Case: A woman in her mid 50s with ER-positive, HER2-low (IHC 1+) metastatic breast cancer with an ESR1 mutation

DR LOVE: Welcome to Oncology Today, a special program focused on the current and future role of oral SERDs in the management of ER-positive metastatic breast cancer. This is medical oncologist Dr Neil Love. For this program I met with Dr Komal Jhaveri from the Memorial Sloan Kettering Cancer Center. In addition to this interview there is also a corresponding video program featuring Dr Jhaveri’s slide presentation.

To begin, we hear about a case from her practice of a 56-year-old woman with ESR1-mutated ER-positive, HER2-low metastatic breast cancer.

DR JHAVERI: This is a 56-year-old patient who presented with de novo ER-positive, HER2-negative metastatic breast cancer. The HER2 is IHC 1+. And she was metastatic to the bone, which was biopsy proven in 2018. She was started at that time with letrozole and palbociclib. And 5 years later, so very good duration of response on this therapy, she had progression both in the bones and in the liver. At that point, a plasma NGS panel was done and that showed an ESR1 mutation, a D538G mutation.

And so the question is, what is the best next treatment option for this patient? Should we be thinking about trastuzumab deruxtecan because she’s IHC 1+? Should we be offering capecitabine? Should we offer her alpelisib with fulvestrant? Or should we offer her elacestrant?

DR LOVE: Can you elaborate a little bit about the type of mutation that she has there?

DR JHAVERI: Right. So the most common ESR1 mutations that we see in clinic are D538G and Y537S. We do see other ESR1 mutations as well, but these 2 are the most common ones that are detected in most of the NGS panels. And so this is not very surprising that this patient who has had a CDK4/6 inhibitor and aromatase inhibitor for 5 years, that under the selective pressure, they developed an ESR1 mutation. And we know that the prognosis of a de novo patient is probably better than a locally recurrent tumor. And so this is truly an endocrine sensitive tumor that under the selective pressure also developed ESR1 mutation which is one of the most common kinds of ESR1 mutations.

DR LOVE: Can you talk a little bit about where the tumor was, what kind of symptoms, if any, she was having at that point?

DR JHAVERI: Yeah. So I think the tumor had progressed in the bones and there were 2 new liver lesions. The liver lesions were small, about 1.5 to 2 cm. And we had done a NGS panel at that time because she was reluctant to do a biopsy in the liver or in the bone.

The bone biopsy last time that she remembered or recalled having was painful and she didn’t want to go through it if it was possible, so that’s why we chose to do a plasma NGS panel and detected this ESR1 mutation in that NGS panel. But she was otherwise very asymptomatic. Had it not been for the scans, it’s not like she had increased bone pain or clinical pain that would have led to a diagnosis looking for this. This was something that we were routinely doing every few months. Her markers actually were also, that I was following because she had markers when she was de novo metastatic and had come down with therapy, remained undetectable at this point. But radiologically, we did see that there was growth.

DR LOVE: I’m curious what you actually recommended to her and whether it might have been different if she had been highly symptomatic or had a lot of, say, more liver disease and more visceral disease.

DR JHAVERI: Yeah. I think, again, a great question. So I did offer her elacestrant because this happened when elacestrant was approved and I had that option to offer that patient. And I was extremely excited about that exploratory analysis we discussed about duration of CDK4/6 inhibitor therapy and how single agent elacestrant yielded 8.6 months in that analysis. And so I was happy to offer that to this patient who was otherwise asymptomatic to maintain her quality-of-life with low-grade nausea, if anything, with elacestrant.

If this tumor would have had other alterations or if this tumor had led to more symptoms, I would have still discussed this given the durability of the first-line response with her and kept a close eye on these liver lesions by repeating scans maybe in 8 to 10 weeks rather than 3 to 4 months which is when we usually think about doing this to make sure that things are headed in the right direction. But if she was truly in a visceral crisis, if you will, so if she was symptomatic, the disease burden was super high in the liver, her LFTs were completely deranged, I have then thought about chemotherapy and maybe even resorted to weekly paclitaxel in that case, if not capecitabine.

DR LOVE: That’s a great point. Would you have thought through it differently if she had either a PIK3 mutation or an AKT alteration?

DR JHAVERI: Yeah. Again, a great question. Fortunately, when we think about both ESR1 and PIK3 or AKT alterations, that’s about 12% of our patient population. And so when we think about ESR1 alone, we’re seeing about 40% depending on when we catch them, 30 to 50% is what I think the range is depending on if you see them in the second-line or the third or the fourth-line. When we’re thinking about PIK3 mutations, say, we’re thinking about 30 to 40%. AKT is in a single digit, about 5%. So I think overall, that pathway mutations, if you think about PTEN, AKT, PIK3 combined, it’s about 45, 48%. Together, they’re 12%. We don’t really have data to suggest that what should be the sequence if patients have both these alterations. Meaning, would they benefit better if we give them elacestrant first or should we give them a PIK3 inhibitor or an AKT inhibitor with fulvestrant first and do elacestrant after? So we really don’t have that data. But maybe a discussion about looking into what is the disease site. What was the durability of response from prior therapies? Is the patient really symptomatic? Can we have a discussion about the toxicity profiles of these drugs with that patient and really have a patient/physician shared decision process is how I think about this because quality-of-life is important. Toxicity is a concern which is not trivial with targeted therapies in terms of what kind of toxicities they can have and the other clinical parameters favor the analysis that we have with elacestrant, I think it would be reasonable to consider elacestrant first and then think about a combination therapy as a third-line option should the tumor progress on elacestrant.

DR LOVE: So let’s see, there’s one other thing I was thinking about with this. Oh. I’m curious, I’m guessing the patient is on elacestrant. How’s she doing?

DR JHAVERI: She’s doing great. And she actually has remained on that. This is her probably sixth month right now. She’s tolerated it very well. Has not required any antiemetics, mild nausea some days, not every day, and has been tolerating it really, really well, is very happy with her current regimen.

DR LOVE: I don’t know if she actually was having tumor-related symptoms. But if she was, like in the bone, did that get better?

DR JHAVERI: Yeah, she did not have any. I have had another patient who I offered elacestrant to with some bone pain, and her hip pain actually started resolving within 3 to 4 weeks of initiation of therapy.

DR LOVE: Interesting. All right. Let’s go to the next case.

Case: A woman in her late 40s with ER-positive, HER2-low ESR1 wild-type metastatic breast cancer who received imlunestrant on a clinical trial 

DR JHAVERI: So this is a Taiwanese woman, 49 years of age currently. Past medical history of anxiety and insomnia, which is controlled.

She originally presented to an outside institution in 2011 with a left-sided cancer, which was ER-positive, and HER2, which was negative, so 2+ and FISH nonamplified, status post lumpectomy, sentinel node dissection, and radiation. Her Oncotype score was really low. She was on tamoxifen and received that from 2011 to 2015 at which point, she was diagnosed with a right-sided, so contralateral, DCIS. Again, had lumpectomy at that time, radiation, and then was put on raloxifene therapy which she was on for 3 years when she actually was seen at Memorial. At that time, she was 43 years when she came to our institution. She was, at that time, found to have a mass in the ipsilateral side, so the left side again. There was a suspicious mass on imaging and that led to a biopsy that confirmed that this was cancerous. It was moderately differentiated invasive ductal. It had DCIS as well, so a new cancer, 95% ER, 98% PR. HER2 1+. Ki-67 was 5 to 10%. She also had a staging scan done at that time given that this was a new focus again on the left side which, unfortunately, did show some findings in the liver and also in the endometrial cavity. We did more workup for the endometrium. That was benign really, chronic changes and squamous metaplasia. We initially did a liver biopsy which turned out to be benign, so we were not sure. It was FDG avid but because we missed it, we repeated a PET scan again at that time. Again, persistent FDG activity. This time, we did repeat a liver biopsy again. And that liver biopsy in March of 2018 confirmed that this was metastatic disease. It was adenocarcinoma, Grade 2, comparable with her primary, ER 99%, HER2-negative. AR was also tested which was 99%. She was started in 2018 with letrozole and palbociclib. She was on it for nearly 31 months before she had progression in the liver.

So this was, again, the liver that acted up. Did not have derangement of liver function test. Did not really have symptoms. We did do a liver biopsy in November of 2020. We ran an NGS panel using our in-house assay, the MSK-IMPACT assay. There was an ATM mutation, a GATA3 mutation, and TBX3. No other alterations. Genetic testing did not reveal any BRCA mutations. We also ran a plasma NGS to ensure there was no ESR1 mutations. There were no ESR1 mutations detected at that time. At that time, we had the Phase I EMBER trial study that was open for enrollment, so we enrolled her into the EMBER trial. And she got the imlunestrant oral SERD and stayed on it for nearly 2 years or nearly over a year, no, 2 years as we see. November 2020 to December 2022 which is when she again progressed in the liver. She tolerated treatment well with Grade 1 nausea and diarrhea requiring some antidiarrheals once in a while if she had to maybe go out or something, but not on a daily basis, and did really well on this therapy for a long time.

DR LOVE: Just amazing, the case. One thing about this case that’s kind of interesting is the high AR. How often do you see that? And how does that fit into the whole concept of what you’ve been talking about, if at all?

DR JHAVERI: Right, right. So AR and ER actually kind of go hand-in-hand of a lot, meaning you will see a lot of AR positivity in ER-positive, strongly positive tumors. It’s not very uncommon to see that. We have some trials. There was one interesting drug, enobosarm, and that showed some data in the ER-positive space and is being evaluated in Phase III trials for the same. We’ve looked at antagonists like bicalutamide and enzalutamide, which have not necessarily panned out as great, but there has been activity that has been reported out from those trials. Unlike triple-negative breast cancer where AR really is also being evaluated in Phase III with these drugs where you would see a slight difference, you would see the luminal AR kind of phenotype of triple-negative that will have AR positivity, but not all triple-negative breast cancers. But unlike that, ER and AR are kind of co-expressed and you can see a whole lot of that ER activity with AR.

DR LOVE: Okay, let’s go to your last case.

Case: A woman in her early 60s with a history of localized breast cancer who received imlunestrant and abemaciclib on a trial for newly diagnosed metastatic breast cancer after disease progression on endocrine therapy 

DR JHAVERI: So my last case, a 60-year-old woman. And at age 40, had DCIS, which was treated with lumpectomy and radiation. In March of 2017, had bilateral mastectomy and right sentinel lymph node biopsy. The right-sided breast showed a 1.1 cm moderately differentiated IDC. ER/PR-positive at 50% and 30%, HER2-low at 1+, node-negative. Oncotype score was low at 6. She was started on tamoxifen which she received from April 2017 to January 2020. She was switched at that time to exemestane; however, did not tolerate it due to arthralgia, so went back on tamoxifen. She then palpated a right breast mass. Ultrasound showed a 1.2 cm x 2 cm complex mass. Biopsy of which in ’21 showed IDC Grade 2 which is ER 100%, PR 80%, HER2 that is negative by FISH. MRI confirmed a 2 cm mass and some indeterminant liver lesions. PET scan done in February ’21 confirmed the hypermetabolic liver lesions, periportal nodes, lytic bone metastases, and MRI was done at that time due to headaches which was negative. She did have a lot of bone pain from this lytic bone metastases, so did receive palliative radiation to the right hip. She did have a biopsy from the bone that confirmed metastatic disease. Again, ER 80%, PR here was less than 1%, HER2 nonamplified. So this is truly a first-line case, right? So this was DCIS and then now newly presented with metastatic disease in 2021 in the right breast that has spread to the liver. So this was post-AI, but presented now with metastatic disease so she was started on oral SERD with abemaciclib here, so this is not first-line, this is second-line. I apologize. So this is post-adjuvant therapy. She received this and has biopsy proven cancer in the liver and bone. And she was enrolled on imlunestrant with abemaciclib on the clinical trial, and remains on trial today. So she started in April of ’21 and she was last seen this month actually and remains on trial. This is ’24, not ’23.

DR LOVE: So just tracking back, her first-line therapy for metastatic disease was what? Exemestane, I’m not sure, or tamoxifen?

DR JHAVERI: So she progressed on tamoxifen and that’s why she was enrolled on the oral SERD with abemaciclib because that was allowed.

DR LOVE: Right, okay. And then can you talk a little bit about, I’ve had enough trouble trying to, honestly, to be honest, I try to be honest about these things because I think everybody else feels the same way a lot of times, but I’m still perplexed about how CDK works. And I’m really perplexed about what would happen if you take CDK and add in a SERD like imlunestrant biologically. What do you think happens?

DR JHAVERI: So if you think about ER, ER is downstream of CDK4/6. And if I were to just think about a linear tree, you think about PI3K, AKT right up top. You do see CDK4/6 here. And then you have ER. And I think it’s a complex cascade, right? They’re all kind of, when you think about CDK4/6, these are kinases that are activated in ER-positive tumors. And they have mechanisms through the retinoblastoma protein. We know the retinoblastoma protein is a tumor suppressor gene. And so what retinoblastoma proteins are doing is they’re unleashing the gates of the cell cycle and making the cell cycle proliferate really rapidly. And that retinoblastoma is doing that because of the upregulation of cyclin D1 in ER tumors which then interacts with CDK 4 and 6. And that along with the retinoblastoma is really making the cycle go in proliferation. So if you inhibit the CDK4 and 6, you’re putting brakes back on the retinoblastoma. You’re actually putting a break on the cell cycle again and preventing this proliferation. And you are to try and do that along with endocrine therapy so that you can have a comprehensive blockade or downregulation of the ER pathway activation. So that’s what you’re trying to do by combining these drugs. Now oral SERDs, they are a good way of targeting the ER, better than, say, AI or better than, say, tamoxifen which is why we’re studying them the way that we are, the hope is that maybe we’ll block this even better. More comprehensively because we’ll degrade and antagonize the ER and we’ll also take care of the mechanisms of resistance to the cyclin D, CDK4/6, RB by combining them. And this is why this patient was treated with the oral SERD and abemaciclib. This was thought to be a good combination of a CDK4/6 and ER-based therapy when her tumor progressed on adjuvant endocrine therapy. And as we’ve seen in these trials that these patients do well with these combinations, this patient has remained on therapy since 2021.

You know, we talk about all these new drugs and we talk about all these clinical trials that are ongoing or being planned, but I think what is really, really the goal here is to try and improve outcomes for our patients. We cannot thank them enough to really trust us to be able to enroll on these trials, get access to these drugs, and the families who support them. So I think that is what really inspires all investigators to really think about developing these new drugs for our patients to improve outcomes. So I think a big thank you goes to them.

DR LOVE: And the great thing is, like you think about the patients you presented today, this is not just a question of trying to help future patients. A lot of people benefit by being in trials. And you presented a couple patients as examples of that.

Beyond the Guidelines: A survey of clinical investigator perspectives on the current and future role of oral SERDs (selective estrogen receptor degraders) for ER-positive metastatic breast cancer 

DR LOVE: Well, let’s talk a little bit about this survey we did of clinical investigators, of 20 clinical investigators. You can see, we have some pretty prominent people there. So I want to try to compare notes with this group and you in terms of how you think through various situations. So just sort of as a background and then we’re going to focus on SERDs. But just a couple questions we asked. We always ask, we’ve been asking this for a long time, which is preferred CDK in the premenopausal patient and in the postmenopausal patient. And I guess everybody’s still into the survival benefit. Although abema looks like it’s coming up a little bit. Any thoughts?

DR JHAVERI: Yeah. I think pre-ASCO 2 years ago when we saw the lack of overall survival with PALOMA-2 is when really the practice pattern started changing. So I think while we do not have any head-to-head trials comparing the 3 drugs and we never will necessarily have that data, what we’ve consistently seen across the MONALEESA program, whether it’s MONALEESA-2 and 3 in postmenopausal women first or second-line, MONALEESA-7 and 3 are perimenopausal women and now we also have early-stage signal from NATALEE, we’re seeing this consistent overall survival benefit with ribociclib, which was really not the primary endpoint. When we look at the primary endpoint of PFS, that was identical. The hazard ratios were the same for all 3 CDK4/6 inhibitors. But despite not requiring the overall survival, the consistency of overall survival in the MONALEESA program made people wonder why not ribociclib, right? When you have a patient in front of you, why not offer them this drug? And that’s why I think the practice patterns have kind of tilted or shifted favoring ribociclib. Again, don’t think that I don’t like the other drugs. It’s just that we have consistent overall survival data and so that has made me sway my practice as well, and I do offer ribociclib. I feel very comfortable to switch over to the other 2 for toxicity reasons or any preference reasons if patients might have any. But otherwise, my go-to has been ribociclib since that data set.

DR LOVE: And it’s interesting because this story has been evolving over the last year or 2. And abema is starting to get some interesting looking data in terms of survival. And poor palbo is lying down there maybe not getting used as much. But I started to hear a lot more about talking about palbo after you presented your triplet study at San Antonio. And people were like whoa, wait a minute. Now palbo, that might be better in a triplet because it’s better tolerated. So we could spend another hour talking about that study, but do you want to just wedge that in because I know it’s just so interesting, that study. We talked about it right before you presented it.

DR JHAVERI: Right. Thank you for bringing that up. I do think I was such a palbo user and I really was very, you know, it took me a week to get out of my denial and my depression of the data of why I should be switching my practice because I really enjoyed giving my patients palbociclib. And I haven’t changed any patients who stay on palbo and have derived benefit. Have not switched my ongoing patients. So there are many patients I still have in my practice on palbociclib. I personally really do not think that palbociclib is that inferior. I do not think that one drug is way superior than the other. I think I’m just challenged with if I have a woman sitting in front of me and we talk about the data that exists, how can I ignore the overall survival data and not offer that? I still discuss the toxicity profiles. I discuss that and then I offer ribociclib. But I do think that when we’re thinking about triplets and with triplets, we always have this skepticism, right? Because the more drugs you add, the more toxicities, obviously, you’re going to naturally get. Yes, you will get more efficacy, but you’re going to get more toxicity. And clearly, the least amount of monitoring and the least amount of toxicities that we have seen to date with a CDK4/6 inhibitor has been palbociclib.

And if you were to take a survey only in Florida, for example, right? I’m just giving one example of a state. You will see a lot more palbo users there than ribociclib even today. And the reason for that is that older patients, which is what we see in Florida, have more medications that they’re taking. And if they’re taking more medications, the risk of QTc prolongation or concurrent issues with 2 drugs causing interactions is much higher. And with palbociclib, we don’t have to worry about that. With ribociclib, there is a worry about QTc prolongation. So I still think that there is variations in practices. If you go X-US, there is still variations in practices depending on what country you’re going to survey. I don’t think we’ve all necessarily settled into one and we go back and forth about our thought process. We first said all are the same. Then we started saying there might be some differences. We’re going back to the idea that they’re kind of the same. We’re never going to know this. I think we might have to use all of them in different contexts.

DR LOVE: So actually, I want to throw in a question that just popped into my head. It has nothing to do with anything, but relates to something I heard, believe it or not, in myeloma that made me think about this which is, because I’ve been wanting to ask somebody this. Do you see more neutropenia with CDK in Black patients?

DR JHAVERI: It is absolutely true. I do see more neutropenia in African American patients and also some Asian patients. And the reason is when you think about baseline neutropenia, that prevalence is higher in both of these patient populations. So you’ll see many young patients, older patients, when you see them for the first time and you do their bloodwork, their WBC and ANC is much lower than your traditional white patient population. And I think that’s where sometimes thinking about abemaciclib over ribociclib or palbociclib might be more attractive given that they already have baseline neutropenia and you might not be able to necessarily give them full doses of these drugs. And abemaciclib with slightly lower neutropenia rates, but more diarrhea might be a more attractive patient option.

DR LOVE: If you have an African American patient with baseline neutropenia, how do you manage it when it goes down in terms of holding it?

DR JHAVERI: Right. So I think I do the same thing that I would do. I would think about maybe depending on the degree of neutropenia think about maybe abemaciclib in that patient population. It’s not that I would not try ribociclib in that patient population. They might be fine with the neutropenia not being a big factor. But I would discuss abemaciclib as well. And then I would dose hold because we do do CBCs every 2 weeks when we start the CDK4/6 inhibitor for the first 2 months, so we’re going to get those values. We’ll know exactly what the patients are going to do. We already know what kind of dose reductions we can do on these drugs. We have some data that despite dose reductions, efficacy is maintained. So there is benefit despite the dose reductions that patients might require. So certainly, I would follow the same for that patient as well.

DR LOVE: So I want to go through some scenarios and particularly biomarker-based. We’ve been presenting breast cancer patient cases for a long time requiring ER and HER2 to be able to present the case. I guess we’re in a situation right now for second-line endocrine therapy. Do you agree that ESR1, PIK3 and AKT needs to be investigated?

DR JHAVERI: Yes, absolutely. I think now that we have approved therapies for these mutations and these alterations, our approach is biomarker-driven in the post-CDK4/6 era. I think we have these biomarkers based on which we can offer therapies. Germline mutations, we have PARP inhibitors. For ESR1 mutants, we have elacestrant. And for the PI3K/AKT/PTEN, we have capiva. PIK3 alone, we have alpelisib. So certainly, we want to do that because we have standard of care drugs approved for this.

DR LOVE: So let’s try to walk through how you’re going to navigate this. This is really recent because I guess it’s really the approval of capivasertib that made this algorithm explode sort of. And you explained earlier how you visualize the pathway here. So I guess this situation of, first of all, looking at this patient who is relapsing after receiving 2 years of adjuvant anastrozole. Right from the beginning, how are you going to be thinking about a case like that compared to somebody, for example, who presents with metastatic disease?

DR JHAVERI: Yeah. So I think here, this was a patient that 2 years after starting adjuvant anastrozole received a CDK4/6 inhibitor with fulvestrant, but stayed on that for 18 months. And then after that has an ESR1 mutation only. And I think we saw that in the EMERALD trial that when we compared elacestrant to fulvestrant which was fulvestrant naïve patients, there were 30% that had already seen fulvestrant, there was a benefit to elacestrant. And more importantly, for patients who were on a CDK4/6 for 12 months or 18 months and more, the benefit of single agent elacestrant was much higher than the all-comer patient population. So putting all of that together, given the genomic profile, the durability of a CDK4/6 inhibitor for 18 months and just ESR1 mutation, I think this is a very appropriate patient who could be treated with elacestrant. Unlike this, if somebody had progression on a CDK4/6 inhibitor in a shorter duration of time, I’m not sure that would have been the best patient for a single agent endocrine-based therapy.

DR LOVE: What would you be thinking about?

DR JHAVERI: So if it’s less than 6 months in the first-line metastatic setting with a CDK4/6 inhibitor, I’m really thinking this is a primary endocrine resistant tumor. So I’m either looking for a clinical trial with an antibody-drug conjugate or I’m starting them on standard of care single agent chemotherapy. Depending on their disease burden and the symptoms, it could be weekly paclitaxel or capecitabine if the disease burden is not that high and I’m okay with an oral agent which really maintains your quality-of-life. So I would think about chemotherapy there or look for a clinical trial that might have an antibody-drug conjugate.

DR LOVE: So we vary the situation and now, we’re saying not only ESR1, but PIK3. And interestingly, now we see, this is how we do consensus conference. Everybody says the same thing, it’s a consensus. Like this, no, this is not a consensus. So only 1 person says alpelisib. I think that’s kind of interesting. But people seem to be split between elacestrant and capi plus endocrine therapy. But it seems like elacestrant would be better tolerated.

DR JHAVERI: Right, right. So I think I picked elacestrant and I picked elacestrant for that reason. I think the biggest point, the reason you’re not seeing a consensus is there cannot be one because that’s a data-free zone. We really do not have any head-to-head trial comparisons to say if one approach is going to be better than the other and what would it look like. I think it’d be very important to understand if we have PFS with elacestrant, what would the PFS look like after elacestrant with combination with, say, capivasertib/alpelisib or vice versa. And we don’t have that. So at this point, because we don’t have that, given that the patient was on a CDK4/6 inhibitor for 18 months, seems like has progressive disease in the bone, has both these mutations, we discuss and think about the toxicity profiles. It seems like elacestrant is very well tolerated with just low-grade nausea. It seems like that might be very appropriate to try and then think about a combination drug which certainly can be efficacious that will have more toxicity that’d be justified at that timepoint. That’s how I think about it. But that’s something I’d want to discuss with my patient and see what the patient thinks about it as well.

DR LOVE: What’s your take on what’s involved with capi? The schedule is kind of strange and different. I don’t know if that’s going to be an issue. But also, and I hear various different things, it seems like it does have some tolerability issues. I’ve heard about diarrhea.

DR JHAVERI: Yeah.

DR LOVE: But what’s your experience and what’s the literature say?

DR JHAVERI: Yeah. So I think when you think about alpelisib, the 2 most important things that you worry about, that you see in clinic, are hyperglycemia and rash. In fact, majority of the discontinuation rates that we have seen were related to hyperglycemia and rash. When we think about capivasertib, we’re thinking about diarrhea and rash. We’re seeing very less Grade 3 hyperglycemia. And that, I think, is a pain point for community doctors, for academic doctors, because overnight, an oncologist is then required to become an endocrinologist and figure out what to do for a patient who might have really terrible Grade 3 or 4 hyperglycemia. I think oncologists are very comfortable with metformin, but anything beyond that is not necessarily so comfortable to manage. And getting access to specialists in a timely way to help your patient to figure out what to do makes it very, very challenging. And so I think this is why most of us are excited about the fact that with capivasertib, you’re going to see less of the hyperglycemia issue. I think with drugs like niraparib, with drugs like abemaciclib, we’ve all become very big experts in managing diarrhea. In the CAPItello trial, there was no primary prophylaxis done for rash. There was no immediate primary prophylaxis for diarrhea. So I think our comfort level for diarrhea management is higher. And rash, if we were to start thinking about using primary prophylaxis, so using cetirizine as soon as you start the patient might perhaps even lower the rates of rash that have been reported on the CAPItello-291 study. And I think because of that, there might be more excitement in the community altogether to think about this combination that works not just for PIK3 mutants, but also AKT and PTEN alterations with alpelisib would not work, plus have a slightly distinct toxicity profile that might be slightly better manageable than what we see with alpelisib. And I think that’s really the bias that people are going to have because this drug is approved and now available to us.

DR LOVE: So incidentally, when we developed these questions with the 3 variables, my team was like, can you really see all these variations? Sometimes, you ask stuff and we were waiting to see whether people on this were going to return it and say, oh you can never see this. But can you basically see every possibility here?

DR JHAVERI: Yes, yes.

DR LOVE: You were mentioning one that was 12%. But theoretically, you need to know all 3.

DR JHAVERI: Yeah. So all 3 might be even rare. Is it possible? Certainly possible. So let’s break it down. What I was saying 12% was ESR1 and PIK3CA mutation together.

DR LOVE: Right, right.

DR JHAVERI: When we think about the CAPItello data set, about 46% had some kind of alteration. Majority of them were PI3K mutants, about over 30%. About 5 to 7% had AKT mutations. About 5 to 7% had PTEN mutations. Then, about 1% had PI3K and AKT or PI3K and PTEN. So it is possible? Yes, it’s possible but even rarer. So having a patient with ESR1, PI3K and AKT? Certainly possible, but even, even rarer. So I would say the possibility of ESR1 and PIK3, highest. PIK3/AKT or PIK3/PTEN, at 1%. And all 3, possible but very, very rare.

DR LOVE: So one of the things that I’ve seen in a lot of these second-line trials that kind of bothers me is that the control arm, which a lot of times is fulvestrant, the PFS is often like 2 months. And I’m wondering, can we identify these people, like this situation where they’re all negative and then add on top of it, particularly in a patient who maybe has some symptoms, can you identify a situation where it’s really not worth giving second-line endocrine therapy? Or is it always worth doing?

DR JHAVERI: Yeah. I think such a great point. I think you’ve raised so many important points here. One, is it ethical now to even have a control arm with fulvestrant? I think when these studies were designed, that was very appropriate. But now that we have so many data sets shouting out and saying just single agent fulvestrant is a modest PFS of 2 months, can we even do that to our patients anymore?

And I think the second point that you raised is, should we just move on to something that might have some real leg and give a real progression free survival benefit and not just a fake 2-month benefit with the first scan showing progression, right? I think there are newer therapies that are now more impactful, if you will. So if you think about capivasertib in this altered patient population, you do see 7 months. And that obviously is more respectable because it’s not 2 months, it’s 7 months. Yes, it comes with some toxicity, but it’s delaying time to chemotherapy which is still very, very important to our patients. And still a very important thing that we’re trying to do for ER-positive breast cancer patients.

Similarly when we think about real-world data sets with everolimus, we’re seeing about 4 to 5 months. So certainly, that’s a good option that we can see. I showed you the data for oral SERD with everolimus with imlunestrant and everolimus. That was 16 months. Granted, it’s a Phase I with 42 patients, but it does seem like maybe with an optimal endocrine backbone and everolimus, we might actually see something good. And it’s reasonably tolerated. Our definition of this is a toxic drug has also evolved, right? When everolimus was approved in 2012, we said it's such a toxic drug, it’s such a terrible drug to give. Now after 3 drugs, we think that’s the easiest, in my mind, to give. Because the stomatitis can be handled with the dexamethasone mouthwash. We’re not seeing crazy hyperglycemia. We’re not seeing crazy diarrhea. We’re not seeing crazy rashes. It’s really become an easier drug. And so everything is so relative.

The CDK4/6 data beyond progression is an interesting signal. MAINTAIN is a Phase II study that did show a signal of 5.2 months in patients who continued endocrine-based approaches. But switch of endocrine partner to fulvestrant, switch of CDK from palbo to ribo, and we did see 5 months. We’re waiting for post-MONARCH and EMERALD-3 to solidify that approach with abemaciclib. So we might have many other tools under our belt beyond the 2-month PFS with fulvestrant that we can offer our patients that meaningfully delay chemotherapy. So I think there is still hope, there is still good data that will help us continue this treatment paradigm of what we have been doing just with different combinations.

DR LOVE: Although it is interesting now that I look at this graphic here, 4 people said they would give capecitabine and skip second-line therapy, so even in that situation. I just want to pick out a couple other scenarios here. This one I thought was very interesting. PIK3.

DR JHAVERI: Nobody wants to give alpelisib anymore.

DR LOVE: That’s what I’m saying. I think the answer to this question was different a few months ago, right?

DR JHAVERI: It was, absolutely.

DR LOVE: This was the classic case to get people to say alpelisib. And now, only 1 person says it. Any thoughts about it? I guess this is related to tolerability, right?

DR JHAVERI: Absolutely.

DR LOVE: It’s all about tolerability.

DR JHAVERI: All about tolerability. Alpelisib data set in SOLAR-1 was 6% CDK4/6 patients that had seen CDK. We had BYLieve, which was a nonrandomized Phase II study that gave us 7 months with alpelisib post-CDK. But the only prospective Phase III data set we have is with capiva, which gave us 7.2 months, but it’s the distinct toxicity profile. Very little hyperglycemia Grade 3, 2% with capivasertib I think is the biggest point that people are going to hope to justify for offering this therapy. That’s why you’re seeing this bias amongst all of us who did this survey.

DR LOVE: This concludes our program. Special thanks to Dr Jhaveri, and thank you for listening. This is Dr Neil Love for Oncology Today.