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New Targeted Therapies for RET Gene in Lung Cancer

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Published on December 10, 2020

Information on RET Fusion-Positive Lung Cancer and New Targeted Therapies

The majority of lung cancer patients have non-small cell lung cancer (NSCLC), and a small percentage of those patients have the RET gene – also known as RET fusion-positive lung cancer. RET stands for “rearranged during transfection,” but what exactly does it mean for lung cancer patients, and what treatments are available? 

In a recent “Answers Now” segment, lung cancer experts met with a RET lung cancer patient and caregiver to discuss these questions and share news about exciting new targeted therapies for the RET gene. Host and patient advocate Michele Nadeem-Baker was joined by Dr. Viola Zhu, Associate Clinical Professor of Medicine at University of California at Irvine, Dr. Karen Reckamp, MD, Director of Medical Oncology at Cedars-Sinai Center, and Lisa Goldman, lung cancer survivor and patient advocate, for this segment.

This program is sponsored by Blueprint Medicines. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.

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Transcript | New Targeted Therapies for RET Gene in Lung Cancer

Michele Nadeem-Baker: Hello, I'm Michele Nadeem-Baker for Patient Power, welcome. I have a blood cancer, CLL, but my father had lung cancer and I was one of his caregivers. So this is a very special and near topic for me. And I'm so happy to be with you today. And joining us about discussions in RET lung cancer are Lisa Goldman, a lung cancer survivor and advocate, and the founder of the ROS1ders. And we have two amazing doctors, Dr. Karen Reckamp, Professor in Medicine, Director of the Division of Medical Oncology at Cedars-Sinai Medical Center and Dr. Viola Zhu, Associate Clinical Professor of Medicine at the University of California Irvine in the Division of Hematology Oncology. Welcome, everyone. To kick us off, we have a quote from a recent interview on Patient Power conducted with Dr. Vivek Subbiah of MD Anderson Cancer Center in Houston.

Lisa Goldman: “A comprehensive genomic testing should be part of diagnosis in lung cancer. One obstacle to prevent metastasis or relapse is a limited ability to select effective targeted therapy. Genomic testing at the outset is a very promising way to more accurately determine prognosis, diagnosis, and therapeutic treatment decisions that we can hone.”

What Is Comprehensive Sequencing, and Why Is it Important?

I wanted to ask Dr. Reckamp this first question which is, how available is comprehensive testing, so that patients who have the RET positive fusion can be treated with targeted therapy?

Dr. Reckamp: The next generation sequencing and comprehensive sequencing that's required now for... I would say all lung cancer patients, especially with advanced disease is pretty ubiquitous now. And most centers or there's a number of platforms that tissue can be sent out to. And really, if you're not going to treat breast cancer without knowing, ER, PR HER2 status, you really shouldn't be treating or starting treatment on a lung cancer patient without now knowing EGFR, ALK, ROS-1, RET, MET, and NTRK before treating them. And so the list is long and the best way to get to those answers is with next generation sequencing and comprehensive genomic sequencing. And RET is a rare enough alteration that it often can be missed if you're not doing a comprehensive sequencing.

How Do You Identify a RET Gene Mutation in Lung Cancer?

Lisa Goldman: Great, so Dr. Zhu, can you explain a little bit how these tests identify a RET alteration and is there any kind of gold standard for identification of this marker? 

Dr. Zhu: Generally speaking, when I approach a newly diagnosed non-small cell lung cancer patient, particularly stage four, or even particularly adenocarcinoma, we would generally do two types of genetic testing. One, is to get the tissue to round the comprehensive molecular analysis on the tissue, on the biopsy specimen or surgical specimen. Two, is to get a so-called liquid biopsy, which is simply to draw blood to do the same type of molecular analysis. I echo what Dr. Reckamp just mentioned that it's really important to run comprehensive genomic testing. And nowadays insurance covers most of the commercially available panels we are routinely using in our daily practice.

Lisa Goldman: So, you don't need to ask your doctor for a specific one. There's not a gold standard, but there are several reliable places to get the testing done. It sounds like.

Dr. Zhu: Yeah, I think the key is not to ask your doctor for the RET testing specifically, the key is to ask your doctor for comprehensive testing. So we're really looking to uncover any potential driver mutations.

Michele Nadeem-Baker: We have a question from the audience that pertains to this and it's on video.

Ginger: Hello, my name is Ginger Head and I'm from Jackson's Gap, Alabama. I'm a patient at MD Anderson in Houston, Texas. I am interested in finding out if you are currently are diligently working on developing other medications that will target the RET mutation.

Dr. Reckamp: It's an important question because even though we've made progress in targeting specific genomic oncogenic drivers, most of these cancers can progress and develop resistance. And so finding the next selective RET inhibitor becomes very, very important. There are a number of multi targeted tyrosine kinase inhibitors that we've used in the past that do target RET, but less specifically. So drugs such as cabozantinib (Cometriq), sorafenib (Nexavar), vandetanib (Calpresa), they've all been tested in looking at RET, but have modest response rates. So some of these might be effective in the future, but they're really not moving the field forward.

There are some more selective RET inhibitors. One is from a company, Turning Point, TPX-0046, that's been presented. And these do overcome some of the mutations that have been described that have developed in response to selpercatinib (Retevmo) and pralsetinib (Gavreto), which are the approved drugs at this time. So there's a lot of work and understanding the resistance that occurs and developing new drugs to overcome that resistance. And we understand that our patients need this. I would also just say that we also know that pemetrexed (Alimta) based chemotherapy is also very effective in RET lung cancer. And so chemotherapy can be an effective tool in the treatment of this RET fusion lung cancer.

What Are Targeted Therapies, and When Should They Be Administered?

Lisa Goldman: So that actually leads to one of my other questions, which is when should a patient begin targeted therapy? Do you start with the systemic chemotherapy or some other type of broader approach first and then switch to targeted, or do you use the targeted therapies as a first line treatment?

Dr. Zhu: It really depends on the clinical situation. If somebody, for instance, is very symptomatic, has a high disease burden that really requires treatment while you're waiting for molecular testing results to come back, you may want to start a patient on chemotherapy, like a couple platinum pemetrexed while waiting for the test result to come back. If the result comes back with a driver mutation with available targeted therapy options, then I would discuss with my patient about switching to the targeted therapy versus continuing chemotherapy.

Generally, most of my patients would rather take a pill, so they would opt to switch. On the other hand, if the patient is relatively asymptomatic with very low disease burden, then I would even argue to just wait while waiting for the molecular testing results to come back, to start a very effective targeted therapy, if available. And that conversation is often harder to carry out, as you can imagine, patients are often very anxious, but it is our job to convey the message that sometimes, waiting is necessary in order for us to find out which targeted therapy is the best treatment option.

Dr. Reckamp: And I would agree with Dr. Zhu. And one important point too is often we get the PD-L1 results back before we get the genetic testing results. And if that PD-L1 is above 50%, it would indicate that somebody might be a good candidate to receive immunotherapy as a single agent therapy. And that gets people very excited and want to start today. And again, as we do often, we caution that immunotherapy is often not very effective in tumors that have oncogenic drivers, such as RET. Response rates with single agents are probably less than 10% and that the majority have tumor growth on these drugs when they're given alone. And so they're not the best single agent treatments. And so waiting until we get those results and treating with the right treatment first, the best treatment first is the most important thing. And again, that it's a long conversation to help a patient understand that it's actually better to wait than to jump forward and get this exciting immunotherapy that again, may not work.

Dr. Zhu: Exactly because oftentimes we also have very effective chemo-immunotherapy combination regimens now available. So while waiting for the test results, some patients may be starting the chemotherapy immunotherapy combination already. So it is actually my practice to... if I suspect a driver mutation, for example, in a never smoking lung cancer patient, I would often just start them on immunotherapy, if starting in treatment is necessary to control the symptoms and disease burden while waiting for the test results, because there are several retrospective analysis showing that if you try to sequence somebody from immunotherapy to targeted therapy, the risk of toxicities may be higher, including pneumonitis for instance.

Lisa Goldman: So, how long of a wait are you talking about?

Dr. Zhu: Meaning, wait for the molecular testing results or?

Lisa Goldman: Yeah.

Dr. Zhu: As soon as I see the patient in the clinic, I do the liquid biopsy on the first visit. And the turnaround time is less than two weeks. So I think that's a reasonable timeframe to wait. And if the patient has not been staged properly, they also need this time to get a PET scan or brain MRI, for example. The tissue testing sometimes can be a little longer because you would have to retrieve the tissue from pathology or from an outside institution. So that takes a little longer. Dr. Reckamp, what is your experience in terms of turnaround timing in your institution? I'm curious.

Dr. Reckamp: For tissue testing, it's about two weeks. And sometimes with communication, we can get those results verbally transmitted to us before that, but it's about two weeks. And blood testing can be about a week to 10 days. And I'll tell you, with COVID, we've all gotten a little bit creative and there are times where I know a newly diagnosed patient is coming or I'm going to do a virtual visit and we'll get somebody sent out to their home or have them go to their local lab station. And we'll get the blood test sent to the vendor for liquid biopsy and genomic testing through blood. And so that way we've been getting it back closer to when we see the patient, which is even more helpful.

Dr. Zhu: Wow, I may adopt your method very soon. So, actually coming back to Ginger's question about the next generation RET inhibitors. I just like to mention, yes, the TPX-0046 trial is actually ongoing at my site. We are actively recruiting patients, and this is from the company Dr. Reckamp has mentioned TP therapeutics. The drug is specifically designed to perhaps overcome the resistance mutation you may see with either selpercatinib or pralsetinib. And there's another RET inhibitor co-developer by Taiho and Helsinn, I believe the company is based maybe in Switzerland. It's a compound called TAS0953. They are opening their phase one trial as well. We will have to see what kind of efficacy and safety it can provide.

Can a Drug Resistant RET Fusion Mutate into Something Else?

Michele Nadeem-Baker: So, I have a question for both of you starting with Dr. Reckamp. And this is from the audience, “Do you know the time for RET fusion to mutate into something else after resistance to a drug occurs and what is the most common mutation that's commonly seen? And what is that?”

Dr. Reckamp: So those are great questions. And so to the first half is how long does it take? And that is somewhat of a moving target at this moment in time, because we have early data from these studies and we have, for selpercatinib, what we call progression free survival. So time for the cancer to progress is kind of what that gives us. And it's about 18 months. And then this duration of response, which shows how long the response can last is about 20 months. So they're usually around the same amount of time. But those numbers are early because this is based on a phase one trial where patients are put on. And there are some patients who haven't been on very long. And so these numbers can shift and usually potentially could get longer.

So, it's not a firm number, but we'd say somewhere around 18 months is the median. So 50% will have the tumor grow within those 18 months and 50% won't. So there's a large number who will continue on beyond that. So I would say for cancer treatment, it's a relatively long time, insufficient, but relatively long. And then for pralsetinib, the follow-up is even shorter. So the duration of response was not reached yet for pralsetinib. And so we don't have those firm numbers, but if we say somewhere around 18 months to two years and we really know very little about what resistance occurs. Most of the data we have are based on the multi targeted tyrosine kinase inhibitors, because more people have received them. They have these... what they call solvent front mutations that are probably the most common. And that's what these new novel inhibitors that Dr. Zhu was talking about will combat.

But there are likely other mutations and other bypass pathways that we haven't seen. And interestingly enough, RET fusion is an alteration that occurs in patients who progress on drugs, like osimertinib (Tagrisso) for EGFR lung cancer, so they can get other types of mutations. But our level of understanding is still at the beginning. And it's something that we need to study and learn.

What Are the Similarities and Differences Between the Two FDA-Approved RET Inhibitors?

Lisa Goldman: So, Dr. Reckamp, how does a patient or a doctor choose between the two RET inhibitors that have been fast tracked with the FDA?

Dr. Reckamp: So, I think we should ask both of us this question because it's the million-dollar question. I personally have more experience with selpercatinib. Their drugs are very, very similar, so they're very highly efficacious. They hit their target very well. They penetrate the brain and cause responses in the brain very well, and they're very well tolerated. And most people are only going to probably see one of these in their lifetime.      

It's one to 2% of lung cancers. And for people like Dr. Zhu and I, who see lung cancer every day we see more of them, but for people who are in general practice, this may be one patient that they end up seeing or one patient every several years. So at this moment, I don't think that there's a significant difference between the two and they're both incredibly good drugs. What we don't know is whether you can use one after another. They're very similar. And so that data is also lacking, but I'd ask Dr. Zhu, what's your favorite drug?

Dr. Zhu: I'm trying to avoid this question, Dr. Reckamp, but I totally agree with you that I think it's really a blessing that nowadays we had two very effective targeted therapy drugs for RET fusion positive lung cancer. And by the way, this RET fusion mutation can be even found in other types of solid tumors, such as thyroid cancer or pancreatic cancer. So I agree, I think two drugs are both very effective. You're talking about response rate around 50 or 60% in patients who have previously seen chemotherapy. And then the response rate can be even higher for a treatment naive patient. And they both have CNS activities, which we really care about in terms of talking about targeted therapy. So they're both very well tolerated in my experience.

Can Someone with a RET Marker Test Positive for Additional Markers?

Lisa Goldman: One of the questions I had was, can somebody who has tested positive for the RET marker, test positive for additional markers? Can you be eligible for multiple types of targeted therapies?

Dr. Zhu: Yes, that's a very, very good question. And generally speaking, we believe all this driver mutations, including EGFR, ALK, ROS-1, RET, MET, HER2, and NTRK, they are mutually exclusive meaning that if you have one driver mutation, most likely you're not going to have another driver mutation. When your test results show two mutations simultaneously, it's important to review your test result first to make sure this is the accurate testing platform and this is an accurate result. I have seen falsely positive results in some patients. That being said, very rarely, you can see case reports of somebody with two simultaneously discovered driver mutations.

And the other thing actually, Dr. Reckamp has briefly mentioned, is RET fusion can be an acquired fusion for someone with EGFR mutations. For example, if your tumor is originally discovered to have EGFR mutations with treatment with EGFR targeted therapies, over time, your tumor may develop resistance and to even have a RET fusion. So, in that instance, it's an acquired resistance mechanism. So, it may be necessary to target both the original EGFR mutation, as well as the RET fusion and simultaneously to treat your cancer.

What Are the Side Effects of Targeted Therapies?

Lisa Goldman: Speaking of, you say these drugs are very tolerable but can you talk a little bit about the side effects that patients experience on them?

Dr. Zhu: I think for both drugs we would need to monitor liver functions as well as blood pressure because both elevated transaminases and hypertension have been reported for both drugs. Now for selpercatinib, quite uniquely it had these very rare incidents of hypersensitivity reaction which seems to have occurred more often with patients with prior immunotherapy. So again, Loxo Lilly is looking at this data and is going to educate the community on how to manage this very rare, less than 10% perhaps toxicity. QTc prolongation may occur so sometimes getting periodic EKG check is important.

Now for the pralsetinib, the drug has activity against the JAK2 meaning that sometimes a myelosuppression may occur. So it's important to monitor the hemoglobin or platelet counts as well. And very rarely you may or may not see pneumonitis, that has been reported by the trials. So again, monitoring any respiratory symptoms is important, but I do want to mention that both drugs are very well tolerated in general.

I think, with all driver mutations, it's really important to understand the resistance mechanisms so that we can develop another drug to combat the resistance. And if you recall, Dr. Reckamp has briefly mentioned about some of the resistance mechanisms. So, I like to mention that, MET amplification has been reported as a resistance mechanism to patients receiving either selpercatinib or pralsetinib. So, it was a nice paper published by Dr. Jessica Lamb from MGH in collaboration with several sites, including us and Dr. Ben Solomon from Australia originally reported the solvent front mutation, the GA10. So that's why I mentioned specifically about TPX-0046, that may have activity against this solvent front mutation. MSKCC, Dr. Alex Drilon’s site has also published a paper describing four cases of MET amplification and you quoted Dr. Subbiah's statement at the beginning.

I know him very well. He's my Twitter friend. And he also recently published a paper describing not only the solvent front mutation, the GA10, but also the specific hinge mutation called the YAO6. So I think this would probably stimulate drug companies to try to see how to combat this specific mutation. So as we have more and more next generation drugs, and I think eventually our tendency would be to use a better drug upfront, to prevent all this resistance and also use combination approach to target a required mutation. So, I think that's how I see, probably in the next couple of years.

Michele Nadeem-Baker: So, I'm going to ask one last question that we do at Patient Power of each of you. And Lisa, I'll start with you, what message of hope do you have for lung cancer patients and their caregivers?

Lisa Goldman: My message of hope is to realize that there have been so many breakthroughs in the past few years, there are so many more treatments now for lung cancer than there were in the previous decades. And I'm a living example of that. I was diagnosed with stage four lung cancer almost seven years ago now. And I'm living a really high quality of life raising my kids, just took my son for his senior class photos yesterday, so.

Michele Nadeem-Baker: That is so fabulous to hear that Lisa, it actually brings tears to my eyes. And Dr. Zhu, what's your message of hope for patients?

Dr. Zhu: I think it's important to know your type of lung cancer. Even if you are diagnosed with stage four non-small cell lung cancer, they are many effective treatments out there. And it's not the end. Please get tested, know your comprehensive molecular profile and then talk to your physician immediately about treatment. And I just like to say that all these patient advocate groups are just terrific and I have learned a great deal actually from my patients about their courage and tenacity in combating lung cancer.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.


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