Oncology Today with Dr Neil Love: Immune Checkpoint Inhibition in Breast Cancer (Audio Program)
Oncology Today with Dr Neil Love: Immune Checkpoint Inhibition in Breast Cancer
Sylvia Adams, MD Biologic rationale for the investigation of immune checkpoint blockade in breast cancer DR LOVE: Welcome to Oncology Today — The Use of Immune Checkpoint Inhibitors in The Management of Breast Cancer. This is medical oncologist Dr Neil Love. For this program, I met with Dr Sylvia Adams from the Perlmutter Cancer Center in New York. In addition to this audio podcast, there is also a video component, with a presentation by Dr Adams. To begin, I asked her to comment on the immunogenicity of breast cancer. DR ADAMS: Yeah. This has actually been known for more than a century that some of the breast cancers have immune cells present, and they do seem to be actually more frequent in tumors that are very aggressive, very poorly differentiated, high-proliferative tumors, and it’s been actually shown over the past decade or so that it does link to a better prognosis. So there’s a — a subtype of breast cancer called medullary breast cancer that is actually known to be really rich in lymphocytes, and this had a much better outcome than other breast cancers of the same bio profile and the same grading system. DR LOVE: What did we learn about TILS? DR ADAMS: So a lot. TILS actually are the patient’s T cells and adaptive immune response to the tumor. And the fact that we find them within the cancer at time of diagnosis without any intervention tells us that the patient has developed a response against the — the tumor. And we have shown, for breast cancer in particular, that each incremental increase of 10% of TILS, when you compare different women with triple-negative breast cancer, that each 10% actually results in a better long-term outcomes for patients, regardless of chemotherapy and other — and other treatments. But this is really — it’s really important to know that the host immunity, the patient’s own immune response to the tumor, affects the outcome. And that was also one of the reasons why we thought that it would be helpful to study immune therapies to — in this particular subset, in triple-negative breast cancer. They do exist in other subtypes, as well, so they are seen also in hormone-positive breast cancers, although it’s a lower percentage. They are seeing similar percentages to the TNBC tumors in HER2-positive breast cancer. And there they also predict a better outcome. However, for hormone-positive breast cancers, that — that link has never been shown. So for those tumors there might — may be other immune parameters, such as macrophages, or TAMs, that are included in the genomic profiling, have a more significant impact on outcome of patients. DR LOVE: So fringe question, but I was doing a webinar with Wally Curran on lung cancer, the radiation oncologist, and he was talking about the fact that if you do radiation therapy it actually is thought to affect the immune system systemically. That it actually — he was talking about lung cancer, and then I was thinking I wonder if we’ve looked at — like you’re mentioning TILS, if you radiate somebody’s bone or some other part of the body, do the TILS drop down? DR ADAMS: Right. So this — this is not what he meant. He actually meant that if you radiate 1 part of the tumor that you can actually accelerate the tumor cell death and therefore a new immune response toward that killed tumor. And then those T cells can actually, in other parts of the body which are not radiated, lead to regression of the tumors. Yeah, so this has actually been studied also over the last century, and we’ve had a couple of trials looking at radiation, actually, as an adjunct to immune therapy. There certainly lots of preclinical studies with — with mice that show that if you add radiation to CTLA4 blockade, for instance, that tumors can get eradicated. And you really develop a stronger immune memory. DR LOVE: Interesting. What about PD-L1 levels and TMB levels in the various subsets of breast cancer? DR ADAMS: Yeah, that’s a — that’s an important question because obviously the antibodies that we have currently on the market target the PD-L and PD-L1 axis. And it’s been shown, again, in triple-negative breast cancer these levels are the highest. They seem to be higher in the earlier breast cancers compared to the metastatic recurrences. And they are, at least in the metastatic setting, a very good biomarker for which patients could respond. We’ll talk about the neoadjuvant studies in a few minutes, but in there, there’s actually not been that — that link between benefit of immune therapy with PD-L1 expression. It’s actually just a marker in general of better response to therapy. In terms of TMB, the tumor mutational burden, which is especially high in lung cancers and melanomas that are induced by carcinogens, you — you have a known association of the TMB levels and response to therapy. In breast cancer, the levels are not that high, actually, even though probably in TNBC it’s the highest. So in big studies, such as the IMpassion130 trial, we have not seen an independent association, only the association as long as it’s PD-L1-positive tumors. IMpassion130: Results from a Phase III trial evaluating atezolizumab/nab paclitaxel as first-line therapy for metastatic triple-negative breast cancer (mTNBC); FDA approval of this regimen for patients with PD-L1-positive disease DR LOVE: So you mentioned the IMpassion130 study, and I think that really introduced the whole issues of checkpoint inhibitors in breast cancer. Can you talk about the design and the eligibility and the findings from the study and what you think it means in terms of practice? DR ADAMS: Yeah, that’s a really groundbreaking, milestone study that — that we actually were involved in. And the design was a 1:1 randomization in 900 women, initially was a smaller study design, just to look at the progression-free survival in patients. But it was later on amended to include overall survival as a primary endpoint, and that’s when the sample size increased. And I’m really glad this was done because that’s exactly where we saw the benefit. So in this trial, this was for women who had either no prior therapy at all, who had de novo metastatic breast cancer that was triple-negative defined by less than 1% ER, or women who had a relapse in more than 1 year from prior therapy. And these women received, as a backbone, nab-paclitaxel. And on top of that 1 group was randomized to placebo, the other was randomized to atezolizumab, an anti-PD-L1 medication. And then treatment was continued until patients had progression. And it was shown that in all patients throughout the — the study there was an improvement in progression-free survival in — about 2 months for the entire population. If you looked at the PD-L1-positive population that was about 40%, 41% of this group. They had 2.5 months progression-free survival, but importantly the overall survival was significantly clinically — in a clinically useful situation, very, very extended. For the very first time we hit the 2-year mark, which is unusual for triple-negative breast cancer that’s metastatic. All the studies showed, usually, a — a survival rate of — at 1 year maybe 1 and a half years. So this is the first time we actually pushed the 2-year mark. This was only in the PD-L1-positive subset, and as you may know, due to the study design, this could not be tested for statistical significance. But it’s certainly clinically meaningful, and that’s one of the reasons that I hope that this remains approved even though the initial approval by the FDA was based on accelerated approval. DR LOVE: What about tolerability? What did we learn from the trial? That it seemed to line up in terms of what’s been seen in terms of other tumors, what they’ve seen. DR ADAMS: Yeah, so there’s no surprises. In breast cancer, it’s very similar to what you see in other malignancies when you combine chemotherapy and immunotherapy. Obviously, there is an increase in numbers for serious adverse events due to the combination, but there’s also — actually when you look at the patient reported outcomes, meaning the effect on quality of life, on any symptoms from patients and treatment effects, there was no difference between both arms. So that is really reassuring, that the addition of immunotherapy did not — was not a detriment to the patient’s wellbeing. DR LOVE: I’m curious in your own clinical experience what the spectrum of tolerability or toxicity is that you’ve observed in these patients. DR ADAMS: So I think the — the main ones are really related to the chemotherapy, the taxane, so you — you do see some cytopenias, and you do see neuropathy. And excitingly, if a patient has a very good, deep response, a complete clinical response on scans, or has plateaued in response, you can actually stop chemotherapy after — after initially maybe 6 cycles or so. So then patients continue on for a year or 2 or 3 on just the checkpoint drug, which is very well tolerated. Obviously, you have to learn about toxicity that is specific for immune therapies, such as these immune-related adverse events. And that’s important to — to convey to patients — to clinicians to watch out for those so that early on you can diagnose them and treat them appropriately so they don’t become very life threatening. DR LOVE: What about the option or possibility of using another taxane other than nab-paclitaxel or another form of chemotherapy with an IO? DR ADAMS: So that’s — that’s an important question because the reason why nab-paclitaxel was chosen as a — as a backbone for — for the combination was that we could avoid steroids in this because of the unique formulation excluding the cremophor. And — and so the initial study, IMpassion130, was positive when it utilized the nab-paclitaxel. The subsequent trial, that was 131, that looked at the substitution of regular paclitaxel, it actually did not show a benefit to — to the PD-L1-positive population or the overall study population. So there is still this question is the typical backbone, is it the taxane backbone or steroid medication or is it just slightly differences in the — in the population? As a note, there was another clinical trial, a Phase III trial that used the pembrolizumab antibody, which is PD-1 inhibition. And they utilized different chemotherapy backbones based on the physician’s choice, and they included a platinum-containing combination. They included nab-paclitaxel, as well as standard paclitaxel, and they did not seem to have this — this big difference, although the study was certainly not powered to look at which chemotherapy would be performing better. DR LOVE: Yeah, that paclitaxel data was just presented, I think, at the ESMO Meeting. Any thoughts? You bring up the issue of the steroids. Any other thoughts? Do you think it could have been just random chance or something about the trial design? DR ADAMS: It — it certainly could be — it could be chance. When you look at the control arm, the survival of the control group is actually really, really long, over 20 months, which is not what we’ve seen ever in any of the single-agent studies in this setting. So — so that raises the question although in terms of stages and de novo metastatic disease, patients seem relatively similar. Design, eligibility criteria and emerging efficacy and safety findings from the Phase III KEYNOTE-355 trial evaluating chemotherapy with or without pembrolizumab for patients with previously untreated mTNBC DR LOVE: You mentioned the pembrolizumab study, that’s KEYNOTE-355, that again was just presented at ASCO. Can you talk about specifically what was seen there? DR ADAMS: Yeah. So this study has — was also a randomized Phase III study. The randomization was 2;1, and it had a — a significant number of patients enrolled. So patients — physicians were able to choose the standard of care arm for — for their patients. And so — so the difference to IMpassion really is — to the IMpassion130 trial, is that you had 3 different chemotherapy backbones, which when positive at the trial, and it was a positive study, really allows us to supplement different chemotherapeutic backbones into these regimens. The other difference was that patients actually had to relapse — or the relapse was restricted to a 6-month period. So IMpassion, you had to have at least a 12-month period to the — to study entry. So they included some higher — higher-risk patients, certainly, patients that are more difficult to treat, between 6 to 12 months of recurrence. But in that group, that was probably the subgroup with the lowest benefit to this study. But here the — any chemotherapy was useful in this trial, and again, the progression-free survival was very — very similar, I think, to the IMpassion study for — depending on the level of PD-L1 expression. So if you had all comers it was about 2 months, and also for the IP scores — or CPS scores of up to 10% it was also — sorry. The CPS scores of 1% also showed a similar improvement in PFS of about 2 months, but when you got to IP — CPS scores of 10, then there was actually a 4-month difference in — in PFS. So — so this study confirmed, basically, that chemoimmunotherapy does have a place in the treatment of PD-L1-positive triple-negative disease that is metastatic in the first line. It also showed us that with increasing levels of PD-L1 positivity in a patient’s tumor there seems to be a higher chance of success. And that different chemotherapy backbones, at least in this setting, were — were acceptable. In IMpassion, when — when you combined the chemotherapy with atezolizumab the FDA put out a warning to not use paclitaxel as the combination partner. But for pembrolizumab in this study, this was not observed. DR LOVE: What about survival in the pembrolizumab study? DR ADAMS: So they have not shown any survival data. When — the only — the only thing is that we — when we do a cross-trial comparison we assume there will be very similar benefits in the PD-L1 population based on the incremental improvement in the PFS. But — but that is not known at this time. DR LOVE: So do you think that this is going to be enough to — for the FDA to approve it? And is it enough for docs in practice, whether the FDA approves it or not, to do it? Use pembro instead of atezolizumab. DR ADAMS: Yeah, so — right. So I — I cannot predict what the FDA — what the criteria are. It’s clearly a positive study based on the PFS endpoint, as was IMpassion130. And I think when it gets FDA approved, certainly the — an option for their clinical practice. DR LOVE: Is it something that you’re tempted to use right now outside of a trial setting? I mean you can maybe give a less frequent interval with pembro. DR ADAMS: We — we would not use that less frequent interval in these scenarios yet. I think this has been an option that has been discussed during the pandemic, but I think in the early — or in the first-line metastatic TNBC setting, where we really try to get patients into — into durable remissions, I’m — I’m not sure I would utilize a 6-week regimen, and also the chemotherapy is certainly not — not that stretchable. But the question is would I use it off label. So I do — I think for one subgroup of patients it could be considered, and these are women who have been on a neoadjuvant or adjuvant taxane within 6 months of — of recurrence. So for those patients, I think switching to a different chemotherapy backbone, the platinum-based combination, would make sense. And then if you do that, obviously you would want to do it with pembrolizumab. DR LOVE: That’s interesting. It’s so interesting to ask people in different tumor areas what they think about the q6wks pembro thing. Some people are like oh yeah, I’m doing it all the time, and other people are — have some concerns. It sounds like you have a few concerns. What are they? DR ADAMS: I think I don’t have experience with that, so I — I don’t feel comfortable using it without knowing the data in my field. But because there’s chemotherapy definitely given in — in combination in breast cancer, it really doesn’t apply as much to us as it would apply to a melanoma patient who’s treated in the adjuvant setting just as a — with a single agent immunotherapy. DR LOVE: Yeah, that’s a really good point. I didn’t even think about that. I mean, yeah sure, the same thing applies in lung cancer. They use single-agent therapy all the time. DR ADAMS: Correct. DR LOVE: You’re right. If you give it with chemo it doesn’t really give you that much advantage. That’s interesting. Activity of single-agent immune checkpoint inhibitors in patients with mTNBC; investigation of anti-PD-1/PD-L1 antibodies in combination with PARP inhibitors DR LOVE: What do we know about single-agent checkpoint inhibitors, in general, in triple-negative breast cancer in terms of response rates. DR ADAMS: In the metastatic setting there is a very interesting reliance on line of therapy. So in the very first line of therapy patients can actually have decent response rates, up to 30 — up to 20% or so if they are PD-L1 positive. Obviously, with higher PD-L1 levels you also have a higher chance of response. But once you hit second line and had some prior chemotherapy treatment, the response rates really go down into the single digits and really shouldn’t be considered off — outside of a clinical trial. DR LOVE: One other thing I was going to ask you about metastatic disease — Hal Burstein accuses me of creating clinical scenarios that never happen, but I’ve always been curious, and I like to ask people what you do with people you know are BRCA positive and have triple-negative breast cancer, first-line metastatic? Like how do you work in checkpoint inhibitors, PARP, et cetera in their strategy? DR ADAMS: That’s a great question. It is not that frequent, but if it happens, I do really urge the physicians to enroll those patients into the trial. There’s an ongoing NCI study, for instance, that allows exactly this scenario, where patients are PD-L1 selected and BRCA selected, and patients will get PARP inhibitor/IO combinations. And that’s really crucial because we know certainly that for first-line metastatic triple-negative disease, if you have a BRCA mutation that is germline mutation, that BRCA — that olaparib or any other PARP inhibitor really can make a difference in survival in that group. So that’s similar to what we know for survival benefit of patients enrolled with PD-L1-positive tumors with IO therapy. So I think merging those 2 and really studying the contribution of each of the 2 components is very crucial. DR LOVE: So for example, if you have somebody who’s got a BRCA germline mutation and they have a high PD-L1, what would your typical first-line therapy be? DR ADAMS: Oh, so you have — you have choices. I definitely would either use a PARP inhibitor or a checkpoint drug, ideally both. So that would be in a clinical trial scenario, so I — I do refer those patients. Outside of a clinical trial, I would probably try to get a platinum in in the first line, and I would do similar to what KEYNOTE — what the KEYNOTE study showed, that you have IO plus platinum combination chemotherapy. DR LOVE: Although you ask general medical oncologists, and you present a case of breast cancer, and half of them do say platinum followed — or chemo followed by PARP inhibitor, even though that’s not the way the trial — but they’re so used to it from ovary, and they believe in it. It kind of does make sense. Are there trials looking at that strategy in breast, incidentally, because — DR ADAMS: I think there are. DR LOVE: — to me it always made a lot of sense. DR ADAMS: There are certainly with checkpoint inhibition to — to see if there’s an ongoing need for maintenance. But in breast cancer, the maintenance story’s a little bit different because all the studies showed that when you stop chemotherapy in metastatic disease you have a worse outcome than if you would continue therapy. So it is not typical that we — that we stop therapy. And so therefore the maintenance question doesn’t really come into play. We — we just continue treatment as long as it works. Novel agents and approaches under investigation for metastatic breast cancer DR LOVE: So I’m just kind of curious where you see things heading in the metastatic setting. What are some of the strategies, new agents, regimens that are being looked at in metastatic disease that you’re excited to see results in? I guess one area would be CTLA4 plus PD-1. I don’t know if there’re trials looking at that, but it kind of seems like almost every tumor they’re looking into that. But what are some of the strategies that you’re — we’re looking at? DR ADAMS: So one major unmet need is PD-L1-negative patients, and I think there the potential combination with an anti-CTLA4 would make sense. The other questions in this field are would we ever consider continuing checkpoint blockade in patients who progress and just change the — the backbone chemotherapy. So we do that in other — in other subtypes of breast cancer, for instance in HER2-positive disease, where we continue some anti-HER2 agent, and we’re looking at that, the CDK inhibitors as well, should you treat beyond progression. So that is a question that has not been answered, and I hope will be in the future. Another exciting part is as you know, the antibody-drug conjugates really have made progress in breast cancer, especially in HER2-positive subtypes. But — but they are also approved for triple-negative breast cancer in the — the third-line setting after failure of 2 chemotherapies. So in those patients, studies are ongoing looking at the combination of these ADC compounds with immunotherapy. And I think that is a really interesting concept too, can we use that — that accelerated cell death and potentially augmenting the antitumor immunity, and then benefit with an anti-PD-1 or PD-L1 drug? DR LOVE: Yeah, that’s a really interesting thought. I know in bladder they’re all excited. They have an antibody-drug conjugate, enfortumab vedotin. I think I’ve seen it in other cancers. Are there any trials right now — where you’re talking about trastuzumab deruxtecan, right? DR ADAMS: No, I’m talking about the IMMU-132 drug that’s — DR LOVE: Sacituzumab? DR ADAMS: — in breast. Yes. Yes. That’s approved in metastatic breast cancer, triple-negative disease, a third-line setting. And that is — is a drug that’s being tested, actually, in combination with atezolizumab and also I think other checkpoint inhibitors. DR LOVE: That’s an antibody-drug conjugate? Sacituzumab? DR ADAMS: Yup. DR LOVE: Interesting. So they’re combining that with — with immunotherapy. Interesting. Just as a byproduct or side question, what have you observed with that agent in terms of efficacy and tolerability? DR ADAMS: So it’s been on the market only relatively recently, and the data probably shows that it benefits maybe a third or so of the patient population, with shrinkage of tumor. So it’s a — it’s an additional option, but it’s, in my mind, not as — not as potent as the immunotherapy. And I would always encourage patients to definitely seek out immunotherapy if possible. Even if you’re PD-L1 negative, I think you should still look for a PD-1/PD-L1 in combination with other treatments on trial because that is the only chance I think we have for potential cure for metastatic patients. But yeah, so this drug is okay. It has some asthenia, some hair loss, some — patients do feel a little bit of nausea. Vomiting can happen as well. Efficacy and tolerability of the antibody-drug conjugate trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer DR ADAMS: I’m definitely more impressed with the — with the other — the deruxtecan compound that — that has just an unbelievably — unbelievable efficacy profile, with responses in really the majority of patients. DR LOVE: Yeah, the waterfall plots on that look amazing. Have you given it to patients? DR ADAMS: Yes, yes. And I — I show the waterfall plots to all of our clinical researchers, to our students, because I think that is really a breakthrough in oncology, where if you have pretreated disease that is resistant to trastuzumab, chemotherapeutics, et cetera, and then seeing such a waterfall plot where pretty much every patient has tumor shrinkage is — is quite inspiring. And yes, I have given it the patients, just after it became approved, and 1 woman, we just actually had a TV special with her the other night. She was coming off opiate therapy after 1 week of being on the — on this drug, because — DR LOVE: Wow. DR ADAMS: — the liver metastases that she had were very, very painful, and just 1 week into treatment she — she was really symptom free. DR LOVE: Any pneumonitis that you’ve seen? DR ADAMS: I have not seen it in — with any of those antibody-drug conjugates. I’ve certainly seen it with the CDK4/6 inhibitors. We’ve seen it also with taxanes and radiation in earlier breast cancer. DR LOVE: So yeah, the lung and GI people are now equally excited about this. We’ll see where that all heads. Available data from Phase III trials documenting the benefit of neoadjuvant anti-PD-1/PD-L1 therapy in combination with chemotherapy compared to chemotherapy alone for TNBC DR LOVE: Let’s talk about the early triple-negative disease, neoadjuvant and adjuvant therapy. There’s lots of interesting questions we’re hearing from docs about that. Can you talk about what we know about neoadjuvant checkpoint inhibitors, particularly in triple-negative disease? DR ADAMS: So there have been — there have been quite a few Phase III trials. I think the initial one was the — the I-SPY — I-SPY adapted Phase II study that looked at if you add PD-1 antibodies to standard neoadjuvant therapy, chemotherapy, then what is your chance of improving your PCR rate? And it was definitely shown to be superior in triple-negative breast cancer, as well as hormone-receptor positive tumors. And it graduated in that design. So the — the main studies that I look toward for neoadjuvant therapy are the — the KEYNOTE study 522 and the IMpassion031 trial. And both of those studies show that the addition of, in one study PD-1 and the other one PD-L1, inhibitors to standard chemotherapies that we use are increasing the pathologic complete response rates quite significantly, by at least 10 points or so. And so this is really, I think encouraging. The differences between the trials, one having platinum, the other one not having a carboplatin backbone, is making it a bit tricky for — for — for us in terms of what do we do going forward. But — but I think in general it — it tells us that there is a success story. We — we don’t yet have, though, the clear indication that the magnitude of change in PCR rates translates into that similar benefit in survival. So one of the studies, the KEYNOTE study, showed early analysis that there was an improvement in event-free survival, so that was the earliest indication. But — but we’re still waiting for those data, and I also wonder what the FDA will do in the meantime. Will they approve it based on a PCR improvement, or will they wait until you really show survival benefit as well? DR LOVE: What are your thoughts on that? Do you think it’s ready for primetime? Not so much a regulatory issue, but just clinically, if you could utilize a checkpoint inhibitor, are there any situations where theoretically you’d want to do it? I mean I guess one thing you might think about, I guess it could be someone who needs shrinkage in order to breast conservation, although maybe that’s not the most common or important objective. But what situation would you want to try to do it? DR ADAMS: Yeah, I think that’s kind of the similar question that we ask ourselves in the clinic, when to add carboplatin to ACT. And — and that also, I think in Europe it’s considered standard. In the US, because of some discrepant data on long-term positive effects, the — it’s still — it’s still not — not a standard across the country. So I use those drugs to increase PCR rate in patients who have very high-risk disease, such as inflammatory breast cancers, where you have a T4d tumor, where you have really inoperable disease, with N3 or matted axillary lymph nodes, lots of skin involvement. So in — in those patients I think right now it should be used as a standard, to use it with carboplatin and a checkpoint inhibitor. And I — I would for those patients certainly try to get compassionate use. But for —for the other patients, especially earlier stage of breast cancer, like a Stage II, node-negative TNBC, I — I still want to see more survival evidence of benefit because, as you remember, in the initial I-SPY trial, there were several patients who were diagnosed with adrenal insufficiency, and those were picked up often later. They were actually picked up, some of them, after surgery. And this is a lifelong, plus life-threatening condition, so yes we can treat it with steroid supplementation, but it is something that could be missed, and also is — is certainly a significant medical condition to have for the rest of your life, requiring long-term attention to this. So I — I don’t think it is — it is right to add the IO drugs to all comers, and obviously biomarkers are important. And we haven’t made lots of progress there, so in this setting, in the neoadjuvant setting, we have not been able to say that PD-L1 is a big — is a big differentiator. It does differentiate who has a greater chance for PCR, but it — you see benefits with the addition of the IO drug, both in the PD-L1-positive, as well as the PD-L1-negative subsets. DR LOVE: Yeah, I mean I think we’ve been so happy about the good tolerability profile of IOs we forget that it does cause problems. We had — in the last few days we’ve had 2 cases that were presented on our CME programs of people with IO-related type 1 diabetes; one of them presented with DKA. That’s not a good thing so to speak. And of course lots of people go into path CR just with chemotherapy as well. Role of (neo)adjuvant immune checkpoint inhibition for patients with TNBC DR LOVE: Let’s talk a little bit about the management of patients who get neoadjuvant therapy for triple-negative disease and then have residual disease. Most patients are getting neoadjuvant therapy, and for those who have residual disease, right now I guess most people are going to get capecitabine. What do we know about immunotherapy in that space? DR ADAMS: So that’s — that’s a very important space, and I think what you’re mentioning is that most patients get this neoadjuvant therapy is really crucial because not only does it potentially downsize tumor, we really get to change our action depending on the outcome at surgery. So for patients who have clearly a pathologic complete response, no further therapy’s needed. For patients with residual cancer, there has not been studies showing that additional chemotherapy, as you mentioned, capecitabine, can further reduce the chance of recurrence, and also ongoing trials that look at this space in particular, adding an IO drug to the — to the patient’s option. And here we heavily enroll into the ongoing SWOG trial that tests if pembrolizumab, the anti-PD-1 antibody, actually can improve the outcomes better for patients. And that trial has very encouraging results so far in terms of accrual. So far 900 women have been enrolled on this study out of the thousand women that were planned. DR LOVE: Wow. DR ADAMS: That really speaks to not only the need for this population, but also the incredible efforts of – of patients and — and physicians to really make a mark in this field. Because yes, if you have not received a checkpoint inhibitor for neoadjuvant manipulation, I think it’s definitely an important strategy to do when patients have residual disease after standard chemotherapy. DR LOVE: I see that the trial’s pembro versus observation. Are you allowed to give capecitabine? DR ADAMS: So the capecitabine actually is allowed to be given beforehand. So when patients went to — or planned going onto the study they are asked to decide with their physician if you want to do capecitabine or not. If so, you continue and you — you actually initiate your cape, give it for 6 to 8 cycles, and then you go onto the pembrolizumab trial. DR LOVE: Interesting. So what about adjuvant therapy with the checkpoint inhibitors? Adjuvant trials? Of course we see in melanoma. We have them approved. What about in breast cancer? What kind of trials are we doing? DR ADAMS: So there’re several — several Phase III trials, as well, that — that look at atezolizumab and pembrolizumab and others in combination with standard adjuvant chemotherapy regimens. The readout will take a long time. So I — I think we’ll definitely have more of a readout from the neoadjuvant studies, as well. And again, personally I — I prefer to have a patient receive neoadjuvant therapy and then be able to, at time of surgery, depending on residual disease or not, make that informed decision on what to do next. And that’s not an opportunity when you — when you run the adjuvant study. DR LOVE: Yeah, the same thing in HER2. I think it’s hard to run adjuvant trials nowadays. DR ADAMS: Yup. Case: A woman in her early 40s with mTNBC develops immune-related autoimmune diabetes while undergoing treatment with atezolizumab/nab paclitaxel DR LOVE: Let’s talk about your cases. These are patients you actually took care of — DR ADAMS: Yeah. DR LOVE: — or hypothetical cases? DR ADAMS: No. All my patients. DR LOVE: Okay, great. Let’s talk a little bit about your 42-year-old lady. DR ADAMS: So — so here, I think you mentioned, actually, recently that you had a discussed about 2 women who had induced diabetes from the immunotherapy, and this woman is very similar. So she is 42 years old, and she was in our very first Phase I trial of atezolizumab and nab-paclitaxel, and she had — she had cutaneous involvement and hepatic metastases. She was recurring I think 4 to 5 months after neoadjuvant AC/T chemotherapy and obviously had a very rough disease course and ultimately, actually also died from her progression — progressing cancer. But what was interesting in her is she had pretty much no side effects from the immunotherapy component, but when she came for her fifth treatment cycle, she had very elevated blood sugars. And she was a very thin Caucasian woman, and she had a sugar in the 400s that was obviously very new for her. She had only been in the 100, 200 range. And obviously this was a Friday evening, as usually happens, so luckily one of her friends actually — was actually an endocrinologist who was able to initiate insulin therapy immediately for the weekend. But what we were able to test — it is helpful to check the C peptides to see what the endogenous insulin production is of these patients, and also the antibody — anti-GAT antibody. It’s very useful because it tells you that this is an autoantibody that develops. And — and there have been several case reports, et cetera, so this is a known side effect of immunotherapy. It is relatively infrequent, I would say probably less than 1% that happens. She also did have pregnancy-related hyperglycemia, but — but that was really just limited to her pregnancy, and she had normal blood sugars before and a normal insulin level before. So — so this is important to — to pick up and to really treat because patients can come in in diabetic ketoacidosis, and obviously that is a life-threatening event. DR LOVE: So how do you determine if it’s type 1 or type 2, and what about her? DR ADAMS: So — so the fact that her insulin levels are so low and that she had an autoantibody it was very clear-cut to us that this was a type 1 diabetes, and she responded really beautifully to — to insulin supplementation. And then we continued her on — on immunotherapy because obviously once the islet cells are gone there’s not detriment to continuing. DR LOVE: Yeah, in one of these cases I was telling you about, I think it was lung cancer or something, they stopped the therapy, and I was like well why? It’s like hypothyroidism, like you said — DR ADAMS: Correct. DR LOVE: — you’ve already done the damage. Right. DR ADAMS: Yup. DR LOVE: Interesting. And did the tumor respond? DR ADAMS: Initially, she did respond, especially — she had a very, very dramatic response in the liver, which was very nice to see. But — but this was not durable for her. DR ADAMS: So I — I think what I recommend to — to anybody is to really look up the guidelines that were published in the JCO 2 years ago. That document is really unbelievably useful. It’s probably 80 pages long, and in there it really breaks down every single potential immune-related adverse event. It also gives you the — the criteria for the grading. It gives you the workup needed, the treatments needed. So — so this is really my — my go-to resource, and it’s easily accessible for — for students and — and other physicians. So I really follow it by — by the “T” and obviously also when — when things are — when patients have higher-grade toxicity I also talk to our colleagues in — in melanoma who have been using these drugs for — for many more years before me. But yeah, we summarized — specifically for breast cancer we summarized the immune-related adverse events arising from checkpoint inhibitors, and there are, in particular, as you said before, rash/dermatological issues. But then the second most common one is the thyroid, so hypothyroidism is very frequent and really should be — should be checked for on a regular basis. So at the beginning of starting checkpoint blockade you need to really look at TFTs and also at regular intervals, maybe every 3 months or so. We do see quite a few patients who have elevated liver function tests that mandate, unfortunately, stopping if — if at a higher grade, stopping immunotherapy. I’ve had patients who were never able to go back onto it because of prolonged requirement for steroids. And then there is the risk of pneumonitis. I think that is something that — that is truly important for us, and there has been questions if the combination with a taxane, which can itself also cause pneumonitis, can increase the — the incidence of it, and probably not much. So in the IMpassion130 study it was slightly greater in the combination compared to the taxane alone. But I have seen 1 woman who had multiple courses of radiation for recurrent — locally-recurrent breast cancer, and she developed pneumonitis about 4 years into her checkpoint medication. So — so it really can happen, and you just have to make sure to discontinue the — the therapy early, to start patients on steroids, low threshold to escalate immunosuppressive therapies if — if they really end up in the hospital and are sick. DR LOVE: One of the things we hear in general, maybe more in lung cancer, is the challenge of working up pneumonitis in the COVID era and the fact that you have to now bring that in. Of course, you’re in New York, where you were at kind of the beginning of this, and so you saw that happen. I’m just kind of curious in any way you changed your practice as it relates to being in a situation where there’s a lot of COVID, any drugs you avoid. Obviously, people try to keep people out of the hospital. Have you seen any breast cancer patients with COVID? DR ADAMS: We’ve had our share. I would say a few patients. But we just actually finished a look at our entire health system in New York at our institution, and out of thousands of women who received treatment, that includes chemotherapy, immunotherapy, and endocrine therapy, there really wasn’t a significant increase in mortality in these patients. Yes, we did see COVID infections. We — there may be slight predisposition in women who are on chemotherapy, but — but really the outcomes have not been bad for our population, so I’m — I’m actually encouraged to see that, and we’re trying to also therefore kind of stay — stay away from — from lowering doses or intervals for especially curative therapies. But yes, during the COVID time, we certainly have tested patients before starting immunotherapy regimens, before starting them on chemotherapy, just out of — out of concern. And yes, it is very difficult to work up the difference between COVID with inflammatory infiltrates and — and pneumonitis from — from these reactions. DR LOVE: This concludes our program. Special thanks to Dr Adams, and thank you for listening. This is Dr Neil Love for Oncology Today. |