%, and progression-free survival was 11.2 months compared with 4 months with placebo. Now, the progression-free survival differences are different between the cabozantinib trial and the vandetanib trial, but it’s important to note that the vandetanib trial did not require patients to have disease progression at study entry whereas the cabozantinib trial did. They are very different patient populations, it’s difficult to compare PFS benefit to PFS benefit between the 2 studies. 

In terms of the adverse effect profile with cabozantinib, it’s similar to the other multikinase inhibitors that target RET as well as VEGFR2. You do see, again, fatigue, diarrhea, anorexia. Hypertension is also seen more commonly with cabozantinib as well One of the markers of the toxicity profile with cabozantinib and vandetanib is the frequency in both of the studies of dose holds and dose reductions, which were not insignificant in both trials, as well as even dose discontinuation due to the adverse effect profile, which occurred in more than 10% of patients, in both studies.

Multikinase TKIs in Medullary Thyroid Cancer

 For medullary thyroid cancer, all patients need to have molecular testing done. Now we’re looking for 2 different things in molecular testing. It’s complicated, though not really. As I mentioned, medullary thyroid cancer [MTC] can be seen in hereditary syndromes, particularly MEN2A and MEN2B. Those patients all harbor germline RET mutations, and in any index case where there isn’t already a known family history of MEN2A [multiple endocrine neoplasia type 2A] or MEN2B [multiple endocrine neoplasia type 2B], we need to rule out familial syndrome in these patients because of the implications not only for patients diagnosed with MTC but also their family members, who are at risk for harboring germline mutations as well. When we find a patient with a germline MEN2A or MEN2B mutation, we need to make sure their family members do not harbor the mutation because of the implications of those patients needing treatment—for example, thyroidectomy, to remove the thyroid before a medullary thyroid cancer becomes established.

There are also somatic RET mutations that can occur. Twenty-five percent of medullary thyroid cancers will be familial, whereas 75% of medullary thyroid cancers will be sporadic. Of those 75% of sporadic cases, 60% of patients will harbor somatic RET mutations in their tumor. Now that we have RET-specific inhibitors available in our arsenal of therapies, any patient who needs systemic therapy should have somatic RET testing done, typically by NGS [next-generation sequencing] assays, to evaluate for a RET mutation. If a patient has medullary thyroid cancer that’s limited to the neck and they’re essentially cured with surgery, there’s not necessarily a role for RET somatic testing in those patients, but anyone with metastatic disease who we know doesn’t have familial syndrome should have RET testing done.

Most patients who are diagnosed with medullary thyroid cancer will have an actionable mutation found. As I mentioned, all patients who have a familial MTC will harbor germline RET mutations. Then, 60% of patients with sporadic MTC will have driver RET mutations in their tumors but not germline. The highest frequency of other mutations seen in MTC are seen in RAS, which aren’t necessarily entirely targetable at this moment. As I mentioned, most patients will harbor RET alterations that are potentially targetable. In patients with sporadic MTC, the most common mutation is RET M918T, which is the germline mutation seen in most patients with MEN2B. The most common MEN2A mutation is in the RET C634, and those mutations and other mutations can be found in sporadic MTC as well.

RET is a receptor tyrosine kinase. When the gene is mutated, the protein receptor tyrosine kinase is constitutively activated by homodimerization, when there’s an extracellular cysteine-rich mutation in RET such as at C634. When there is a RET M918T mutation, the protein is constitutively activated intracellularly, and homodimerization is not necessarily required for activation of the tyrosine kinase.

The idea of targeting RET specifically came about in part because of the known role that RET plays in MTC, but also RET fusions are seen in a small subset of patients with non–small cell lung cancer as well as in patients with RET fusion, other thyroid cancers such as differentiated thyroid cancer, poorly differentiated thyroid cancer, or even anaplastic thyroid cancer. With the awareness of the role of RET activation in these multiple tumor types and the fact that RET is a tyrosine kinase, that has certainly presented itself as a rationale target for drug development. Thus, the first generation of RET inhibitors has been studied. Selpercatinib is the first RET-specific inhibitor that was FDA approved and basically was designed to very specifically and potently inhibit the RET kinase and not inhibit other kinases, such as KDR, VEGFR2, and other kinases that are inhibited in the multikinase inhibitors that we have in our arsenal in oncology. The idea there is that you can really drive up RET inhibition but limit the adverse-effect profile that comes into play when there are multiple other kinases inhibited as well.

Actionable Driver Mutations in Medullary Thyroid Cancer

 The epidemiology of medullary thyroid cancer [MTC] is notable for the fact that it is a rare cancer. MTC accounts for less than 5% of all thyroid cancers that are diagnosed in the United States and worldwide. For the diagnostic work-up for MTC, typically patients will present with a neck mass that’s found incidentally on another imaging study or a neck mass that they notice or that their primary care physician notices on physical exam. 

The next step typically is an ultrasound-guided fine-needle aspiration, and many times a cytologic diagnosis of medullary thyroid cancer will be made at that time. Sometimes it’s difficult for cytopathologists to put the nickel down on the diagnosis. Other testing can be helpful as well, particularly if MTC is suspected on cytology, a serum calcitonin can easily be checked to confirm the diagnosis because, as you know, medullary thyroid cancers do secrete calcitonin. That will typically be elevated at the time of diagnosis.

Following that, many patients will be referred to a surgeon for surgery. The 1 important thing to be aware of is that patients can have hereditary medullary thyroid cancer syndromes. Those MEN2A [multiple endocrine neoplasia type 2A] and MEN2B [multiple endocrine neoplasia type 2A] syndromes are also associated with pheochromocytoma. Before patients go to surgery when they have a new diagnosis of MTC, they should have pheochromocytoma ruled out on typically blood studies before they’re on the operating room because of the potentially devastating consequences of an unknown pheochromocytoma intraoperatively.

Do patients need to have a distant metastatic disease work-up prior to surgery? Not necessarily, because thyroidectomy plus nodal dissection to remove the disease that’s in the neck would be indicated even if a patient did have metastatic disease in most cases. Often, patients will proceed to surgery and then have further work-up subsequently. Further work-up can be determined in part by the postoperative calcitonin and CEA [carcinoembryonic antigen] levels. If postoperatively calcitonin and CEA levels are elevated, then certainly further work-up needs to be done to rule out distant metastatic disease.

It’s important to note that the half-life of the serum calcitonin and CEA is rather long, so you don’t want to look 2 weeks after surgery. Give it some time—4 to 6 weeks after surgery—to account for the longer half-life before measuring. When distant metastases are suspected based on serum calcitonin and CEA, then neck and chest CT can be done to rule out any residual neck disease and rule out mediastinal hilar adenopathy and lung metastases. In looking for disease beyond the chest, 1 of the most frequent sites of disease is liver metastases that can be difficult to find on routine abdominal CT. Liver-directed imaging with either liver sequences on CT scan or, perhaps even better, MRI can be helpful. We can also see small bone metastases in patients, so careful attention for bone metastases may be indicated as well.

Lastly, I note that many medullary thyroid cancers aren’t particularly FDG-avid, so a standard FDG [fluorodeoxyglucose]–PET [positron emission tomography]–CT may not be all that helpful. When available, a gallium Ga 68-DOTATATE PET CT, however, may be helpful.

Epidemiology of Medullary Thyroid Cancer

 We’ll have to see how it goes. Where do we go from here? We talked about pralsetinib and selpercatinib, testing. Are there unmet needs? Where do we go here in the future for this genotype and in all genotypes?

 I’ll summarize what’s easy. What do you see as No. 1? Every nonsquamous stage IV patient absolutely merits molecular testing. Ideally that molecular testing should be a next-generation platform with a good RNA fusion panel. We’ve told you our opinions on what those are. No. 2, if you find RET, you should treat RET, in my opinion, in the front line. Certainly it should be treated, and it should not be treated with the old-school ineffective and toxic agents. It should be treated with selpercatinib or pralsetinib.

As an academic, I was obliged to take that diversion before actually answering the questions you asked, which is what is the unmet need, and where do we go from here? I would say that while a PFS [progression free survival] of 19 months or so is great when compared with chemotherapy, and while these toxicities are great compared with chemotherapy, it’s really not that long. If I came into your office tomorrow, and you said, “Jared, you have lung cancer—congratulations, I can control it for 19 months with this pill,” I’m not going to be that happy, right, because compared with a noncancer life, that’s not as good as we want. We have moved onto a next-generation drug, but I’m excited to eventually see drugs that last a lot longer than this in the front line. As you mentioned, we don’t know a lot about the resistance changes in RET. My suspicion is that they’re going to be quite heterogeneous in contrast to, for example, what we saw in the frontline EGFR experience. Of course, once we know what those are with greater granularity, people are going to try to action them, and we’ll have next-line drugs.

 I’ve been on some recent calls in which the questions have been for all genotypes: Where do we go? Where does the science delve into? Clearly 1 of the areas that the science has to delve is in sequencing strategies, and the sequencing strategies are based on understanding mechanisms of resistance that we can then target. Another area we need to think about is up front with the drug. What can we combine with these drugs that can improve that PFS or make it even longer? You know, we’ve been in this field a long time, or at least it feels like a long time. We know that they’re baby steps. With each scientific gain, it’s baby steps. This is a big step, but I’m curious to see where the science will head. Can we eliminate heterogeneity up front before we wait for resistance and give another targeted drug? This is where there are a lot of challenges on trial design. Are we going to do trials that look at a TKI [tyrosine kinase inhibitor] plus drug up front, and we do trials where we give the TKI first? Then when they develop mechanisms of resistance, we’re going to layer in another drug? I would agree with you. If a patient comes in and you’re telling them that you can give them a drug, and the durability of response is 20 months, it’s still just 2 years. We’re in 2020, although it feels like we’re way behind in this country.

 We’ve got to advance it further. We’ve got to capitalize on the science and move it quickly. But it’s an exciting time. 

 We’ve had this nice advance. You and I are both of the opinion to use this agent in the front line. I want to express an opinion that the tools that we’ve learned from EGFR and ALK and others can probably be applied to RET. What I mean is that if you have slow progression that is not a threat to the patient, there’s nothing wrong with continuing drug-path progression. If you have oligo- progression, meaning just 1 or 2 spots growing, there’s nothing wrong with using a little help from your neighborhood surgeon or radiation oncologist to prolong benefit of drug. If you have a lot of intracranial disease that you’ve cleared up with 1 of these agents, and you’re looking to switch to chemotherapy, it’s not standard. There is no approval for this, but in my opinion, it is reasonable to continue 1 of these agents with chemotherapy.

 I agree. Progression is heterogeneous. Trying to understand what to do is important and critically thinking at that pivot point what you’re going to do can make meaningful difference for a patient.

: I will address 1 question that a community partner recently asked me by text message: Does chemotherapy work for these patients? It works at least as well for these patients. And there’s some anecdotal evidence out there that, like ALK, pemetrexed-based regimens may work particularly well in the RET population. Once you’re done with RET-targeted therapy, whether you rebiopsy or not, if you’re moving onto chemotherapy, pembrolizumab-carboplatin or pembrolizumab-carboplatin-bevacizumab are perfectly reasonable options to consider. 

 Agreed. That’s a good, clinically relevant point about what to do when these drugs unfortunately stop working outside a clinical trial.

Next Steps for RET Fusion+ NSCLC

 If I were sitting at home and I hadn’t had the privilege of treating a dozen or 2 dozen patients on 1 of the trials, my next question might be, what am I going to use the next time I find RET? You’ve told me, you’ve armed me with whatever next-generation panel I can order. I’m going to pick up some RET now and again. What should I order? Do you see any key differences among these trials or drugs?

 I don’t know. The initial presentation looked like a response rate of 58%. The updated analysis at ASCO [American Society of Clinical Oncology Annual Meeting] for pralsetinib by Dr Justin Gainor looks like the response rate is around 65%, which is identical to selpercatinib. I don’t know if there are any meaningful differences in these drugs. There may be some differences in toxicity. Unbiased, as you mentioned, and I think you are too—we’ve only used selpercatinib. That’s probably going to be my go-to drug only because I’m a creature of habit and have put so many patients on the study. I would certainly be willing to give pralsetinib a try. It looks similar. The waterfall plot, if you put them next to one another—maybe a few of those bars don’t reach the 30% line on the pralsetinib arm that reached it in the selpercatinib arm, but they look fairly similar to me. I don’t know if there are going to be meaningful differences between these 2 drugs. I don’t know. What are your thoughts on that?

 Unless you work for 1 of the companies or you’re an analyst, these look much more similar than different.

Anything different in the era of COVID-19 [coronavirus disease 2019] in terms of patient selection or management of toxicities?

 Yes. I’ve been on many COVID-19 calls, and I think we’re getting back to normal. The oral therapy certainly helped. Sometimes we can manage these better through telemedicine than a patient coming in every 3 weeks. That said, I still try to bring these people back so we can monitor that. I don’t try to marginalize their care unless we can do an optimal video, a telemedicine. I’ve gotten video-telemedicine fatigue. In the era of COVID-19, I don’t think the targeted therapies’ implementation or following has changed all that much. Maybe they don’t come back for 1 visit or 2 visits where I would have seen them and done labs. Maybe we do the labs off-site and we do a telemedicine visit rather than come back. I am protective of these patients. I do like to see them every 6 to 8 weeks to check in on them or via telemedicine. I know that’s aggressive, but I do like to lay eyes on them every 6 to 8 weeks just to see how they’re doing.

 Yes. Any COVID-19 changes for these patients?

: The major change is that COVID-19 has accelerated our experimentation with virtual care out of necessity. I’m thinking about which populations it has gone well for and which it has not. For targeted therapy populations, it has gone much better than for my chemotherapy or chemotherapy I/O [immuno-oncology] patients. There are a number of reasons. They tend to have fewer adverse effects, but also, they’re more likely to be socioeconomically advantaged. And along with socioeconomic advantage comes broadband, internet, and social support. Someone else will call if there is a problem. In particular, broadband internet is a big deal. If I can see you face-to-face and we can see each other’s facial expressions and we can understand the words that we’re speaking to each other, that’s going to be a much higher-quality doctor-patient interaction than if the video is cutting in and out and the words sound like a robot and I understand every other word. For our targeted therapy population, I’ll probably do a lot more virtual care even after COVID-19 is over. Some of these patients travel a great distance to see their doctors. You’re at Hopkins the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, so your travel distance is probably hours on average, and you can probably care for some of these patients just fine for many of those virtual visits. My travel distance, because I’m at an academic institution and on clinical trials but also because we’re the state hospital, is quite long. For patients who have good broadband so we can properly understand each other, I’m going to keep doing mostly virtual for my targeted therapy patients.

 That’s not a bad idea. We’ll see how the world changes after COVID-19, whenever that is.

RET Fusion+ NSCLC and COVID-19

Let’s focus on brain metastases, because these are a major source of harm to our patients.

 You and I again have had a lot of experience in the trial with selpercatinib. We've seen it firsthand, and we've obviously read it here, and CNS [central nervous system] metastases are sometimes the bane of our existence, specifically for patients without drivers. We're challenged always, and we try so hard not to give whole brain radiation to patients anymore, and radiation oncologists are finally on board with this in some ways, the advent of novel radiation techniques. Can you give your experience with CNS metastases for RET fusion–positive patients and what we think the prevalence is, and how important is it that we can give these drugs that elicit meaningful responses in the brain?

 Our patients care the most about quality of life, right? They tell us that again and again. In terms of quality of life, of course we need to think about the harm from the disease and the harm from the treatments. In terms of the harm from the disease, the brain is tightly packed upon itself. It's densely packed in there, and any extra mass, such as from cancer, can cost terrible suffering, headaches, nausea, vomiting, confusion, falls. Brain metastases are a big deal in terms of the suffering they cause. And you mentioned the toxicity of whole brain [radiation], that manifests itself over time. In the era when all we had was chemotherapy, unfortunately our patients didn't live long enough to really manifest those neurocognitive effects and be harmed all that much by them, and so we didn’t worry about it that much. Happily, we now have this new problem that we have patients living for years, and over those years they suffer much more from the effects of whole brain [radiation].

In terms of frequency of the problem, our friend and colleague from New York, Alex Drilon, MD, has looked at this rigorously. You mentioned the problem with ALK. He looked at ALK, RET, and ROS1, I believe. And numerically, as we all see in practice, ALK was the highest for cumulative incidence of brain metastases. RET was somewhere in between, and ROS1 was the least. Zooming in on RET, that study found that a quarter of RET patients will have metastases at diagnosis, and 46% will have metastases at some point in their lives. That sounds about right to me.

My experience is consistent with the trial, which is that when you treat patients with one of these agents who have brain metastases, just like the other brain-penetrating agents, like osimertinib against EGFR, or alectinib against ALK, you see dramatic intracranial efficacy. It's quick, it works, and so for all but my most dramatic CNS presentations, I'm using upfront TKIs [tyrosine kinase inhibitors] when I find brain metastases.

 I would agree, well stated. A response rate for selpercatinib in the brain of 90%. It’s a small number of patients, but this mirrors, like you said, some of the data we've seen in other genotypes, and brain metastases are prevalent. These mutations have a tropism to go to the brain. These cells that harbor this mutation have a tropism for the brain. It has altered the way that we handle these patients, and the way that we also communicate with our radiation oncologists, and the way that we communicate with patients. I would agree. 

My experience in many of the patients who we had, at least on the selpercatinib study, is that these responses happened quickly. They're durable, they're meaningful, they circumvent the need for even SRS [stereotactic radiosurgery], or whole brain radiation, or steroids, all of these things that impact quality of life. You and I can agree we're playing the long game with these patients, and it's important, we're not playing the short, 3-inning game. It's trying to figure out how we can sequence therapies and give the best therapies in an ultra-thon, not even a marathon. I think that all targeted therapies have, especially for patients with brain metastases, altered the treatment paradigm and altered the way that we navigate patients through treatment. It's been certainly a welcome change.

 I agree with all that. The only thing I would add as an educational point is that if you're using a TKI to control brain metastases, you need to survey the brain frequently. In my practice, for RET, that means every 3 months. I don't know, do you survey any more or less frequently than that?

No, that's right based on the data, I try to get an MRI for patients with known brain metastases every 12 weeks or 3 months. If they don't have brain metastases, and I'm surveilling, I'd probably do it every 6 months, but I don't think we have any great data on that, and we need to be careful with these patients.

Intracranial Response Rates from RET Inhibitors

 Now, for EGFR and ALK certainly, when we see these response rates of roughly two-thirds, PFS [progression-free survival] of 10 to 20 months, these kind of toxicity profiles, what we've done there has moved the drugs to the front line. If you look at the FDA approval of these 2 agents, the FDA “forgot” to mention line of therapy. These are both indicated for RET-rearranged lung cancer. In your practice, are you planning on using these as frontline agents?

 Yes, you get 1 chance to get it right for lung cancer. You mentioned early in our conversation how unforgiving of a disease it can be, so you need to identify these up front and give your best drug first. This is a call for testing. This means that you must identify it. This means you need to pick an optimal platform and consider plasma as well, so that you can deliver the drug first. Every line of therapy that a patient gets, you lose an opportunity. We know there is drop-off and patients, unfortunately, when their tumors progress, some of them are not candidates for treatments. For all those reasons, I tend to try to give this drug first. I don't know what your thoughts are on this.

 Absolutely. Even in the absence of direct data, I would be doing it, with this kind of toxicity, response rate, and durability. But we actually do have data. The selpercatinib patients who were treated as their first treatment, the response rate was a whopping 85%, and you’re not even out of the box. The FDA has let you out of that. In my opinion, everyone should be tested at diagnosis, and if an activating RET fusion is found, one of these drugs should be used in the first line.

 I couldn't agree more. It's again, it's a call for testing. You can't give the drug unless you do it. And what I hear providers say is that this is only 1% to 2% of patients. But the conversation and the outcome that goes down when you identify this fusion and deliver these types of drugs is different than the conversation that goes down and the outcome that may happen when you're just delivering nonselective chemotherapy or, dare I even say, immunotherapy.

We should touch on that at least briefly. There are some data on immunotherapy in RET positive patients.

 These data come out of France. It's a retrospective analysis. It’s been published in the Annals of Oncology. It was presented 2 years back at ASCO [the American Society of Clinical Oncology annual meeting], the immuno-targeted data. The bottom line is they looked at multiple different genotypes, not only RET but others, and the single-agent activity of immunotherapy for RET-altered or RET-fused non–small cell lung cancer is very low, and the response rates aren't durable and the PFS [progression-free survival] is somewhere between 3 and 4 months. I don't know if those are the data you're alluding to or if there are others….

 Yes, that's 1 of the 3. There are 3 retrospective case series I'm aware of. Two of them looked absolutely horrible. One looked like about a 30% response rate, if I remember right. If you sum them all together, it's about a 10% response rate, as you say, not great durability. And as well, there is anecdotal experience that the toxicities of the TKIs [tyrosine kinase inhibitors] may be worse after PD-1s. When considering both the opportunity cost in terms of drugs like pralsetinib and selpercatinib, as well as just the lack of efficacy, I wouldn't say I would never offer a PD-1 drug to a RET-rearranged patient, but it wouldn't be my first- or second-line treatment. It would be a deep salvage that I would have to have a conversation with the patient about. 

 Yes, I think the single-agent activity, if I'm going to give it, it may have to be in combination with chemotherapy. But I would agree a consideration for immunotherapy in this case would have to be at a salvage, no trial or anything else going on for that patient, in which we were fourth, fifth line; it certainly may be something to consider.

Importance of Frontline RET Inhibition in NSCLC

 Let’s start with the FDA approval of pralsetinib and selpercatinib in RET fusion–positive lung cancer. You can start with the arrow. These are the more recent data that were presented and led to the second drug that is FDA approved. Why don't we start there with, with the pralsetinib data? We had an update from ASCO [the American Society of Clinical Oncology meeting 2020]. We had original presentations, and we’ve had some updates. Give us your 10,000-foot overview of the data and what you think.

Well, at 10,000 feet, these are both beautiful drugs. These have limited adverse effects, and it's real targeted therapy. I should define what I mean by that. In lung cancer we have set a minimum bar of a response rate of about 60%, and a minimum PFS [progression-free survival] of about 10 months as the beginning of what we call true targeted therapy. And with modern agents, we've appropriately gotten greedier and expected better, both in terms of efficacy and tolerability, and we're seeing that here. We cleanly meet that bar, and we cleanly crush chemotherapy. We crush the so-called dirty TKIs [tyrosine kinase inhibitors] with both agents. I'll start with pralsetinib, but I do want to disclose, just to be frank, that I was a selpercatinib investigator. I believe you were as well, but these are both great drugs. 

We're looking here at ASCO, at phase 1 dose escalation data, followed by a phase 2 dose expansion study, so no randomization here. Appropriate to the phase 1 design, the primary end points were response rate and safety. At ASCO, we saw data on 354 patients. Just over half of those had lung cancer. All patients were previously treated with a platinum doublet, and nearly half also had a PD-1 or PD-L1 inhibitor.

The intention-to-treat population response rate was 58%, and happily the median duration of response has not yet been reached, but the 95% confidence interval lower bound is 11.3 months. We know that even if everything terrible happens to every subsequent patient, we've met that bar. And of course, that doesn't look like it's happening. Now with modern TKIs, in addition to expecting that response rate to edge up, the toxicity to edge down, the PFS to edge up, we’ve also started to expect brain penetration. And we got that here. In a limited number of patients, pralsetinib certainly delivered. Nine patients entered the study with measurable intracranial disease. Intracranial response rate there was 56%, including some complete responders. Overall this is a very well-tolerated drug. We saw a number of low-grade toxicities, but very few at high grade. The most common of these were increased LFTs [liver function tests], anemia, constipation, and hypertension. And at high-grade, hypertension and neutropenia. I have no clinical experience with pralsetinib, but what I've heard from those who have had it is that this is a very good drug, very efficacious, rapid dramatic responses and very well tolerated. With that, I'll turn the tables on you and ask you to talk about selpercatinib.

 You made my job easy, because the thing is, it is very similar. We can talk about cross-trial comparisons and the things that we do. But selpercatinib is a highly selective RET-directed therapy also recently published, you and I were both investigators in the study, in the New England Journal of Medicine and led to the FDA approval. It is looking at 105 patients who had RET fusion+ non–small cell lung cancer who had previously been treated with a line of platinum-based chemotherapy. Also included were roughly 40, 39 patients who were untreated. And similar to the pralsetinib data, the response rate for the 105 previously treated patients who had received platinum-based chemotherapy, the response rate was 65%. The duration of response—that's important. We talk about responses, but are these responses durable? The median duration of response in these patients was around 18 months. It's remarkable for a tyrosine kinase inhibitor, and probably is on the far end of duration of response for the tyrosine kinase inhibitors that I'm aware of for lung cancer, in terms of their ability to elicit durable responses. Looking at the roughly 40 patients who were treatment naive, it looked like a response rate close to 85% to 90%, it’s remarkable, with a duration of response that's ongoing.

Importantly, similar to the pralsetinib data, there were patients in this trial who had measurable central nervous system disease, or CNS metastases, who were enrolled, and the intercranial response was 91%. All the data that I share with you are highlighting why it got approved fairly quickly, similar to pralsetinib. The responses are meaningful, they happened in platinum-refractory patients as well as treatment-naive patients. The responses are not only meaningful but durable, with a median duration of response anywhere from 17 months to 20 months. And there is an intracranial response rate. These drugs can cross the blood-brain barrier and elicit meaningful responses in the brain. And as you and I know Jared, this alters the way that we marshal patients through treatment. Where they used to get radiation therapy, they can just get a TKI that can take care of disease above the neck and below the neck.

Looking at toxicities, we've put a fair amount of patients on this study. We can both agree the drug is very well tolerated. But looking at the toxicity, there were some VEGF toxicities here, hypertension was seen, grade 3 hypertension was seen in roughly 15% of patients, and then LFT abnormalities. And then an interesting adverse effect that I saw a couple of times in my patients is hyponatremia, which is a little bit of a challenge to manage. But overall, it is a very clean drug, a well-tolerated drug that elicits meaningful responses. For me, these are both a welcome change for the patients with RET fusion+ lung cancer.

FDA Approval of RET Inhibitors in NSCLC 

 I want to address our attention to a much harder question that I know you don't want to answer, and I'm going to find uncomfortable too, but it will be of extraordinary utility to our community partners. When we do education events like this, we all talk about a broad and sensitive next-generation sequencing panel, or we may get a little more specific, and say one with a good RNA fusion panel, right? Our colleagues sitting at home are asking the question, “What should I order tomorrow with my white coat on; what is the best panel for my patients?”

 Based on the platforms’ technology, I would say at Johns Hopkins Sidney Kimmel Cancer Center the safe answer for me is that we've moved to a DNA- and RNA-based platform, we do everything in house. But playing the role of somebody who doesn’t have that in-house capability, I’d recommend Caris Life Sciences and Tempus as 2 platforms that have a DNA- and RNA-based sequencing platform. FoundationOne also is moving that way, and you can order through FoundationOne a heme sarcoma panel. But on a routine basis, not that I have any dog in the fight here with these platforms, just looking at their technologies, if we're asking for a DNA- and an RNA-based platform, those are the 2 platforms that are the furthest along. I don't know what your thoughts are on that.

 We tend to use Tempus at my institution. I don't know a lot about the Caris platform, honestly, and I won’t address what I don't know well. Foundation’s heme panel is fine, but I've had some nonscience-based issues with it. More specifically, I've asked for it from community partners and had blood drawn. The word hemes has been sort of confused with plasma, and as well I’ve had at least 2 payers refused to pay it because the patient doesn't have lymphoma or leukemia. The name trips them up. Yes, I think scientifically it's a fine panel. I use Tempus just more for practical reasons than scientific ones, and I'm quite happy with that. I don't know much about the Caris platform.

 They're both good. Again, I think our comments come on the line of just where the technology is and what technology suits the optimal interrogation for our patients.

 I did just want to arm our viewers with something that you can order commercially. I would also like to arm you to note that, just because the test says that it detects something doesn't mean that it actually does so very well. RET is one example of this. Another example that we have fresh data on is MET exon 14 deletion, where if you have a DNA-only panel, you're almost as likely to miss it as to catch it despite the DNA panel saying that they evaluate from that.

 That's right, and good point. Practitioners out there need to know that RNA-based platforms are preferred for the detection of fusions, and there are commercially available assays that probably do this better than others.

 And payers pay for them, right? It's not an academic, pie in the sky, can't get it, crazy expensive thing. It's usable in everyday practice.

Best Practices for NGS Selection in NSCLC 

 I’m not getting away with doing 1 of these without talking about plasma. What we’ve learned from some critical data sets is that when you add plasma to tissue at the same time from the same patient, you increase your likelihood of detecting an alteration of interest, which would allow you to give targeted therapies. Tissue is fraught with challenges. It is still the gold standard in my mind, but it certainly is fraught with challenges in terms of heterogeneity depending on where the needle is, tissue sufficiency. You mentioned tissue stewardship, immuno-stained tissue exhaustion. The journey the tissue takes from procurement from the lung to the pathologist and the result is quite incredible. There are so many steps along the way where things can go wrong and enters plasma. It’s an easy test to do. You’ve heard me say this joke before: You and I may have a tough time identifying a good interventional radiologist, but we all know a good phlebotomist. And you know, 10 cc of blood, and we’ve learned that adding blood to tissue can enhance capture of alterations that leads to targeted-therapy treatment.

But the question comes up, and I’d just be curious to know—fusion detection in plasma maybe a little harder than just mutations—your experience with plasma and how you see this all playing out now and in the future for all mutations but also for RET.

 You and I have spoken about this over time. I will confess to you, however many of our friends are watching this, that I was a little wrong on plasma. My feelings on it have evolved as data have evolved. I was a little skeptical of plasma when it was new, and increasingly I’ve come around to your viewpoint that it’s very much additive. It’s additive when you have a lack of tissue. You can sometimes find things that you don’t find in tissue, particularly in addressing heterogeneity. In my practice, what is most relevant is that it’s fast, right? You talked about the journey of tissue. At some institutions it can take a week or 2 from biopsy to getting that tissue in the mail, never mind the amount of time it takes to do a comprehensive next-generation platform. There is a tremendous role for plasma. I do think that when we’re talking about fusions like RET, this is a place where it’s weaker in terms of sensitivity. If you pick it up, it’s real. You can action it. You don’t have to question that, but if you don’t find it and you don’t find another oncogene driver, then you have to go to a good tissue-based test. What I mean by that is that a test can be negative in 2 ways, right? If I send off a liquid test, and I get KRAS G12V, it’s negative in the sense that I can’t do anything with that to help my patient. I’m bummed out, but I can be done. I know the answer. I don’t like the answer, but I know the answer. On the other hand, if I don’t find anything that’s a clear driver, that’s when it’s really important to go to tissue for greater sensitivity.

 Great point. Knowing that a negative really doesn’t tell you anything—a positive, you can kind of rule in. But for a negative, in terms of negative driver mutation or known driver or known alteration, you need to reflex the tissue. That’s an important point. The thing that also comes up is not just the routine use of plasma, but also how often should we be doing next-generation sequencing on our patients? Is it just at 1 point, or is it through a continuum? For me, we’re just starting to learn about mechanisms of resistance for RET fusions in lung cancer with gatekeeper mutations and mirroring some of the things that we’re doing in ALK, RAS, and EGFR. I tend to want to know, at least from a research standpoint, what’s going on for patients. Now I will be transparent. Of all the patients we’ve had on selpercatinib, who are RET-fusion-positive, they haven’t progressed. But I don’t have a lot of experience with rebiopsying these patients. What are your thoughts on that? Do you rebiopsy patients upon progression for all targeted therapies? Should we do it for RET patients?

 We’re doing it sometimes because we’re an academic institution and that’s what we’re here to do. But when I counsel patients about this, I do counsel them that it may not be actionable. It may not be useful clinically. I tend to use a little more liquid here because even knowing the limitations of liquid that we’ve talked about, at least I don’t have a risk of hurting my patient in doing it. But honestly, if 1 of our community partners said, “I’m just not doing that now,” there is nothing wrong with not retesting in the case of RET on progression because we don’t know what to do with it.

Use of Liquid Biopsy for RET Detection 

 As wonderful as these drugs are, we can’t take action with these drugs unless we find RET. This is true of RET because it’s been historically an EGFR, ALK, RAS1 and most recently a spate of others in lung cancer. It’s natural to turn our conversation toward testing. Perhaps I can start by asking you how do you find RET?

 It depends on when you ask this question. If you would have asked maybe 5 years ago, you could say that, you know, picking up rearrangements may be optimally done by FISH [fluorescence in situ hybridization], dare I say. I think that the needle is certainly moving in the right direction. Historically—you can probably explain this a little better based on the biological platform—testing for fusions like ALK, RAS, NTRK, and RET, FISH has been 1 of the ways we’ve been able to do that. Another way ALK has been done is with IHC [immunohistochemistry], looking at the protein product. I think we’ve got newer diagnostic, more sensitive platforms that do a deeper interrogation called next-generation sequencing [NGS].

If we look at next-generation sequencing—that’s a buzzword, but there are different platforms for next-generation sequencing. There are certainly DNA-based platforms commercially available, also in-house, and there are RNA-based platforms as well. What we’re beginning to learn is that RET fusions can be detected by DNA in NGS-based platforms, but the sensitivity increases dramatically when you layer in an RNA, NGS platform. I will give you my anecdotal experience because we participated in some of the trials with selpercatinib. FISH is not an ideal way to pick these up. It often misses them, and even DNA-based NGS platforms may miss these fusions.

 It may be worth noting that FISH is highly operator dependent, particularly for RET. I mean, to do RET FISH right, you need to do a lot of RET FISH. If someone is doing a lot of RET FISH you probably have a good next-gen platform.

 Yes, I will tell you that, given all the things you just said, even at Hopkins [Johns Hopkins Sidney Kimmel Comprehensive Cancer Center], we had an internal platform that we use religiously on all our patients. We’ve shared stories about this before. We were using FISH for our ALK, RAS, RET, and NTRK until about 3 months ago when we realized how many of these alterations and fusions we were missing. Given all the reasons you just stated, and we have now moved to a DNA and an RNA panel in parallel, so we can optimize our genetic interrogation and do comprehensive genomic profiling. Because as you mentioned, if you can’t find the mutation or the fusion, you can’t give the drug. There is an educational gap on optimal platforms that need to be used or utilized to identify all these mutations. Jared, you and I have spoken before. Not all commercially available assays are the same. Some may be better than others in detecting fusions, and if 1 of the more important components of this whole discussion is testing. I don’t know what your thoughts are on this and what you guys are doing at Carolina Lineberger Comprehensive Cancer Center. Is it any different in how you view this changing over time?

 I strongly agree that the testing modality matters. We’ve never had RET FISH, but we’ve always been heavily invested since the next-generation sequencing. As you’ve outlined very nicely, it’s more comprehensive. It is more sensitive to multiple changes, including some changes older than RET. Critically there’s also a tissue stewardship issue, where if you’re doing lots of serial testing, you’re using up the tissue and using up a lot of time too, which can matter for patients.

There is also an issue of complexity. If you think about our community partners, they don’t have the privilege that you and I have to nerd out on 1 narrow area all day, right? My wife makes fun of us that we we’re left-little-toe doctors. You know, if all you study is the left little toe, you don’t know how to treat, I don’t know, a fracture of the arm. It’s not as hard to be an expert in the left little toe. Even the most brilliant of our community partners, I have no idea how they keep up with a new change that 2% of lung cancer, while they’re also keeping up with breast cancer and benign heme disorders. I’m impressed by it, but if you translate that to the practicality of the busyness of these people, even with their extraordinary intelligence and diligence, this needs to be simplified for them. What I like about a good next-gen panel is that instead of having to order EGFR, then ALK, RAS1, RET, and so forth, you can just press the easy button and order 1 broad comprehensive path.

 That’s very well stated. For all of us, I think you would agree that all of us are trying, even as left-toe doctors, to educate others. The left little toe. That up-front NGS testing should be done on all advanced-stage patients and some new data are suggesting even for adjuvant TKIs. It’s not the topic here, that maybe earlier stage is important too, but at least for advanced adenocarcinoma of the lung up front, NGS testing should be done, and we can’t give drugs unless we identify the target.

Optimal Detection of RET Fusions

 Prior to these drugs, your options were chemotherapy or nonspecific TKIs [tyrosine kinase inhibitors]. By 

, I mostly mean cabozantinib and vandetanib. More recently, alectinib has been approved for 

 activity as well. But most of the clinical experiences are with the first 2 of those agents. Scientifically, these are drugs not targeting 

 but rather targeting other targets, particularly VEGF receptors and then what we sometimes colloquially referred to as dirty kinase inhibitors, meaning that they have broad activity in the kinome, and that’s why we’re able to bring them in here. Part of that dirtiness happens to include 

. But in terms of thinking about their adverse effects and their efficacy, it’s important to note that they’re not particularly potent against 

. They have lots of activity elsewhere that’s not helpful in these cancers but does lead to toxicity. In summary, these agents are not that great in lung cancer. Their response rates are low, their PFS [progression-free survival] is low, and their toxicity is quite real.

Only 1 of these agents has randomized data, and that is vandetanib. These data are not against another agent, and vandetanib is not even in lung cancer. It’s against placebo in medullary thyroid. The best experience I can cite for you is that response rate was better than placebo. Interestingly, placebo had a response rate. PFS was better than placebo, although medullary thyroid can be invalid, and you get a decent PFS with placebo alone. Overall survival wasn’t even budged despite being a large and well-powered trial. Efficacy was not what we’re looking for, and toxicity is pretty bad with these agents. Vandetanib, for example, has a black box warning for both torsades de pointes and death. We see a lot of GI [gastrointestinal] toxicity, hypertension, and LFT [liver function test] elevations. That nonspecific access is critically important from a human standpoint but not captured in toxicity tables. That spectrum of “Doc, I feel great” to “Doc, I feel awful.” Patients feel awful on cabozantinib and vandetanib. These are not patient-friendly drugs.

 Have you used these drugs in your clinic? I don’t have a lot of experience with these drugs. I’ve used it maybe once or twice. I would agree with you that the toxicity can be prohibitive. They have a lot of off-target effects. They aren’t that selective. The responses, if they are there, are not that durable in lung cancer. What do you experience with vandetanib and cabozantinib in non–small cell lung cancer?

 My secret as a thoracic expert is that I also treat head and neck cancer. In that context, I do have a decent amount of experience using these agents for medullary thyroid. Medullary thyroid and lung are different diseases, though. The biology is different as you explained very nicely earlier, but clinically they look different. My most common and favorite treatment of medullary thyroid cancer is a chemotherapy with absolutely no adverse effects, known as no treatment at all. We watch medullary thyroid all the time. We’re watching the bulk of disease, its anatomic location and its growth rate. In summary, you asked if it is a threat to the patient, right? Is this disease going to risk to the patient’s life or quality of life? Imaging thyroid is very often no, and we have the privilege of observing.

In lung cancer we almost never choose that path. In fact, just about every time it’s been tried in a clinical trial, either in an unselected population or in a highly selected 1, active observation has gone disastrously. That’s because, unlike medullary thyroid, the toxicity of lung cancer itself is awful, perhaps even worse than some of our most awful cytotoxic chemotherapy agents. I have used these in medullary thyroid. You do see disease control. It’s better than the awful and completely inactive chemotherapy that people sometimes used historically. But even in medullary thyroid, where it looks better than in lung, one can’t have great enthusiasm. Because we’re in a lung program, I’ll shift quickly back to that and just leave a summary statement that these drugs are absolutely and completely replaced by the new specific TKIs in 

 I agree with you. In my experience with the dirty TKIs, as you called them, it is the cabozantinib and vandetanib not eliciting meaningful activity and toxicities. The times I’ve used them I’ve struggled a tremendous amount with rash and diarrhea. These are not easy drugs to give, and this is a welcome change to have selpercatinib and pralsetinib, which we’ll talk about next or at least further down the line. They certainly have altered the way we perceive these types of tumors and the way we treat them.

Multikinase TKIs for RET Fusion+ NSCLC

Hello, I’m Jared Weiss. I’m a thoracic oncologist at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill. It’s a privilege to be joined by a good friend and colleague, Dr Benjamin Levy, also a thoracic oncologist at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

 genetic alteration, and why is it an attractive therapy for targeting?

 proto-oncogene like many oncogenes encodes the transmembrane receptor tyrosine kinase, and we were well aware that constitutive activation of tyrosine kinase can lead to uncontrolled growth. For 

, this constitutive activation can occur through 2 distinct mechanisms, and it’s important to talk about these 2 distinct alterations. 

 can be altered in 2 distinct ways. No. 1, it can be a point mutation. These point mutations are found predominantly in medullary thyroid cancer, which comes in different shapes and varieties. There is obviously a familial form of medullary thyroid cancer, of which 

 mutations make up about 90%, and then there is a sporadic medullary thyroid cancer, and 

 mutations are about 60% of those. Mutations are important specifically for thyroid cancers, but perhaps more relevant and germane to our discussion are fusions.

Fusions, just like point mutations, can lead to an altered receptor tyrosine kinase that can be constitutively activated. Fusions, interestingly, are seen in papillary thyroid cancer, but they’re more relevant: 1% to 2% of all non–small cell lung cancer harbors a 

 fusion. It’s important that this nomenclature distinguishes between 

 fusions or arrangements because both can be relevant in solid tumor cancers. Both can lead to constitutive activation of an altered receptor tyrosine kinase. But perhaps more relevant here are the fusions that seem to predict efficacy to tyrosine kinase inhibitors [TKIs], which we will talk about. Mutations in lung cancer, 

 mutations, don’t seem to do that, so it’s a little confusing. For the purpose of this conversation, 

 fusions are what we’re trying to identify in non–small cell lung cancer.

There are 2 new drugs, and so a natural segue may be to ask what the rationale is for actioning these targets with these drugs?

We have a track record in lung cancer of developing tyrosine kinase inhibitors. The whole goal of developing these drugs is that, 1), they’re selective for 

 tyrosine kinase, so they have very few off target effects, and 2), they are potent, so they can elicit responses below the neck and across the blood-brain barrier. They’re highly selective for the 

 mutation. Given that 2% of all lung cancers have 

 fusions, it makes a lot of sense, given our track record, to develop tyrosine kinase inhibitors that selectively target and shut the constitutive activation of the receptor tyrosine kinase off. It’s been nice to have a track record with this in 

I just want to mention that similar to the 

 fusion, there are different partners. The most common partners for 

 fusions are to the KIF5B. That’s probably 70% of all the fusion partners, but there are other fusion partners as well. CCDC6, NCOA4, these are also fusion partners that can exist. I mention these only because we’re still learning about whether fusion partners matter in terms of the efficacy these of these drugs that we’re talking about. It makes a lot of sense, and we’ll talk about this. Jared, we’ll flip the switch here, and I’ll start asking you some questions about the approved drugs prior to the approval of these TKIs. But I think you would agree that these new drugs, for which we will go in and deep-dive, have been a real game changer for patients with 

Benjamin P. Levy, MD, John Hopkins Sidney Kimmel Cancer Center

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