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Banu Arun, MD: Hello. I'm Banu Arun, a medical oncologist from the University of Texas MD Anderson Cancer Center. Welcome to Medscape's InDiscussion series on advanced and metastatic breast cancer. Today we'll discuss immunotoxicity in diverse populations and toxicity management. First, let me introduce my guest, Dr Hope Rugo, a medical oncologist specializing in breast cancer research and treatment. Dr Rugo is a professor of medicine and Winterhof Family Professor of breast oncology in the division of Hematology and Oncology at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, where she is also the director of Breast Oncology and Clinical Trials Education. Welcome to InDiscussion.
Hope, thank you for being here. What do you think is the most relevant and exciting topic in advanced and metastatic breast cancer today?
Hope S. Rugo, MD: It's such a pleasure talking to you and thank you for inviting me to talk with you today, Banu. Metastatic breast cancer is an exciting area where we've made significant advances and still have a lot of places to go. I think talking about the most relevant issue in advanced or metastatic breast cancer is kind of funny, because we've really learned how to differentiate our treatment and our thinking into subtypes with new subtypes developing. I think that we've markedly improved our treatment for hormone receptor–positive disease. We have the CDK4/6 inhibitors firmly established, and we have new targeted agents and endocrine therapies either getting approved this year or will be approved in the next year or two. I think that's been a huge advance for HER2-positive disease. I think we're all aware of the remarkable improvements from the antibody-drug conjugate (ADC) trastuzumab deruxtecan and other agents and other studies that are ongoing, as well as moving that agent into the earlier line of metastatic disease and earlier-stage therapy. I think this has been a huge advance in an area where we thought we might have already reached the ceiling. It gives us a lot of encouragement for the future.
For triple-negative breast cancer (TNBC), we have made a lot of advances in the treatments for metastatic disease. We have checkpoint inhibitors and immunotherapy, but this is only effective for a minority of patients with metastatic triple-negative disease. There's been an urgent need to try and expand the number of patients who can benefit and to understand any additional subpopulations that we're missing, as well as to understand how long patients should be treated and how to improve the efficacy of what we have. The ADCs have been a huge and exciting advance, allowing additional treatment options for either all patients or a subset of patients with triple-negative disease. These three treatments — two ADCs and the immunotherapy — have all improved survival. When you have treatments that improve survival, what you want to do is to help more people. Also, I think it really encourages us by moving these treatments earlier in the metastatic line of therapy. More importantly, by moving these treatments to early-stage disease in the neoadjuvant and post-neoadjuvant settings, we're going to really be able to prevent metastatic disease in a larger number of patients.
People will always have metastatic disease because we have patients whose cancers are very plastic and flexible. They are able to develop resistance to what we give them. So, understanding sequencing in the metastatic setting is of critical importance. We also have the PARP inhibitors, and I think this is an area of great interest because of combining PARP inhibitors with immunotherapy and how we can expand the population of patients who could benefit from that treatment as well. Talking about one issue is hard because I think there are so many issues of great importance and interest.
Arun: Thank you so much for the wonderful overview. It was very encouraging and helpful. As you said, we want to narrow it down a little bit to immunotherapy. Can you tell us about immunotherapy for advanced disease, where we are right now, where we are going, and its limitations?
Rugo: Yes. This is an interesting history. The idea was that the majority of breast cancers were immunologically silent, so we couldn't use immunotherapy even as we saw improvements in melanoma, lung cancer, and renal cell carcinoma. It actually took some additional studies looking at triple-negative breast cancer to see that this was a population of tumors in patients that we already knew were very aggressive, but the aggressive phenotype was associated with more tumor-infiltrating lymphocytes (TILs), suggesting immune activation and also more PD-L1 expression compared to other subtypes. That was a first important step. Then, as had been done in other diseases, three checkpoint inhibitors were tested in patients who had treated and untreated metastatic TNBC. We saw response rates that were just under 20%, some of which were quite durable. That was exciting. This led to larger studies looking in the first- and greater-line setting, which definitively showed us that the checkpoint inhibitors were going to be much more effective in the first line compared to later-line setting due to a number of factors. You continuously decrease PD-L1 expression, TILs, and increase the tumor heterogeneity and resistance to therapy under the pressure of treatment in these tumors, which are more proliferative and, therefore, can generate more resistance quicker than some other tumors. That led to randomized trials evaluating immunotherapy in the first-line setting. There was also data from the preclinical setting, as well as other tumors, suggesting that by combining immunotherapy with chemotherapy, you could enhance the effectiveness of immunotherapy by increasing the immune infiltrate by the host, while you're causing some immunosuppression. You could increase PD-L1 expression potentially and increase expression of neoantigens. There are three randomized phase 3 trials that have been reported. The first two trials with atezolizumab and the third trial, which led to our current approval in the United States with pembrolizumab. The first trial that gave us this tremendous hope for the future of immunotherapy in breast cancer tested atezolizumab with nab-paclitaxel vs placebo and nab-paclitaxel. Patients had to be at least a year out from their last chemo for early-stage disease or have de novo disease. The trial was powered to look at progression-free survival (PFS) and overall survival (OS) in the intent-to-treat and PD-L1-positive population. What's important here is they used a hierarchical design, so you had to show significance in the intent-to-treat population to generate significance in the PD-L1-positive population. PD-L1 for atezolizumab is defined as an SP142 in the tumor-immune cells of 1% or greater. The trial showed an improvement in PFS in the intent-to-treat populations. In the PD-L1-positive population, we were very excited and saw overall survival benefit. Unfortunately, this was not in the intent-to-treat population, only in the PD-L1-positive population, with an absolute improvement at 7 months. That was exciting, but unfortunately, it didn't meet the statistical plan for significance in OS. The US Food & Drug Administration (FDA), giving it accelerated approval, required that there be a second confirmatory study. Unfortunately, the second study showed no benefit, adding atezolizumab to paclitaxel in a similar patient population with a 2:1 randomization. In that trial, remarkably, the OS in the PD-L1-positive placebo and paclitaxel group was 28 months, which is longer than we've seen in any other trial before or after — where we see OS is in the less than 20 months in the chemotherapy alone group. To understand that further, we really need to go back and look at the biologic characteristics, TILs, and the intrinsic subtypes — and that hasn't been done in the IMpassion131 population. Unfortunately, because of that, the atezolizumab approval was withdrawn in the US but not in the rest of the world.
Then we had KEYNOTE-355. That trial looked at pembrolizumab or placebo with a menu of chemotherapy, paclitaxel, nab-paclitaxel, and GemCarbo, as long as patients had their last chemo in the early-stage setting at least 6 months beforehand. This trial also showed an improvement in PFS, which was very impressive, and then OS in the PD-L1-positive population. But the trial didn't use that hierarchical design. It was powered to look at OS and PFS in the PD-L1-positive population, with PD-L1 defined as a combined positive score (CPS) of 10 or greater. It's not a percentage; it's a score that combines immune cells and tumor cells, and it uses another antibody called 22C3. It's interesting to know that there's not complete overlap between PD-L1 positivity using these different tests, which we showed looking at the IMpassion130 population. That data was quite encouraging. The median improvement in overall survival, the absolute difference was 6.9 months, almost identical to IMpassion130, and that led to FDA approval of this treatment in the United States. It's now a standard of care. But unfortunately in KEYNOTE-355, only 38% of patients had PD-L1-positive disease. In the Impassion130 trial, it was about 40%. This seems to be what we're seeing, even though there's incomplete overlap. That really means that most of our patients aren't going to benefit from checkpoint inhibitors, which has led to a lot of interest in how we can further expand the efficacy of checkpoint inhibitors in patients with advanced TNBC. It's also led to a whole host of additional studies looking at pembrolizumab in the neoadjuvant setting and KEYNOTE-522, which have completely changed how we treat early-stage TNBC. There's also ongoing studies looking at immunotherapy in more proliferative hormone-receptor positive and HER2-positive disease.
Arun: Thank you, Hope, for a great review. You mentioned a segue to our next topic: The selection of biomarkers and subgroup cohorts might benefit more, and the difference between those IMpassion studies and KEYNOTE-355 is maybe the subgroup selection. Where are we with studies looking at different biological subtypes? You just mentioned the early stage, but how can we take what we learned in the metastatic setting and apply it to the early setting as well as different biological subtypes?
Rugo: This is really a fascinating area of exploration. At a recent St. Gallen Early Breast Cancer Consensus meeting in 2023, investigators spoke passionately about TILs and their value in identifying patients who might benefit from immunotherapy or who might have a very good outcome even without treatment. I think it's going to be hard for us to ever identify that group of patients. In the metastatic setting, we'd like to find additional biomarkers that would identify patients whose cancers could benefit. Obviously, the intent-to-treat group is not it. PD-L1 is one marker, and it's the best we have right now. But there's been a lot of interest in finding immune signatures that would predict response that may identify a broader population than PD-L1 alone. There are companies that now have immune signatures. It's possible that by looking at this in a real-world population, we may be able to identify more. It's possible that just by going back and looking at tumor samples from the trials that have been done, we'll be able to further look at this and really expand the use of immunotherapy in metastatic disease. In terms of the other biologic subtypes, this is an area of great interest, as these immune gene signatures might identify the right hormone-receptor positive disease subset that could benefit from immunotherapy. We know that a tiny subset of hormone receptor–positive diseases basal-like by intrinsic subtypes and our I-SPY 2 neoadjuvant data suggest that these are patients who benefit significantly from the addition of immunotherapy. How that works in metastatic disease remains to be seen. Could patients who have luminal B but very proliferative disease also be patients whose tumors could benefit from immunotherapy? KEYNOTE-B49 is a trial that's now looking at pembrolizumab in the first-line setting in patients with hormone receptor-positive disease who have a CPS of at least 1. That is going to be important, because we can only benefit patients where immunotherapy sometimes can result in long-term disease suppression. I think that those are important studies. We also have looked at combining immunotherapy with ADCs and with PARP inhibitors, and there is preclinical data for both of these combinations suggesting that different immune-active pathways are activated by these combinations. There are trials looking at sacituzumab govitecan with pembrolizumab in the first-line PD-L1-positive triple-negative population. There's also an exploratory trial that ran a randomized phase 2 out of Dana-Farber Cancer Institute looking at patients, regardless of PD-L1 positivity, both triple-negative and hormone-receptor positive. Those are important studies. There will be additional trials looking at adding checkpoint inhibitors to immunotherapy in several settings. One area that is currently being evaluated is adding the checkpoint inhibitors to ADCs in patients with residual disease after neoadjuvant therapy for TNBC. There is the ASCENT-05 with sacituzumab and then another trial, TROPION-Breast03, looking at datopotamab deruxtecan with durvalumab, another checkpoint inhibitor. You can see a tremendous number of different strategies that are being evaluated to further expand the use of checkpoint inhibitors. With PARP inhibitors, we saw some interesting data from the Dora trial at San Antonio, but it's a tiny trial looking at a checkpoint inhibitor plus a PARP inhibitor as maintenance in patients with metastatic TNBC. We need more biomarkers to understand that data. We'll also see data from the KEYLYNK-009 trial that looked at the same strategy of pembrolizumab plus olaparib as a combination maintenance strategy. As you can see, it's widespread and quite varied.
Arun: Thank you. The opportunities out there are amazing, and the ongoing trials will really advance the field. One important area in oncology treatment that obviously includes breast cancer is diversity. What data do we have that these advances and these positive outcomes are applicable to diverse populations?
Rugo: It's a great question and, of course, it's limited somewhat by the fact that checkpoint inhibitors for TNBC are not yet available worldwide, although approval continues to increase across the world in different areas. Some groups have looked at the Black American population to see what the biologic diversity is in the TNBCs to understand how sensitive these cancers would be to immunotherapy. The Yale Cancer Center Tumor Study has done most of this work. They have shown that there seem to be more TILs, suggesting more of an inflamed phenotype and bringing up the hypothesis that tumors in Black American women might potentially be more sensitive to immunotherapy, but we don't have any clinical data yet to back this up. It's quite interesting. We haven't seen variations in efficacy in the clinical trial populations. Obviously, numbers of different subsets are small, but the benefits appear to be across different racial and ethnic groups. We also haven't seen that one group vs another have more toxicity, which I think is also an important area to look at because we have seen that some of our drugs, mainly orally administered drugs, seem to have quite variable toxicity across different ethnic and racial subgroups due to pharmacogenomics.
Arun: You just touched on an important topic that is evolving in cancer medicine. How do we identify and manage immunotherapy related toxicities?
Rugo: This is a really interesting area. It's made all of us into much more diverse and better-educated clinicians, because now we have to look at all these varied toxicities that our patients get with a new and fresh eye. Any organ in the body can be affected by immunotherapy. We see endocrine toxicities that appear to be permanent and lifelong but can be treated with replacement hormones. That's fairly easy for thyroid, quite straightforward for adrenal insufficiency, and more complicated for diabetes (which, thankfully, is much rarer). Any other organ can be involved. There's a certain time course that people have published over time — first in 2019. There's been a lot more data since then suggesting that some of the toxicities, like skin and thyroid, tend to occur early. But by no means are toxicities limited to a specific time course, as pneumonitis and adrenal insufficiency tend to be a little bit later. I've seen immune toxicity up to 4 months after the last dose of a checkpoint inhibitor in the early-stage setting. I've also seen toxicity develop quite late into the course of treatment a year after starting. I think that we need to be hypervigilant and aware, educating our staff, patients, and ourselves about a high suspicion for immune-related toxicity. If a patient comes in with an unusual symptom or a persistent symptom that you wouldn't expect, it's always better to treat with steroids and do your differential diagnostic workup as you're treating rather than wait a long time because the toxicity can significantly worsen over time. We generally hold checkpoint inhibitors for non-endocrine toxicities and wait for the toxicity to improve under treatment. The question about who we should rechallenge exists, and we generally rechallenge for low-grade toxicities that have improved or resolved when the potential for benefit is greater than the risk of toxicity. But for high-grade toxicities, Grade 3 or greater, we generally don't rechallenge.
Arun: Great answer. I think we all, as oncologists, have to tap into our internal medicine skills to recognize, deal, and most likely collaborate. That's what we do with our internal medicine colleagues at our institutions or outside. I have a follow-up question on toxicity: Do we have any data at all related to the toxicity in different racial and ethnic populations?
Rugo: We really don't. What we need to do now is look at specific baseline issues. If you come in with comorbidities, does that increase your risk? For example, it doesn't seem like having type 2 diabetes increases your risk of getting type 1 diabetes, which is a really significant toxicity, although it's rare. It's a big deal for the patient in terms of toxicities from immunotherapy. Could hypertension make you at higher risk for renal toxicity? That doesn't appear to be the case. We haven't seen any specific comorbidities that increase risks. It does appear that patients who have underlying undiagnosed Hashimoto's thyroiditis are probably at higher risk for hypothyroidism because a little push is all it takes to make them hypothyroid. I think there's also an emerging area of literature looking at human leukocyte antigen (HLA) types to see whether there are specific HLA types that increase risk. Those will probably align against particular racial and ethnic subgroups. This is an area of great interest with new data to come in the future.
Arun: Thank you so much for joining us today, Hope. We've talked with Dr Hope Rugo about immunotherapy, immunotoxicity, and diverse patient populations. Thank you for tuning in. Take a moment to download the Medscape app to listen and subscribe to this podcast series on advanced and metastatic breast cancer. This is Banu Arun for InDiscussion.
Primary Results From IMpassion131, a Double-blind, Placebo-controlled, Randomised Phase III Trial of First-line Paclitaxel With or Without Atezolizumab for Unresectable Locally Advanced/Metastatic Triple-negative Breast Cancer
Prognostic and Predictive Value of Immune-related Gene Expression Signatures vs Tumor-infiltrating Lymphocytes in Early-stage ERBB2/HER2-positive Breast Cancer: A Correlative Analysis of the CALGB 40601 and PAMELA Trials
Study of Sacituzumab Govitecan-hziy and Pembrolizumab Versus Treatment of Physician's Choice in Patients With Triple Negative Breast Cancer Who Have Residual Invasive Disease After Surgery and Neoadjuvant Therapy (ASCENT-05)
A Study of Dato-DXd With or Without Durvalumab Versus Investigator's Choice of Therapy in Patients With Stage I-III Triple-negative Breast Cancer Without Pathological Complete Response Following Neoadjuvant Therapy (TROPION-Breast03)
Dora: A Phase II, Multicenter, International Study of Olaparib With or Without Durvalumab as a Chemotherapy-free Maintenance Strategy in Platinum-pretreated Advanced Triple-negative Breast Cancer (TNBC)
Study of Olaparib Plus Pembrolizumab Versus Chemotherapy Plus Pembrolizumab After Induction With First-line Chemotherapy Plus Pembrolizumab in Triple Negative Breast Cancer (TNBC) (MK-7339-009/KEYLYNK-009)
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Cite this: Immunotherapy, Immunotoxicity, and the Impact on Diverse Patient Populations in Advanced and Metastatic Breast Cancer - Medscape - Jul 05, 2023.