Heather L. McArthur, MD, MPH presents a case study using immunotherapy to treat Metastatic Breast Cancer. Dr. McArthur also reviews clinical trials and discusses future treatment options.
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it is now my pleasure to present our next speaker. On behalf of the Bernard L. Schwartz lectureship. Bernard Schwartz was a successful industrious along the East Coast who later pursued a distinguished second career in portrait photography. He received his oncology Carrot Scripts clinic, and we're fortunate that his legacy lives on through this lectureship series. Our prior speakers represent a Hall of Fame roster of human biology oncology, and we are pleased to add Dr Heather MacArthur to this distinguished list. It is now my pleasure to introduce Dr McArthur, medical director in the Department of Breast Oncology at Cedars Sinai Medical Center. She will be speaking on optimizing immuno therapy for metastatic breast cancer. Dr. MacArthur is a good friend of this conference and has always been well received. Please welcome her to our Bernard L. Schwartz lectureship. Remember, if you have questions, please use the ask a question chat function, and we will address them during the panel session. Thank you so much for the kind introduction. It's particularly an honor to be giving the Bernard Lee Schwartz cancer lectureship today. Today I'm going to be talking about optimizing immuno therapy for metastatic breast cancer and here are my disclosures. I wanted to start out with a case study just to highlight where, why there's so much enthusiasm for immune therapy for the treatment of breast cancer. I was previously attending physician at Memorial Sloan Kettering in New York, and this is a patient who I treated at that time. She was a 32 year old physician was staged to three centimeter grade, three triple negative breast cancer that was diagnosed in 2013. She had no deleterious mutations and received neo achievement. Does dance a CT chemotherapy, followed by lump back to me and sentinel lymph node biopsy. Notably, She had a good response to chemotherapy but did not achieve a complete response and went on to receive adjuvant radiation and then was placed on surveillance. The following year, she presented with a local in breast recurrence, she had staging with a pet CT that was negative for distant metastases. So she underwent total mastectomy and received a subsidy. Subsequent course of adjuvant chemotherapy for the color your study. Specifically, she received gem side of being plus carbo platinum adjuvant chemotherapy. Unfortunately, within a few months of completing that chemotherapy, she became short of breath. She had another pet CT at that time that was suspicious for lung and lymph node metastases. You can see the lung metastases. So one of the lung metastases identified here, and she underwent biopsy as per standard of care of one of the lymph nodes that confirmed metastatic triple negative breast cancer. And I was really distraught at this stage because not only had she received the best available systemic chemotherapy that I had on offer, I really had no other great options to offer her. So I called my friend Sylvia Adams, who is at N. Y. U at the time and said, Do you have any interesting trials for someone with newly diagnosed metastatic, triple negative breast cancer? And in fact, she did. At that time, she had the Phase one B trial of PD L one directed therapy with a T cell is map together with chemotherapy in the form of paclitaxel for patients with metastatic triple negative breast cancer. And here was our course on steady. On the left, you can see a lung metastasis highlighted in blue and on the right, a lymph node metastases that was suspicious on her baseline pet scan. she received two cycles of therapy. The lung metastases shrunk down dramatically. However, one of the lymph node metastases grew. The trial allowed for continuation of treatment, regardless of progression and lymph nodes, and she continued to receive the regimen. And ultimately, after four cycles, she had complete resolution of all of her disease. So on this study she had two episodes of new initiatives that improve with supportive management but ultimately necessitated discontinuation. So she stopped receiving the A T cell is mob, and she stopped receiving chemotherapy and was followed on surveillance. And not only did she remain without a valuable disease, she is now more than six years after her metastatic breast cancer diagnosis, she remains without any a valuable disease. She continues to go for routine pet scans, and she remains on observation. She has not received any systemic therapy for many years now, and so this generates the idea that potentially we could cure women with metastatic disease, and that's a word that we haven't really been permitted to use in the setting of metastatic disease. The word cure. But this gives us the signal that cure might actually be possible in this setting and Here's the aggregate of data from this phase one city after media and just more than two years of follow up. There were several patients, not just my patient, but several patients who had actually achieved 100% complete response. And when you look at the lower spider plots, you can see, as evidenced by those horizontal lines, that these responses can be incredibly durable. So that's the promise of these strategies. If you can successfully train the immune system to recognize cancer specific information and generate memory to that information, you could potentially identify or confer long term immunity to tumors and, in fact, cure. So that's the ultimate hope. And here's the aggregate of what we know about checkpoint blockade mono therapy across multiple tumor types. The most robust responses have been seen in triple negative breast cancer, and we've learned that these strategies as monotherapy are more effective when administered in the first line setting, then, when administered in the second line and beyond. And when asked to identify strategies that might optimize or enrich for responders to these strategies, there are a number of different factors that have been interrogated. The first is line of therapy with which I just showed you and show you again here on the left that responses are more robust in the first line than they are in the second line and beyond. However, the presence of tumor infiltrating lymphocytes has also been shown now across multiple studies to confer predictive information about response to checkpoint blockade. And in fact, when you combine multiple factors, including line of therapy, presence or absence of tumor, infiltrating lymphocytes and PD l one positive positivity versus not you can really, incredibly enrich for response to treatment. We also know that tumor mutation all burden may enrich for response to treatment. The idea is that if you have more mutations, you're more likely to have novel antigens presented for the immune cells to respond to. And this is the study keynote. 119 It was a study of PD One directed therapy in the form of Pemberley is a mob versus physician's choice. Chemotherapy in either the second or third line for metastatic triple negative breast cancer, and the study overall was a negative study. However, there was a trend towards improvement in overall response rate and overall survival for those who had high tumor mutation all burden specifically greater than 10 mutations per mega base. However, unfortunately, only the minority in this case approximately 10% of patients had tumor mutation, all burdens that were greater than 10. So that's really the aggregate of data for monotherapy. We know that improved responses can be conferred if we combine checkpoint blockade with other drugs, uh, specifically chemotherapy. And although we historically think about chemotherapy is being suppressive, we also know that the right agents in the right doses at the right time can actually induce T cell infiltration into tumors. And many of the drugs that we regularly used in the treatment of breast cancer has shown here can actually induce this ImmunoGen IQ effect and may be optimal. Partners for checkpoint blockade And the first large randomized phase three study to be reported was the impassioned 1 30 study. This was a study that took previously untreated, metastatic or inoperable locally advanced patients with triple negative breast cancer and good performance status, and randomize them 1 to 1. To receive chemotherapy in the form of nab paclitaxel with either placebo or a diesel is a map. There were various stratification factors prior taxing, use the presence or absence of liver metastases and PD l one status. The study was initially power to look at progression free survival, but along the way, a co primary endpoint of overall survival was adopted, and this became incredibly important. As it ultimately informed. Our thinking about the role of a T cell is a map for this treatment of metastatic triple negative breast cancer, as I'll show you in a moment. So 902 patients participated in this study and looking at their baseline characteristics. It's worth noting that approximately 60% received prior neo adjuvant, or adjuvant, chemotherapy, indicating that 40% of patients in the study had de novo metastatic disease, the number that's maybe a little bit higher than what we routinely see in clinical practice. And notably, about 40% of patients had tumors that were deemed pd L one by the essay used in this study, and that would be the Van Tana SP 1 42 s A. And here's the bottom line from this study. In the intention to treat analysis for overall survival, there was no statistically significant improvement in overall survival and by their statistical design. They were only allowed to do a formal analysis in the PD l one subset if the intention to treat analysis had been statistically significant, so that did not occur. So what's presented here is an informal analysis for the PD l one positive subset that demonstrated a clinically meaningful 9.5 month improvement in overall survival. This is really an unprecedented improvement in overall survival, but again was identified in an exploratory, not a priori statistical analysis. So the investigators were interested in looking at other predictors of response to treatment. Was PD L one the only enriching factor predicting for overall survival? They looked at a variety of other biomarkers. The presence of CD eight positive cells, the presence of the tumor infiltrating lymphocytes, the presence of any mutations that might, um, enhanced neo antigen exposure. But ultimately, tumors derived clinical benefit only if their tumors were also PD L one positive. So there was no other biomarker identified that enriched beyond PD l one positive status. So in March of 2019, the FDA granted accelerated approval to it is Elizabeth in combination with protein bound paclitaxel for patients with under a septal locally advanced or metastatic triple negative breast cancer whose tumors expressed PD L one and here PD L one was stained on tumor infiltrating immune cells. So not on cancer cells but on immune cells of any intensity covering greater than or equal to 1% of the tumor area. And again, on this study, it was the Ventana SP 1 42 essay that was used to interrogate those immune cells. After the FDA approval, there was an updated overall survival analysis that was presented at the most recent Ehsmoh meeting, and this demonstrated with longer follow up, maintained overall survival benefit in the PD l one positive subset. Here it was a 7.5 month improvement in overall survival and then looking at the three year overall survival 36% in favorite Tesla's map, versus 22% in favor of placebo. So I maintained overall survival analysis, combined with FDA approval that ultimately led to a practice change for the treatment of this subset of patients, namely patients with PD l one positive, metastatic, newly diagnosed triple negative breast cancer. But what's the cost of that survival benefit and specifically, what's the cost in terms of toxicity, and here you'll see the toxicity greater than or equal to 20% incidents. A T cell is a map here is highlighted in blue. Placebo arm is highlighted in red, and you can see by the incredible symmetry in this figure that most of the toxicity is incurred by the chemotherapy backbone and looking at adverse events of special interest. The toxicity issues here, particularly immune related events very consistent with what we've seen in other studies, both in breast cancer and other studies with the most common immune related event being hypo or low thyroid is, um, here 18% and across trials we've seen 15 to 20% so this is very consistent. Less often, we see hyperthyroidism here 5%. The other immune related events were very rare. Um, and rationed, potentially non immune related adverse event occurs in about a third of patients. So is there other data for metastatic triple negative breast cancer? Well, yes. The keynote 355 study was presented at ASCO last year. This is a study, uh, looking at patients with triple negative breast cancer, also locally advanced or metastatic, triple negative breast cancer, A very similar population to the impassioned 1 30 population. The only difference here is that patients had to have completed their curative intent treatment within six months prior to first disease recurrence. And in the Passion 1 30 study, that period of time was 12 months. So this allowed for even earlier recurrences than those seen on the impassioned 1 30 study. And, um, patients in this day were randomized 2 to 1 to receive physician's choice. Chemotherapy with either pebble is a map or placebo. The chemotherapy options are highlighted here in red, the options where paclitaxel nab paclitaxel or a combination of gem side of being with carbo platinum. And there are a number of stratification factors. And in interrogating the baseline characteristics, as we did with the last study, you'll see here that using the, um, the combined positive score. Uh, so the 22 c three s a here to generate a combined positive score greater than or equal to 1, 75 or three quarters of patients were deemed PD L one positive. Using that cut off if you used a higher threshold, namely a combined positive score greater than or equal to 10, about 40% of patients where pd L one positive and that number would be very similar to what was seen in the impassioned 1 30 steady here. Approximately 30% of patients had to novo metastatic disease. Again, you'll recall, in the impassioned 1 30 study, that number was about 40%. Um, so a lower number of untreated patients were enrolled on this study. And here's the progression free survival analysis for the intention to treat population. There was an approximately two month improvement in progression free survival that was statistically significant, with a hazard ratio of 0.82 And when interrogating progression free survival by combined positive score, you could see that the improvement in progression free survival was magnified for patients who had a score greater than or equal to 10 here 56 versus 97 months. Overall survival analyses have not yet been presented, but are highly anticipated. And one of the interesting things from the study was that patients who received a taxi in either in the form of paclitaxel er, nab paclitaxel seemed to derive more benefit from this strategy than patients with Jim said to be in our carbon Platon and was Perhaps even more notable was that patients treated with the same prior class of chemotherapy, in other words, in the abdomen setting or neo adjuvant setting, received a taxi and then received a taxi. Non study seemed to derive benefit even if they had been exposed to that prior chemotherapeutic. So those were interesting findings. And in November 2020 the FDA granted accelerated approval to Pemberley. Is a mob in combination with chemotherapy so abroad? Label here for patients with under a sectoral or metastatic triple negative breast cancer whose tumors express PD L one defined by a combined positive score greater than or equal to 10. So those are the two FDA approvals that we have so far in the metastatic setting. Both of them are dependent on PD l one status, using different definitions in different essays. There was also a recent study that was presented that kind of threw a wrench into our thinking, and that's the compassion. 1 31 study does the pay, uh, study. It was a randomized Phase three study that randomized patients with metastatic, or un respectable, locally advanced triple negative breast cancer patients were randomized to 21 to receive paclitaxel with either a T cell is a map or placebo. And as you'll recall, the impassioned 1 30 study looked at nab paclitaxel with either placebo and a T cell is mob. So this study aimed to look at paclitaxel as the chemotherapy backbone. There are a never number of stratification, and the primary endpoint here was progression free survival. So no cold primary endpoint of overall survival here In this study, approximately 30% of patients had de novo metastatic breast cancer, so more similar to the keynote 355 experience. And here's the bottom line. Primary analysis progression free survival in the PD l one positive subset. There was no difference, um, in favor of a tease Eliza mob compared with placebo. And in fact, there was some concern early on, with the day to cut off in November 2019 with a hazard ratio of 1.55 in the PD l one positive population, indicating that there might actually be a detriment with the addition of a tease Elizabeth to paclitaxel chemotherapy. Um, but then, with the subsequent update of August 2020 cut off, that number actually came down substantially. Hazard ratio of 1.12 indicating essential equivalence between the two regiments. So that was reassuring that second analysis. So how do we account for this disconnect between this impassioned 1 31 data and the two regiments that led to FDA approvals from both impassioned 1 30 Kino 355 which of course, included a paclitaxel chemotherapy option? Well, it could be a number of factors, and one of those factors could be chemotherapy administration. A number of cycles exposed when the placebo arm the number of cycles. The media number of cycles was six, whereas in the eighties, Eliza map armed, the media number of cycles was five. So that's a difference of one cycle, which is actually a difference of a month of exposure. So a month of exposure for patients who historically have had a median survival of 12 to 18 months might actually have a clinical impact. So that that's one reason why there might be this discord in the impassioned 1 31 data. There also may be some differences in the population in this study that we haven't been able to tease out. It could be just chance and power this was a smaller study than the other two randomized studies. The chemotherapy backbone could be an issue, although the Kino 355 doesn't support that clearly, steroid administration has been discussed because, of course, we give steroid pre medication before paclitaxel, but not with nab paclitaxel. So that's been brought into question, although it is not clear to me, because there have been some positive studies using paclitaxel. So I spy two and keynote 5 to 2 in the curative intent setting were both positive studies using paclitaxel and, conversely, the neo trip and get Bar Nuevo studies in the curative intent setting that used nab paclitaxel were both negative studies. So there's a bit of a discordance in the data that we have to date, and it's not clear to me that there's yet an optimal chemotherapy backbone. Unfortunately, a lot of additional effort is underway to understand what's the optimal partner for checkpoint blockade. And, of course, can we optimize chemotherapy or de escalate some of the site of toxic therapy to administer more rational combinations that are less toxic and improve cure rates? So there's a lot of interest in that, and to that end, I with my group of colleagues have asked this question many times. Could we actually do something rational that would allow us to dial down the side of toxic chemotherapy backbone? And there are a number of strategies that we have explored in our group and in collaboration with others with this very intent. So we thought a lot about radiation and the immunogenicity of radiation. So radiation does a few things. It causes inflammation, so it draws immune cells into the area. But it also causes, um um tumor destruction. So it breaks tumor down into tiny fragments that might be more easily digested by immune cells. So drawing immune cells in breaking down a tumor into more digestible fragments might make that a perfect partner for immune augmentation with checkpoint blockade. And there's a lot of preclinical data demonstrating tremendous synergy between radiation and checkpoint blockade. So this led us to, um, design the first study of radiation with checkpoint blockade therapy for the treatment of breast cancer. We first did a study of brain radiation, which I'll show you a moment, and then we took on a study of palliative radiations of standard of care, palliative radiation for patients with metastatic triple negative breast cancer. Specifically, here's one of the patients that participated in this study, and this study was undertaken at Memorial Sloan Kettering in New York and Cedars Sinai in Los Angeles. And you can see here that the patient has a large breast primary tumor, and in this case, clinically, it was about to break through the skin, so she was referred for palliative radiation. But you can see that she also has a lot of central lymph node and lung metastases, as well as bilateral axillary metastases. So she was treated on study with a combination of Pemberley is a map with radiation, and she experienced complete resolution of her disease outside of the radiation field. So the so called ABS couple effect and as you'll recall immune therapy alone in patients with heavily pre treated disease like this person had are unlikely to respond to checkpoint blockade alone. So we think that this demonstrates tremendous synergy between checkpoint blockade and radiation, and in fact, in this study of 17 people, eight patients progressed or died quickly before the first evaluation point. But among the nine women, who were evaluated at 12 weeks, three of them had complete responses outside of the radiation field, one of which was durable for over two years. And like that case that I showed you up front, she actually became without a valuable disease and did not require any systemic therapy for control of her disease. So again, we questioned whether we had actually cured someone of this disease as she went on for two years without requiring systemic therapy and unfortunately went on to die of complications unrelated to her breast cancer. But that has since led us to explore these strategies in the curative intent setting. We have undertaken a study of that same strategy. Pebble is a map with radiation before standard of care, chemotherapy and demonstrated pathologic complete response rates greater than 70% which, in the context of the 45 to 50% that we usually achieve with chemotherapy alone, we think is very encouraging and are planning a larger study exploring these strategies. I also wanted to show you the case of a patient, and this was the first study to my knowledge combining radiation with checkpoint blockade. In this case, C T L. A four directed therapy with Tremmel. Um Ahmad. And one of our first thoughts about the use of standard of care radiation was the use of brain radiation for the treatment of brain metastases. Uh and so we thought we would treat patients, um, of any kind of histology with breast cancer brain metastases going for standard of care, brain radiation and concurrently administer trimming lim a mob. And for those patients with her two positive breast cancer, we co administered her to directed therapy in the form of trust us Mom. So this is a woman who had multiple episodes of prior brain metastases treated with SRS. She now had innumerable brain metastases requiring whole brain radiation. And as you can see, she had a very large burden of central lymph node and lung metastases. She'd had multiple prior lines of her to directed therapy and was thought to have tries to cement refractory disease. And when treated with brain radiation, trustees map and trim the limo mob had complete resolution of her, uh, central lung and lymph node metastases, a response that was ultimately durable. Um, and so additional studies, looking at immune therapy together with radiation and perhaps with some of these novel, uh, drugs such as to catnip. Let's have, um, impressive benefit in the brain metastases population, specifically, um, are planned at the present time. Moreover, studies looking at these strategies combining her two directed therapy with checkpoint blockade are also now being undertaken in the curative intent setting. Because, of course, whenever we see terrific innovation in the metastatic setting, we always want to move those strategies forward earlier on in the course of disease. So those efforts are ongoing. So is there anything that we can do? I just showed you to, um, studies that we're undertaking combining checkpoint blockade with radiation. Any other strategies that might be, um, effective partner with checkpoint blockade and so cryo ablation are freezing represents another such local strategy. Again, the idea is that it causes inflammation, but it also physically disrupts tur to break it down into tiny pieces that might be more readily digested by the immune system. And this is a set of experiments that was done by Rebecca Wait. She was in Jim Allison's lab, and, of course, Dr Alison went on to receive the Nobel Prize for his seminal work in identifying CTL, a four as a key checkpoint blockade, UM, mechanism that led to successful development of, um relevant related drugs. And his group did this set of experiments injecting a tumor into a mouse flank, cryo blading it, giving immune modulation and then trying to inject that same tumor into the contra lateral flank. And what they showed is that they were unsuccessful in re challenging in the contra lateral flank, indicating that with cryo ablation and immune modulation, they had successfully train the immune cells to recognize and reject cancer when that same cancer information was presented at a later date. So we were really excited about that work. He was doing that while he was at Sloan Kettering and and had the chance to work with him at that time and have adopted several cryo ablation studies together with radiation studies. And again, whenever we see success in the metastatic setting, are interested in exploring these in the curative intent setting. And this is one such effort where we administered cryo ablation versus checkpoint blockade. In patients with early stage disease, you can see the white circle is tumor There. The black probe in the center is the tip of the cryo ablation needle. You can create an ice ball here under MRI guidance, but it can also be done readily under ultrasound guidance. And then you can see the tiny tumor fragments there. And we saw that not only were we able to induce robust responses within the tumor environment, but also robust systemic immune responses indicating that we had generated a systemic response to those strategies. So there are a number of studies ongoing looking at curative intent and palliative intent, cryo ablation strategies together with immune therapy. We since completed a second pilot study in our first pilot study. With more than five years of follow up, we've had no recurrences, including in our triple negative cohort. And we have an ongoing study looking at the very high risk population of women with residual triple negative breast cancer after standard of care neo adjuvant chemotherapy. I just point this out as extensions of efforts from the metastatic setting. But certainly there are a number of groups who are looking at these local strategies together with palliative checkpoint blockade, and I think this, um is a really exciting area of innovation. So certainly looking forward when we look at the cancer immunity cycle, cancer cells have to go through a number of different phases. Together with immune cells, immune cells have to become antigen presenting cells. There has to be priming and activation. They have to get to the location where the tumor is to actually exert their, um, effects. And therefore, it's not surprising that PD one PD L one therapy, which really acts at this final stage, is not going to be sufficient for most patients. And combination strategies will most certainly be required in order to touch on each of these other areas of the cancer immunity cycle. So, in summary, where are we and where are we going? An informal overall survival analysis from the impassioned 1 30 study led to the FDA approval of a T cell is map together with NAB, paclitaxel and, ultimately, a practice change for a PD L one positive metastatic triple negative breast cancer. It has now become a standard of care for that population, and soon thereafter we saw a progression free survival benefit from keynote 355 that led to FDA approval up Embolism AB, together with chemotherapy, where chemotherapy was not defined in the FDA label and a practice change for PD l one positive metastatic, triple negative breast cancer, indicating that we could potentially use a variety of different chemotherapeutic agents together with our checkpoint blockade. Agent of choice. What still remains a question is, what's the optimal chemotherapy to administer with these drugs? And how do we select patients who are most likely to benefit from therapy and is sequencing an issue? I haven't shown the data here, but in the curative intent setting, we have seen data indicating that maybe a run in with immune therapy before initiation of chemotherapy or local therapy with the radiation, for example, might be effective if these drugs become approved and, uh, the keynote five to to pay embolism. A based regimen just went to the Kodak committee earlier this week and has been deferred. But it's anticipated that these regiments will be FDA approved in the not too distant future for curative intent. Which begs the question. If we're giving immune therapy somewhat ubiquitously, what are we going to do for our first line patients when they develop a metastatic recurrence and we really need a lot more energy in that space? If that is to be the future We're also teaching at the role in hormone receptor Positive and her two positive disease. Some preliminary data there. There could be some efficacy and certainly synergy with her to directed therapy for her two positive disease. But larger trials are needed. There are innumerable ongoing studies looking at checkpoint blockade with other biologics, targeted therapies and local regional strategies, only some of which I've shown you here today, Um, and the question about optimal curative intent approaches. What's the optimal set of toxic regimen? Can it be dialed down for some patients and escalated for others? And we need desperately biomarkers to identify predictors for not only response but also toxicity. There is no doubt in my mind that there will not be a one size fits all approach, and we will need to look at several different features. If we are going to identify patients who are most likely to benefit from these strategies, we're going to have to look at the innate immune activity of a tur. Is that hot, or is it cold? We're going to have to look at the phenotype of the cancer itself. What kind of subtype is it is a basil like is metta plastic. And then we have to look at the host to see what the host environment and the tumor micro environment have to contribute. And I think that it will only be with understanding and further insights into all of these different layers, that we will have success with immune therapy for the majority of patients rather than at this time just the minority. And I'll stop there. And I'll thank you. Um, but it is my hope that this is the future cover of Science magazine, which I've doctored here. That cancer is cured with immunotherapy combinations. And I would also like to just take a moment to think my many collaborators. I presented a lot of data today. Um and I'm very proud of the relationships and the efforts of my many, many collaborators who have brought this data to like, Thank you
