INAVO120 - FDA Approval of Inavolisib in Endocrine-Resistant, PIK3CA-mut, HR+ Advanced Breast Cancer

Intro Welcome back to another episode of the Oncology Brothers Podcast. I'm Rahul Gosain here with my brother and Co host Rohit Gosain. Today, our focus is going to be on Enavola SIB that recently got approved for metastatic hormone receptor positive breast cancer based off Enavo 120 study. This study was first presented as a late breaking abstract last year at SABCS 2023. And then on October 10th, 2024, based on its findings, a Nautilus said was approved. To unpack the key takeaways from disapproval and how does this drug really fit in in our current treatment landscape, we're joined by Doctor Komal Chavery, a medical oncologist and the senior author on this study from the Memorial Sloan Catherine Cancer Center. Enavola SIB Cuomo, thank you so much for joining us. Speaker 2 Raul and Rohit, thank you so much for having me today and delighted to talk to you about another listen and the data that we presented and now that's published as of this month or this past month I should say, in the New England Journal. So thank you so much for having me today. Speaker 3 Como welcome and congratulations on the study and especially on top of that FDA approval. This metastatic space indeed is getting crowded and which is in fact a good problem to have where the current standard of care in metastatic space stands as CDK 46 inhibitor plus AI in frontline for metastatic hormone receptor positive patients. And after progression here we start looking for actionable mutations. If one has big three CA mutation or alteration choice becomes CAPIO assertive or L pulsib or if ESR one mutation then LSS strength or BRACA 1 mutation, then we're relying on PARP inhibitor. Also, we know we're dealing with something aggressive when the disease in fact progresses within 12 months of AI or shortly after completion. With that background in mind, can you please walk us through the study design of your in Novel 120? Study Design of Innovate120 Absolutely. So in novel 120, it really was born out of the data that we actually initially presented and now is published as well from the phase one trial that evaluated this novel. PI3K alpha is a form specific PI3K in a better in novel a set. And really this, you know, the uniqueness in, in terms of the preclinical data for the novelistic is that one, it is very, very potent for the alpha isoform compared to the other three isoforms, the beta, delta and the gamma, which is attractive because we know that that's where the oncogenic driver is the the P3 CA mutation, which is what we're going after. But also preclinically, it actually causes degradation of the mutant PP 110A. And that is what could potentially explain the slight differences in the toxicity profile and how we view the efficacy data and how we were able to actually study a triplet regimen and show that it was safe and tolerable in the phase one setting. But then another 120, which is the registration of phase three that was designed was really focusing on a group of patients which was very unique, right? It was not that we were trying to study all patients with P3 CM mutations. We went after the the most, you know a troublesome patient group in that the most poor prognostic patient group and how did we identify that group? So we're talking about patients who progressed on or within 12 months of their adjuvant endocrine therapy for which normally we would have offered fulvestrant with the CDK 46 inhibitor as a standard of care. Now these patients were required obviously to have EPIC 3 CM mutation so that we can target it with an alpha specific BI 3K inhibitor. They were required to have measurable disease on this trial. And the way the pick three CA mutation was detected was that majority of these patients had this alteration detected through selfie DNA. So this tells you that there is enough disease burden that's spilling in the plasma, which is how we're detecting this pick three CA. Now pick three, CA is a clonal or a truncal alteration. You can certainly test it in primary tissue, you can test it in metastatic tissue, you can test it in plasma and all of that is OK because it's truncal, it's clonal, what's present and driving the biology stays that way throughout the journey. But here we identified majority for patients that were detected to the plasma just kind of telling you that these were patients with you know a lot of visceral metastases, 50% had liver metastases and that is what is reflective of this patient population. Now unique criteria about hemoglobin A1C and fasting glucose. Also to bear in mind based on the toxicity profile that we've studied in the phase one setting, when we had seen you know hypoglycemia with this drug like we see with other PICK inhibitors, because it's an on target effect, it's the inhibition of the wild type as well that we see which causes this on target side effect. We had chosen a hemoglobin A1C cut off of less than 6% and a fasting glucose value of 126 milligrams per deciliter. These patients 325 of them within randomized 1 is to one to the triplet regimen of fulvestrant palbociclib and enabolism which is administered at 9 milligrams orderly daily based on the dose that was identified in the phase one that I was talking about compared to palbociclib, placebo and fulvestrant for the primary endpoint of progression free survival by investigator assess. Speaker 1 Como, thank you for laying that foundation. The primary endpoint, PFS, secondary endpoint was overall survival benefit. What the study shows What did the study show? Of course, this study was a positive study that led to the approval of this drug. But can you walk us through the findings and what does this really mean for our patients? Speaker 2 Absolutely. I think that's that's exactly what is really, really important. So you know, first of all I want to say this was a median follow up of about 21 months. And at that follow up, we saw a near doubling of progression fee survival by investigator assessment at primary endpoint, an improvement from 7.3 months in the control arm to 15 months with the addition of a novel SF to full Western and Palvis eclip. The hazard ratio here is 0.43 and AP value which was highly statistically significant. Now if you look at the Kaplan Meyer curves, the Kaplan Meyer curves start separating right from the get go and many a times in ER positive studies, you'll see that initial drop off and then you'll start seeing the curve separating after. But here you're seeing this benefit predominantly beginning very early on in these patients as well. More importantly, when we did the landmark analysis as well, we also saw that even at a a time point that we were looking at around 18 months or 12 months, we were looking at a progression free rate which was more than doubled than the control arm. For instance, the progression free survival rate in the landmark analysis improved to about 46 months, 46% compared to 21%. So really something that we saw in this patient population with respect to primary endpoint. Now the secondary endpoint we did have a a hazard ratio of 0.64, which is very favorable. We did have AP value of 0.038. But I have to say that that P value cannot be claiming statistical significance at this time point at the same median follow up of 21 months. And we're really eagerly awaiting mature follow up data for this overall survival as well. But what really caught my eye even in the Kaplan Maya curves off that overall survival data again, when we look at the landmark analysis at the six month time point, So very early on, on a first line trial, right, patients have not had any other therapy but this first therapy. And we saw that, that 90% were alive in the control arm at six months, which means 10% were not in contrast to 97% that were alive with the addition of anabolicip. So this is really again highlighting and underscoring the fact that this was really a poor prognostic group that otherwise does not perform well. And with the addition of anabolicip, we did see this benefit at ASCO this past year or this year, I should say. It feels like a long time ago at this point. But at ASCO, we also presented data for PFS 2 and time to chemotherapy. And again, we showed that there was benefit with the triplet regimen even when we look at PFS 2 and delay in time to chemotherapy, that was significant as well. So I think now we're really awaiting the mature overall survival data. But again, this is approved as you pointed out and I would say really, really highlights the importance of testing pick three CA mutations first thing when patients have a diagnosis of metastatic, especially if they have recurred on or within 12 months of their adjuvant endocrine therapy. So if you have an endocrine resistant patient, I think this would be very valuable to consider given this dramatical increase in PFS that we're already seeing, which is so statistically significant. Speaker 3 Thanks for reiterating the important findings here, especially talking about the delay progression free survival from PFS to as well as PFS and impact. In fact, the overall survival benefit doubling of PFS in a very high risk patient population. This is remarkable, especially when you talk about this high risk population here. And as we can see, it's from the comparator arm as you've mentioned KOMO, these patients usually don't do well if you're just starting them out on just AI plus CDK 4/6 komo. When to get NGS testing In your practice, when do you get NGS testing? And is liquid biopsy good enough here? I know you mentioned that right at the start of metastatic itself, but on progression and is liquid biopsies good enough? Speaker 2 Yeah, I know that's a fantastic question and very important one that we actually should discuss. So I, I'm practicing obviously at Memorial Sloan Catering Cancer Center and I have to say we have our in house NGS assay called MSK Impact. And honestly we've been doing NGS testing from tumor tissue at the time of metastatic diagnosis for years now. And at that point I think we had initially started doing it for trial purposes, for understanding the genomic landscape between primary and metastatic disease. So the way we tried to do it was not because we knew that trials like in our 120 would be approved and the importance will be becoming much more important, but that's how the field has evolved. So back in the day, we were to think about when should we test the tissue at the very minimum, right? Because obviously, in the United States, access is different, but globally, the access could be different as well. And one has to bear that in mind. We would say that first line, every patient should get CDK 46 inhibitor and at least at the time of progression on a CDK 46 inhibitor in the second line setting, we now have approval for LSS TRIAND if they have an ESR one mutation, if they have a germline mutation in BRCAB RCA1R2, we have PARP inhibitors. We have 3 drugs available targeting the PICKAKTM Tor pathway. We had approval for everolimus regardless of any mutation testing. We have approval now for Capyva surtip as of November 2023 by the USFDA where we can offer that drug with fulvestrant to patients that whose tumors harbor pick three CAP 10 or AKT alterations. We have opalicip since 2019 for patients who have PIT mutations. And so we were definitely doing it at least in the second line setting. But the way I have been practicing for a while now and now I feel like it's becoming more and more evident and important with these data is that it's very easy to get access to metastatic tissue because you're doing a biopsy anyway to confirm the diagnosis, right? So say, if you have a de Novo patient, you certainly need a biopsy to prove that a metastatic disease. If you have a patient who was already treated and now has suspicion for recurrence, you are going to do a biopsy and you will need to test the tissue. So because you have that tissue and if you already know that this patient record on or within 12 months of adjuvant endocrine therapy, really, really important to remind yourself to the NGS because Big three mutations are clonal or truncal. So you don't really have to wait for progression on a CDK 46 inhibitor to know what happened to the tumor. For a big three CI, even if you were to test primary tissue, you would still be able to offer the same therapy to these patients with a new diagnosis where you couldn't test the metastatic tissue, but you already had the data available from primary tissue. So in my practice, newly diagnosed patients, everybody gets tissue. During the Enavo 120 study, when I was enrolling patients to the clinical trial, I would also send out a CTDNA test because the turn around time for CTDNA was about 7 to 8 days. With Garden 360. Right now, the companion diagnostic that has been approved with the Enavo 120 data is the Foundation Medicine Assay. So certainly you have options available, you have clear certified assays that can help identify these alterations. I do tissue at the time of diagnosis. I do selfie DNA usually serially, but definitely at the time of progression of CDK 46 inhibitor and I would certainly consider repeating biopsies during the metastatic journey for a patient for the right setting. Very limited duration of treatment response on a therapy or if I were to look for her to low disease to offer them trastuzumab drastic and amongst other reasons to do this, but at least at the time of diagnosis and cell PDN at the time of progression. Speaker 1 Absolutely. And as a community oncologist, we're doing this more and more already be it in lung cancer, of course, and breast cancer. And the reason to even consider serially something that we don't do for other diseases is to look for ongoing mutations like ESR 1 and so forth, because you do have potential options. Como, you touched on this a little. Captiva Certa Captiva Certa which is also approved here in second line for AKTP 10 and pick three CM mutation is a novelist active for AKT and P10 mutation as well. Speaker 2 Fantastic question again. And the answer is no. This is a alpha isoform specific PI3K inhibitor and one of the potential mechanisms of resistance to PI3K inhibitors is actually development of or acquired P10 alterations. And that's where we would think that AKT inhibitors potentially could play a role. So right now, you should only be offering enabolisib or alpalisib to patients with big three California mutations only. In contrast, Capive assertive could be offered to patients with pick three CA mutation with AKT mutation or AP10 mutation. So that's the difference. Right now in practice, we don't have data for Capive assertive in a triplet regimen in the first line setting yet, but the trial of Capitola 292 is currently ongoing and hopefully we'll have an answer to that question for that triplet as well in the future. Speaker 3 Thanks for covering that Homo. Just to push you a little bit on the NGS theme again here, what if we have ESR and pick three CA commutation though we have a utility with L assessment which especially for a slow progressing disease. ESR1 and CA commutation However, if we know that these patients are going to be aggressive, if they are progressing within that 12 month frame of initiating AI, would you be committing these patients to triplet regimen based on a novel 120? Speaker 2 Yes, I would. So the short answer is yes, I would. If you recall when we looked at all the data and the CTDNA analysis from the CDK 46 inhibitor trials just as a doublet with endocrine therapy and CDK 46 inhibitors. You know we did see that there was responses that you would see especially if you were thinking about ESR one and you would offer them full restaurant as well as a combination right upfront. ESR one mutation rates are lower that you know increases with second or third line therapy. So if you were to look at the Mona Lisa two data which evaluated ribocyclib with fulvestrant and that looked at baseline CTDNAE SR1 mutations, the prevalence there was 4%. Now certainly we anticipate that maybe perhaps with extended adjuvant endocrine therapy, this rate might be higher potentially in patients and we need to learn a little bit more about that. But when we're talking about second or third line ESR one mutation prevalence, we're talking about 40 to 50%. So very different there. Here the patients are certainly getting fulvestrant which would cover at least some of this ESR one mutations already there is some data to suggest that maybe ESR 1 Wi-Fi 37S is not the great mutation that full western can have activity for, but for the others it would. And again the prevalence is going to be lower, much lower in the first line setting to have a Co occurring alteration for which we would worry about because we're still going to give them full restaurant, we're still going to give them ACDK 46 inhibitor and we're going to still give them API 3K inhibitor for the three alteration. And one more point to make to that was, you know, even with the para one trial, which really looked at emerging ESR 1 mutations, we followed patients who started on an AI with the CDK 4/6. And if they develop a E SR1 mutation but do not have radiological progression, we randomize them to continuing the same treatment or switching them to full Western TENA CDK 4/6 and show that that is beneficial. So again, that supports the idea that fulvestrin might be appropriate and this prevalence rate is going to be much lower in the first line. So hopefully that answers your question. Speaker 1 No, absolutely. Right. Then I think you're bringing this up because LSSN is well tolerated and we all get nervous around tolerability and how to manage side effects of anything that is newly approved. So Cuomo, I think this is a good segue. If you can take next few minutes to focus on this side effect profile and some clinical paroles that you can offer on how to manage some of the key toxicities as you've mentioned and neutropenia, Again, we're using CDK 46 inhibitors here. Side Effects and Clinical Parameters Hyperglycemia, GI side effects are more of a class effect that we tend to see with us. Any thoughts about this? Speaker 2 Yeah, I know it's a fantastic question. Certainly, efficacy is very important, but safety is equally important just to make sure that patients can really adhere to a therapy that we intend to give them to improve their outcomes. And so, yes, I think the short answer is there were no new signals of safety profile than what they're already aware of. If we think about the individual contribution or the individual side effect profile for the drugs, the trial showed that the same side effects that we would have expected from Pavociclibor, from fulvestrant and with the PI3K inhibitor is what we saw with the triplet. Again, very important to appreciate here that while the precritical data really supports the synergy of these three drugs and we've been able to show efficacy here, this was not a new thing. We had attempted that with other drugs as well. We had attempted the three triplet regimen even with Alpalisib and and riboseclib and endocrine therapy, but that was not safe and tolerable. That perhaps speaks to the the pre critical differences that I was referring to with the novolisib. But certainly we see hyperglycemia rates. We did see about 58% of the patients with all great hyperglycemia, grade 3 or 4 hyperglycemia rates, but about 5.6% we did see stomatitis with this the triplet combination as well. It was 51%, all great stomatitis. We did see some grade 3 stomatitis as well. Not all patients got primary prophylaxis with the dexamethasone mouthwash, which is what we normally now do with drugs like Everolimus and should do with this also in the control arm, in the palbociclipal vestrant arm, approximately 27% of the patients had stomatitis as well. So certainly we do see stomatitis. I think very important for us to remember to use dexamethasone mouthwash when we start utilizing this drug in clinic. We did see some diarrhea rates as well, well grade diarrhea and and some low grade 3 diarrhea of about 3 to 4% or up to 5% if I recall the right numbers for diarrhea and rash. We did see low grade rash, but there were no grade 3 rash. Now this is slightly different from what we've seen with say Kapivaserta where the grade 3 rash was 12% or with Alpelisib where we also saw grade 3 rash and discontinuations related to rash as well. So we don't see grade 3 rash with this drug, again, slightly different. So while all of these side effects, dermatitis, hypoglycemia, diarrhea, rash are a class effect, we do see that there are slum differences between all these agents that target these pathway agents, right? Every Alimus causes predominantly mouth sores or or there's dermatitis. When you look at Capyva Surti, we worry about diarrhea and rash. When we look at L pallis, if we think about hyperglycemia, diarrhea and rash with an ovilusive, I would say it's hyperglycemia with the triplet. You should keep an eye on the stermatitis and there is some low grade rash but no grade 3 rash that was seen. Speaker 3 Thanks for covering that, Cuomo. And as you stated, this is a class effect. Cuomo before we wrap up any ongoing study with a novel particularly with ABEMA or RIBO because of course with as we know the CDK 46 inhibitors where ABEMA and RIBO has better survival data when compared to Powerball. Speaker 2 Yeah, fantastic question, Rohit. I'll just add one more thing to to remind ourselves that the discontinuation rates with this triplet regimen were rather low. So it was very reassuring to see there was about 6% for the triplet, which is definitely different than what we've seen as discontinuation rates with the other agents and other trials as well and with with other trials that are currently ongoing. The more fierce phase one study is currently evaluating the exact question you were asking enavolisib in combination with endocrine therapy and ribociclib and enavolisib in combination with endocrine therapy and abemaciclib to generate that safety and tolerability data as well. But currently the approval for Enavol 120 and this first line regimen is with palbociclib. And I do think that given that it was a randomized study and given that it's a 3 drug regimen, I'm not so sure unless we know from a head to head study what that individual contribution for a different CDK 46 inhibitor in this triplet would look like. But I think it'd be very, very important to generate the data as we are given that our control arm certainly has evolved since this trial was designed. Another study that I should point out is ENABLE 121 which is actually in the second line setting a head to head trial comparing Enavo fulvestrant with Alpelisib fulvestrant. So we'll have some second line data as well to be able to tell are there truly any differences between the two drugs and should we be thinking about one over the other with respect to efficacy and safety? Speaker 1 Como, thank you so much for sharing your thoughts and walking us through a novel 120, which again has led to the approval of a novelosib and selective locally advanced or metastatic hormone receptor positive breast cancer for our listeners. Outro Let's go over quick recaps from today's discussion. Speaker 3 Today with Doctor Javeri, we had a chance to focus on a novel 120 study that has led to the approval of enalosib with fulvestrant and palbociclib, an endocrine resistant disease with PIX BCA mutated hormone receptor positive, her two negative locally advanced or metastatic breast cancer following recurrence on or after completion of adjuvant endocrine therapy. Speaker 1 Novel acid resulted in significant improvement in PFS as we saw median progression free survival of 15 months with novel acid versus 7.3 months in a control arm. It is important to keep side effects including neutropenia, hyperglycemia, and GI toxicities in mind while using a novel acid. Given its approval, this option should now be considered in a selected hormone receptor positive breast cancer patients. Thanks for joining us. We also look forward to seeing you in person at SABCS 2024 to discuss this quickly changing treatment landscape. We are the oncology brothers.