Expert Conversations on Treating RET Mutations

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Monitoring Patients While Addressing Adherence Barriers and Goals of Care

Last Updated: Monday, June 17, 2024

Juna Jovani, PharmD, BCPS, BCOP, and Alexander Robinweiler, PA-C, MCHS, review the barriers patients can face when trying to get their medications, and the importance of having a goals of care discussion with those patients. Juna and Alex also discuss the advantages of targeted therapies for RET mutations, as well as the ways they monitor and educate their patients to ensure the patients know how to take their medications and what to expect from their treatment.



Meet the faculty


Juna Jovani

PharmD, BCPS, BCOP

The US Oncology Network – McKesson

Juna Jovani is a senior clinical pharmacist, responsible for the oversight and modification of pharmacotherapy for adult oncology patients in the community setting, specializing in breast oncology with sub-specialties in thoracic, head and neck, central nervous system, genitourinary, cutaneous, and gynecologic oncology. Juna participates in the development, implementation, and ongoing review of pharmacy policies and procedures within the ClinReview team.

 

Alex Robinweiler

PA-C, MCHS

Fred Hutch Cancer Center, Teaching Associate, University of Washington School of Medicine

Alex Robinweiler is a physician assistant at Fred Hutch and a teaching associate at the University of Washington. Before joining Fred Hutch at Overlake Cancer Center, he worked in family medicine and urgent care for several years. His area of clinical practice is working with patients in general medical oncology, benign and malignant hematology, at a community oncology site.

Juna Jovani

Hi Alex. I’d like to start this conversation by talking about monitoring our patients. From a pharmacist perspective, it’s important to monitor for any side effects and signs of toxicity, and make sure that patients are adherent and aware of the importance of taking their medications as prescribed. We also try to make sure that there are no barriers to the patient getting their medications, because we know things like drug shortages and drug costs can affect whether the medication is taken as intended, impacting the care of the patient.

Alex Robinweiler

Those are important considerations. It’s critical for our patients to take their medications as recommended.

Juna Jovani

How do you measure adherence or specific symptoms that patients may be having? And how often do you do it, since, for instance, patients don’t go into the clinic for IV administration.

Alex Robinweiler

Thank you for asking that, Juna. The patient population I work with most often have non-small cell lung cancers and are on selpercatinib. We look at their risk factors, based upon their age, comorbidities, etc., and we follow the drug manufacturer’s recommendations. On average, the patient gets labs every few weeks, likely a little more often at the beginning and then a little less often later.

In a typical patient experience, they come in and get an education session with us, usually involving some time with a nurse educator, and time with one of our pharmacists. This education is meant to reinforce if there are any extra things that they need to watch out for, like drug-drug interactions. We talk about some of the antacid medications that are pretty common but are often not recorded in the charts. Afterward, a nurse calls the patient after a week or two to check in, see how they’re doing, or see if there are questions or concerns, or if anything unexpected came up. We also typically schedule a provider visit about 2 to 4 weeks out. We usually correspond that visit with a recommended lab visit so we don’t have to inconvenience the patients too much from a time-toxicity standpoint.

Provided everything is going well for the patient, we’ll continue with labs every couple of weeks for the first few months. Provider visits are scheduled for every month or so, unless unexpected side effects pop up, in which case we see the patient more often. Of course, if we find some abnormalities, we’ll likely order more labs and get into more frequent monitoring. A patient who potentially has metastatic stage 4 non-small lung cancer will also receive surveillance imaging, usually with CT scans but potentially PET scans, depending on the modality of choice, what gets paid for, and perhaps what the prior modality was.

We plan these scans usually about every 3 months, just to monitor the disease, and to ensure that we’re seeing an adequate response. And as we would with most of these types of medications, we continue the drug until treatment toxicity and/or treatment failure. Usually with these types of medications, RET inhibitors in particular, we see patients with average progression-free survival of almost two years, which is pretty great.

Juna Jovani

You mentioned working with patients with non-small cell lung cancer. These RET fusion mutations are found in about 1 to 2% of non-small cell lung cancers.1 And with RET mutations more prevalent in the younger, non-smoking generation,2 how do you discuss treatment with a younger patient vs. a patient that is in the geriatric phase of their life?

Alex Robinweiler

Yes, it’s a completely different animal as it were, a different type of conversation when we’re talking about somebody with metastatic disease, somebody with stage 4 disease. Particularly with younger people, it’s important to manage expectations to make sure the patient fully understands that the treatment is palliative, with the goal of long remissions, but not necessarily cure. There’s a lot of potential for painful and difficult conversations as we work with patients to decide what the goals of treatment are, making sure that they understand what the limitations of treatment are.

Juna Jovani

That’s certainly an important part of care. We discussed that most of these medications are utilized in non-small cell lung cancer or medullary carcinoma, unresectable distant metastases or local regional disease. What is the goal of treatment in this space, in this subset population?

Alex Robinweiler

I get 30 minutes for patient appointments, although they often give me extra time for the patients who need it. When having goals of care discussions, we need to find out why they’re treating and how long they want to treat for and then make plans for the future. And to be realistic, we need to talk about what happens after these treatments fail, as in whether we’ll move to chemotherapy, immunotherapy, or, depending on the patient’s frame of mind, a comfort approach with hospice. I never want to bring up all of that at one time, but if I’m seeing the patient once a month, I’ll ask, "How are things going? Have you thought about your future? What are you doing next summer?" There are little things you can do to get your foot in the door to start these discussions. 

Juna Jovani

Thank you for that, Alex.

I want to shift gears here. We’ve talked about some of the side effects of these RET-specific inhibitor drugs as far as potentially causing hypertension and adverse effects such as constipation, diarrhea, and thyroid abnormalities. I want to ask you about your experience with the overlooked side effect of financial toxicity. While oral therapies such as RET inhibitors may be beneficial as far as convenience of administration is concerned, based on my experience as a pharmacist, they add a lot of cost-sharing pressure and burden on patients as compared to intravenous options.

Some patients may be eligible for financial assistance programs by manufacturers or charity care programs, so at what point do you intervene in getting these medications approved? Do you have any barriers from an individual practice level as a PA to getting these medications approved at a modest cost for patients? And how often do you feel that you modify treatment from selective inhibitors to a broader IV therapy in this population space because of financial barriers?

Alex Robinweiler

As we’ve talked about before, many of these patients are younger and they’re typically healthier if they have no comorbidities or have never been smokers. The nice part about that is, if there is a nice part, is that they probably have commercial insurance which usually equates to lower out-of-pocket costs. In the past, APs and sometimes the pharmaceutical companies, foundations, and hospitals were able to find the patients at risk of slipping through the cracks and not able to afford their medications. Say four to six years ago, we’d see about 10% of patients who were financially challenged by a co-pay of $3,000 to $5,000 a month for these types of medications.

For those patients, this kind of co-pay is something that’s going to beggar them, that is intolerable for them. We may search out foundational support on behalf of the patient and find that it either doesn’t exist or that it’s already been used up that year. Fortunately, in a lot of these drug classes, RET inhibitors included, oftentimes there’s more than one appropriate drug available. While one drug may have better statistics and the likelihood of a better outcome, we may have to go with the more affordable option because one of these drugs is better than nothing. Interestingly, the intravenous options are often better covered by commercial insurance and Medicare.

Juna Jovani

Great. Thank you for explaining that.

I’d like to circle back to our first conversation [Identifying and Managing Adverse Effects and Drug-Drug Interactions in Patients With RET-mutated Thyroid Cancers] where we talked about the point in clinical staging when biomarker testing occurs. You mentioned that the earlier in the staging process it occurs the better since genetic testing provides highly specific guidance to the proper drugs for these patients. As we know, some of these test results can take quite a while to come back as most facilities can’t perform them onsite and must outsource them. Do you feel that your group in your current practice has enough education and a clear understanding of genetic testing availability in this space? And what do you think the patient’s barriers are to genetic testing?

Alex Robinweiler

The big barriers are cost, knowledge, and availability. And at my center we have to outsource a lot of our genetic testing since it can’t be done onsite. We expect turnaround time to be 1-2 weeks. We’ve run into the issue of getting back the testing on ALK, ROS, BRAF, and EGFR, and they’re all negative, but then we ran out of tissue. We don’t always know that that’s the case because the testing is reflexed, so if one test is negative, the lab reflexes to the next, and then reflexes to the next. In general, we prefer to get next-generation sequencing which is able to parse out the entire genome. This typically requires a little less tissue, so we don’t run into any problems with waiting on or running out of tissue. We don’t want to wait another week or two to get the patient in or worry about the possibility of financial constraints or insurance coverage issues because the cancer waits for no one. We don’t want to move on to a first-line treatment that’s not ideal.

Juna Jovani

Being able to use testing results to target treatment is so important.

Alex Robinweiler

What do you see as the biggest challenge to educating patients on these targeted treatments?

Juna Jovani

When patients think about cancer therapy, they gravitate toward the IV administration that occurs in the clinic. And with more specific inhibitor drugs that target these cell mutations, it might be harder for the patient to understand what a RET mutation is. It’s incumbent on the provider to explain the specificity of these drugs. And from the pharmacist perspective, it’s important to do a comparison as these targeted therapies are a big step forward toward precision medicine. One of the biggest benefits is these drugs can limit toxicity because they’re targeting cells that are mutagenic. It doesn’t mean that there won’t be any side effects, but the potential is there for fewer side effects, less toxicity, increased adherence, and increased duration of treatment. That’s one of the angles that we as pharmacists would use to explain the importance of these drugs vs. more generalized drugs (like the previous multikinase inhibitors) to these patients.

Alex Robinweiler

One of the more rewarding parts of my job is being able to talk with patients and facilitate that understanding, particularly with those who are a bit less well versed in medicine. I like to give patients the 100,000-foot view and the 50,000-foot view and then respond to the patients who have a lot more specific questions, giving them background on how these mechanisms work. And frankly, most of the time the patients don’t care that much, they just want to get moving with treatment, get to the next phase of this whole process.

Juna Jovani

Absolutely. Another advantage of having specifically targeted medications, especially those that come in a capsule or tablet form, is the convenience of administration and the better quality of life that a patient has, especially in the younger ones who have a lot of ambitions or have a busy life. Lab monitoring is still essential, of course, especially on a weekly or biweekly basis for the first three months, and then maintenance every month and/or when clinically warranted.

Alex Robinweiler

Exactly. It’s not just quality of life. Patients on these targeted therapies have an average overall survival of 1-2 years longer than patients who either don’t have these mutations or weren’t offered the medications for those mutations.3 These medications have been an absolute game changer in improving quality and length of life. My overall goal is to be put out of an oncology job, so let’s cure this cancer already and I’ll go practice family medicine again.

Thank you for chatting with me today, Juna. I learned a lot.

Juna Jovani

Thank you, Alex. It was nice to get your perspective on this matter.

References

  1. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients. Clin Cancer Res. 2017;23(8):1988-1997. https://doi.org/10.1158/1078-0432.CCR-16-1679
  1. Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F. State-of-the-Art Strategies for Targeting RET-Dependent Cancers. J Clin Oncol. 2020;38(11):1209-1221. https://doi.org/10.1200/JCO.19.02551
  1. Chi SA, Yu H, Choi YL, et al. Trends in Survival Rates of Non-Small Cell Lung Cancer With Use of Molecular Testing and Targeted Therapy in Korea, 2010-2020. JAMA Netw Open. 2023;6(3):e232002. Published 2023 Mar 1. https://doi.org/10.1001/jamanetworkopen.2023.2002