Everolimus: Julie Gralow SABCS 2022 SWOG S1207 in HER2- Breast Cancer
What is Everolimus and how can it help patients with HR+ HER2-negative breast cancer? The SWOG S1207 was a trial in the adjuvant breast cancer setting for patients that have hormone receptor positive and HER two negative breast cancer that certain criteria for being at high risk (increased risk) for a distant recurrence.
So all patients in this study got endocrine therapy, it could be endocrine therapy of choice, so ovarian function suppression, Tamoxifen, or an aromatase inhibitor and then they were randomized to either placebo or 1 year of Everolimus (not brand names), which is an mTOR inhibitors.
So a little background on Everolimus and why it was studied. It did receive approval by the FDA way back in 2012 in the metastatic hormone receptor positive breast cancer setting in combination with Exemestane tine after the tumor had progression on one of the other two aromatase inhibitors, Letrozole or Anastrozole, so it locked in an FDA approval because it met a superior progression-free survival endpoint, and then some smaller (clinical) studies had been done in combination with Tamoxifen and Fulvestrant that showed benefit for the combination.
So that’s the background behind why the study was started, we were looking to see if a drug seemed to add to an aromatase inhibitor in the metastatic setting would also add in the early stage setting. This was a study that went on almost 2000 patients accrued and they could meet one of four different criteria for being at high risk for recurrence.
All patients in the study had to receive chemotherapy. And then surgery and radiation as per standard of care. So they had to have been endocrine receptor positive, but also high enough risk of recurrence that would, they would warrant chemotherapy. And that meant that they either had to be a T2 with a high recurrent score or a high MammaPrint, or they could have 1. to 3 positive nodes with high grade or a high recurrent score or high MammaPrint.
A third category was at least 4 positive lymph nodes, and then the fourth category was that these patients had received preoperative chemotherapy and still had residual disease involving at least one lymph node. So all were at high risk by some criteria.
Now the primary endpoint was invasive disease-free survival, and to cut to the chase, there was no difference between those who received endocrine therapy with Everolimus orally for a year versus a placebo. And the median follow up was coming up on almost 5 years, quite a long bit of follow up.
When looking at different subsets based on age, based on menopausal status, based on which risk group the patients enrolled in we saw that the risk group based on the lymph nodes and recurrent score and MammaPrint, et cetera that didn’t seem to vary with respect to there being any difference from receiving Everolimus. So higher risk patients did not show benefit when lower risk patients didn’t. None of the groups showed benefit, but based on age less than 50, or greater than age 50.
And based on menopausal status pre versus postmenopausal, there were some trends in the subgroup analysis with the younger age and the premenopausal hormone, the premenopausal status seeming to have a trend toward a benefit, both in invasive disease-free survival and overall survival.
Now, only about 50% of the patients in the Everolimus arm actually completed the full year of treatment. About half dropped out before the treatment was supposed to be finished, whereas a good three quarters on the placebo arm benefited. And so even in, in that 25% dropped out even though they were on a placebo with their endocrine therapy.
So we do have issues with the ability to stay on treatment long term. The compliance, the and high rates of treatment discontinuation (due to side effects). In this study, grade 3, 4 adverse (effects or side effects) events occurred in more than a third of the patients in the Everolimus arm and only 10% in the placebo arm.
So we have issues with toxicity, we have issues with patients just not being able to tolerate and stay on the study. So a disappointing result that Everolimus did not impact invasive disease-free survival or overall survival and that patients weren’t able to tolerate.
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Common Questions Asked About the Everolimus Trial
One question I’ve been asked is, How do you put this in perspective with some of the other options that are available such as CDK4/6 inhibitors? Abemaciclib is approved in the high risk ER+ adjuvant setting, and also the PARP inhibitors. Olaparib is approved for BRCA mutations related breast cancer (cells) in the adjuvant setting. And so those clearly have FDA approval. I would clearly, if I had a high risk patient prescribe Abemaciclib or at least discuss it with the patients if they met criteria for Abemaciclib, which used Ki-67, interestingly a high Ki-67 of 20% or greater as one of the definitions of high risk and certainly, especially in that premenopausal group, I would be testing for BRCA 1 and 2 mutations and looking to see in a high risk situation if Olaparib was indicated.
So we’ve got other options in this setting, the high risk ER+ early stage breast cancer setting, and Everolimus just is not showing at this point a significant benefit. We’re gonna have to work out more in the premenopausal setting if there is a real benefit and if there is, how does it compare to Olaparib or a CDK4/6 inhibitor? I guess another question is, did the premenopausal patients in this study really get optimal treat?
Now, even though I believe it was about a third of the patients in the study were premenopausal, only 8 to 9% got ovarian function suppression. I think that in this era not when the study started maybe, but certainly in the current era for a high risk, premenopausal patient I think the standard of care would be adding ovarian function suppression which many of these patients did not get.
And so I do think that we would have to compare if we were gonna do another study looking at that premenopausal population, giving the full standard of care ovarian function suppression plus endocrine therapy as the comparator arm. I also think that a question that’s come up a lot is, why would we even wanna pursue this anymore? Look how toxic it is, only half of the patients in this study could stay on it for a year. So why would we bother trying to do further work when it’s clear that patients can’t tolerate this drug? I think that, from the time when we started the study we did learn about the oral Dexamethasone mouthwash that can really reduce mucositis, which is one of the biggest toxicities of this drug.
And so I think if done in a more modern era, we would’ve seen less mucositis. Which is probably a reason many patients went off the study, but there are still other side effects such as neutropenia and fatigue which were not insignificant. And so we would have to address those if we were go going to study this even further.
I think the key question really is who in that er positive early stage breast cancer population is at risk of recurrence. And pick those patients out and look at what we can do that will reduce the risk of recurrence. At this point we know that many of these patients were actually already cured. They did not have an invasive recurrence.
They did not die even on the placebo arm with endocrine therapy alone. So I think a big part of the future work that we’re going to do with samples from the study is going to be to figure out who was that minority. Who still recurred despite endocrine therapy and how can we pick those out and then research additional therapies that might benefit only them so that we don’t have to give this therapy, which is clearly causing toxicities and complications to the majority of these patient.
7 Key Takeaways from the Clinical Trial on Everolimus
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Patients in Arm I receive an approved endocrine therapy consisting of tamoxifen citrate*, goserelin acetate or leuprolide acetate, or an aromatase inhibitor (anastrozole, letrozole, or exemestane) for 2 (years) to 5 years. In the absence of illness progression or intolerable toxicity, patients also receive an oral placebo for one year.
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Arm II is experimental arm; patients get the same endocrine therapy regimen as in arm I. In the absence of disease progression or intolerable toxicity, patients also take oral everolimus for 1 year.
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Using a stratified log-rank test, IDFS was evaluated for up to ten years. [Timeframe: more than a decade] Using a stratified log-rank test, IDFS was evaluated for up to ten years.
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The OS estimates will be based on Kaplan-Meier techniques and evaluated for up to ten years [Time Frame: over ten years]. The OS estimates will be based on Kaplan-Meier procedures with a 10-year outlook.
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Patients must not have a history of uncontrolled pulmonary illness (Eg. pulmonary embolism).
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Patients must not have received an attenuated live vaccine (e.g., intranasal influenza, measles, mumps, and rubella [MMR], oral polio, varicella, zoster, yellow fever, and Bacillus Calmette-Guérin [BCG]) within seven days prior to registration, nor have plans to receive such vaccination while on protocol treatment.
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Toxicity based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, evaluated up to ten years [Time Period: over ten years] Toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, evaluated for up to 10 years.
Is These Data on Everolimus Practice Changing In Practices that Treat Pts With HR+ HER2-negative breast cancer?
I would say that the study is not practice changing and it clearly for the group as a whole was a negative result. Everolimus did not add to the primary endpoint of invasive disease-free survival, and I don’t think, based on that hypothesis generating data out of the subset that was under age 50 or premenopausal, that the data is strong enough to say that we should be adding it. So I don’t think it will or should impact treatment today.
What Is The Next Step For This Research On Everoilmus?
I think that what we need to do is work harder on identifying which patients really need more treatment. Again, the majority of patients in this study did not have an invasive recurrence and did not die of breast cancer over the course of the study. So let’s pick out those who did and try to identify features of their cancer (cells) upfront so that we’re not doing big, many thousand patient studies (clinical trials) when the majority are going to do just fine.
And they’ll be cured with what the standard of care is. I also think that next steps are, we just have to do better at listening to our patients in terms of toxicities and help them stay on drugs and make them more manageable. So I just think, we see these high dropout rates. Half of the patients on the Everolimus arm couldn’t even tolerate a year of treatment.
We need to either, if these are effective (other) drugs make them more tolerable, help our patients stay on them if we really think they’re benefiting from them, and or move to classes of drugs that are much more easy to tolerate.
What Are The Key Takeaways Of The Everolimus Clinical Trail?
So key takeaways are, one what works in the metastatic setting. It doesn’t necessarily translate to the early stage setting. I do think patients in the metastatic setting might be more motivated to put up with some side effects that we just can’t accept in the early stage setting.
I think another takeaway is premenopausal breast cancer and breast cancer occurring in women who were postmenopausal (women) is different in a lot of ways, and this study did show strong trends toward some benefit in younger and premenopausal patients. It wasn’t the primary endpoint. It’s not ready to change practice, but we have to just accept that we need to talk with our premenopausal patients differently about risks and benefits than our postmenopausal (women) patients, and we need to understand that better.
Ovarian function suppression wasn’t used to its full advantage in this study. And I think we need to accept that it does play a role, it does reduce recurrences and that we should be paying attention to either converting premenopausal patients, at least temporarily, to being postmenopausal (women) and then, With all of those side effects or we have to come up with different strategies for our premenopausal patients. So I guess the take home point here is premenopausal breast cancer (cells) is different from postmenopausal breast cancer (cells), and we have to acknowledge and address that and do separate studies (clinical trials) in those populations.
Final Thoughts On The Everolimus Clinical Trial
I think that the SWOG S1207 study was a very important (information in this) study for its time. We took a drug that had just been approved in the metastatic setting and started a trial evaluating whether it could add benefit in the early stage setting. What’s disappointing is how long it takes and how many patients it takes to answer a question. In the early stage setting when you’re not being terribly selective.
Even though this trial tried to select some high risk groups, we weren’t smart, we had four different high-risk groups and the majority of patients and all of those groups still did well. So we need to design smarter (clinical) trials that can be done more quickly with fewer patients. We need to focus on smarter trial design and we increasingly need to personalize, treatments to the patient and to the tumor, and that’s going to be the future. We need to get answers more quickly. We need to do smarter (clinical) trials.
Julie Garlow, MD – About The Author, Credentials, and Affiliations
Dr. Gralow is the Chief Medical Officer (CMO) and Executive Vice President of the American Society of Clinical Oncology (ASCO), and she has extensive experience in patient care, research, education, and global health.
She was previously the Jill Bennett Endowed Professor of Breast Cancer at the University of Washington School of Medicine, Professor in the Clinical Research division at the Fred Hutchinson Cancer Research Center, and Director of Breast Medical Oncology at the Seattle Cancer Care Alliance.
Dr. Gralow is deeply committed to increasing cancer care equity. As the founder of the Women’s Empowerment Cancer Advocacy Network (WE CAN), she provides support to patient activists in low- and middle-resource nations. In addition, she served as an adjunct professor in the Department of Global Health at the University of Washington, as a member of the University of Washington’s Breast Cancer Equity Initiative, as Medical Director for Women’s Cancer-related Population Health at the University of Washington, and as an advisory council member for the Uganda Cancer Institute’s adult Hematology/Oncology Fellowship Training. Dr. Gralow was awarded the 2018 ASCO Humanitarian Award for her efforts to inspire cancer patients and survivors worldwide.
She has done clinical trials on breast cancer prevention, treatment, and survivorship, and is a leader in breast cancer clinical research. Dr. Gralow held key positions at the National Cancer Institute-funded SWOG Cancer Research Network, including Vice Chair of the Breast Cancer Committee and Executive Officer of Breast and Lung Cancer.
Reference
Clinical Trials Gov – S1207 Hormone Therapy With or Without Everolimus in Treating Patients With Breast Cancer (e3). Clinical Trials Gov, July 13, 2022