SABCS 2023 HER2+ Breast Cancer Highlights – APHINITY Sub-analysis, KATHERINE update, HER2CLIMB-02

SABCS 2023 HER2+ Highlights: APHINITY Trial Update Hello everyone, I am Rahul Hussain. Speaker 2 And I'm Rohit Hussain. Speaker 1 And we are oncology brothers. We're on the verge of wrapping up our highlights from San Antonio Breast Cancer Symposium 2023. But before we close in this last series we have three more studies update from Affinity and Catherine trial and then her two climb O2 study. All this and her two positive disease to cover these important data sets. We're joined by Doctor Daniel Stover from the Ohio State University. Dan, it was great seeing you in Texas. Thank you so much for joining us today. Speaker 3 Thanks for having me and excited to talk about these three abstracts and what they mean for us in clinic. Speaker 2 Awesome Dan. To start off with our her two space from locally disease to locally advanced and then diving into metastatic settings. Before we jump into our first study which is the AFFINITY trial where we utilize her two therapy in adjuvant setting. It is important to acknowledge that we have been utilizing dual anti her two therapy in our neoadjuvant settings along with chemotherapy based off of Neosphere and Trifenous study. Now looking at the AFFINITY trial, we all continue to wonder how much truly is anti dual. Her two therapy is adding in adjuvant settings. AFFINITY trial was initially published in NEJM back in 2017 and here we have an update on a subset analysis and your take on these findings. Speaker 3 Yeah. So I agree with you. I think you know there are some clear side effects to the addition of pertuzumab. We all I think have gotten comfortable with the management of diarrhea, but it certainly is more in some patients than others. I think the important thing of this affinity sub analysis is many of us had wondered whether there were different receptor subtype combinations that may benefit more or less from the addition of protuzumab. And as we can see in the forest plot, it really seemed to demonstrate benefit across subtypes. So how fish high or how amplified the her two was as well as whether it was ER positive or ER negative all had really similar benefits to the addition of protuzumab. The confidence intervals are a little bit wider, but that really varies based on the size of each of those subsets. So my take home was that in general most patients seem to benefit from the addition of pertuzumab. And you know when we think about clinical practice, it's you know trying to give that as an opportunity for most patients as long as they can tolerate it in terms of side effects then likely we are hopefully going to add a little bit of additional risk reduction benefit for them. Speaker 1 Dan, thank you so much for glancing over that data. Rohit, you brought up Neosphere. I'm not even going to dive into how insurance declined TCHP regimen for my heart to positive inflammatory breast cancer neoadjuvant settings. But coming back to this discussion then we have neoadjuvant data from Neosphere. We have affinity data from adjuvant settings, not even just the subset analysis. Looking at overall, if you've achieved PCR, how much is protuzumab adding in that settings? Speaker 3 Yeah, I think it is a great question and we know that patients who achieve A pathologic complete response from neoadjuvant data do very well, although there are recurrences. And you know I think as we'll talk about you know later on, you know including particularly in the CNSI, they typically end up thinking about continuing pertuzumab just because we don't have definitive data that dropping it is equivalent. But I do have a little bit more hesitation of of trying to you know, push it in patients who have achieved a past CR, maybe those that started with slightly lower risk disease, you know, ones with higher risk disease. We probably want to throw everything at it even with the complete response. But but I think that without sort of a definitive prospective study, it's hard to make those interpretations. What do you all think about this in your own practices? Speaker 1 Yeah, I think as medical oncologists we're all trained to over treat rather than under treat till we have the right marker or these prospective studies. So as of now we continue these dual anti heritage therapy even if there is pat CR. Speaker 2 And I think that hesitation is always there, but I guess you have a bit more real room with slightly elderly population with younger patients definitely go in with aggressive route, but with older patient population especially with the side effect profile to tailor back certainly in certain situations with an idea. Speaker 3 Yeah. And we do have the ECOG Akron Compass, her two PCR study that has now accrued and I think will also give us some guidance when that reads out in the coming years. Speaker 1 Absolutely. Speaker 2 So we'll be looking forward to that data. TDM-1 Standard of Care for Residual HER2+ Disease Now moving along to our next study here which is Catherine study. So this study was looking at TDM one benefit in adjuvant setting after a patient has received chemo with her two directed therapy post surgery. If there is residual disease, is there benefit of TDM one versus trastuzumab? Tianne, what are your thoughts on the eight-year update with this trial? Speaker 3 So I think that we were all impressed with the initial data and the publication in the New England Journal with the apparent invasive disease free survival benefit that at the original analysis the overall survival data had a hazard ratio that was low but was not statistically significant. I think it's very reassuring to see that the invasive disease free survival data remains pretty significant. You know at 7 years almost 81 percent Idfs versus 67% in those who got trastuzumab alone, suggesting a clear benefit to the TDM one in these in these patients. I think many of us are utilizing TDM one in the adjuvant setting for patients with residual disease. In practice, it's tough sometimes because patients have had a lot of chemotherapy in the new adjuvant setting if they received TCHP. But clearly these data reinforce that there's benefit to escalating from Herceptin to TDM. One, you know the question is, is there additional benefit to pertuzumab in between there, You know as we said earlier we don't know. I think the last thing that I would say is you know the overall survival data are perhaps more modest but I also wonder whether this really reflects how effective anti her two therapies are in the metastatic setting once patients have developed relapse. So I'm not sure that we you know with how effective those therapies are, how well patients are doing for years in the in the metastatic setting would see a dramatic difference. My take home from this is that this sort of really reminded me that that there is value to TDM one Ioffer it to all of my patients with residual disease. But I think that I'm going to bring these data back to those patients that maybe are on the fence to at least try it or try to sustain on the TDM one if we can manage neuropathy and other side effects. Speaker 1 Absolutely. This data just continues to reiterate TDM one still being our standard of care right now with residual disease and TDM one was one of the first antibody drug conjugates in breast cancer. Now we're almost seeing one getting approved every year. Speaker 3 Yeah, definitely. It definitely feels like that. I think the, you know the other sort of future question and we mentioned the COMPASS studies earlier. The COMPASS Rd. study looks at TDM one alone or with tucatanib as an escalation in the in the adjuvant setting. You know that's more drugs, that's more toxicity. We'll have to see if that you know if there's an effect in terms of benefit when that reads out. But I think for now we certainly know that TDM one in the adjuvant setting for patients with residual disease after near adjuvant chemotherapy clearly adds benefits benefit for these patients who are relatively high risk. TDM-1 + Tucatinib for Metastatic HER2+ Brain Metastases Then that's that's a good set up for our next study her two climb O2 study, where we are indeed looking at the combination of TDM one and to catanib. TDM one was our second line option before TDXD or the triplet to catanib capes cytopine and trastizumab. TDM one's trying to make a comeback here. Your thoughts on her to climb O2 study? Speaker 3 So I think one of the most interesting things about this study was 43% of patients had brain metastasis and this is a sea change in in breast cancer clinical trials. Previously patients with with brain metastases or particularly active brain metastases were excluded from clinical trials. And I think the voice of patients advocates and clinicians saying we need more options for these patients and to understand how these medications work has importantly included these patients. And that really I think was the most interesting take home of this, which is the effect of this combination in patients with brain metastases where they're clearly as we can see in the lower left here, clearly seem to be a benefit of the addition of tecatinib to TDM one in patients with brain metastases. Speaker 2 Thanks for covering that Dan. And we did talk to Doctor Tulaney about the same study as well where the thought or the discussion has always been around. It is remarkable and hats off to the clinicians and patients who were involved in this to include brain metastasy patient and especially we have seen that similar thing was seen with the triplet combination though TDXD did not include that but we have seen more CNS activity with that as well. Now now given promising results from the doublet and triplet and knowing the activity of TDXD in CNS, if this was to get approved and you have all these three options available, which one are to utilize in clinic and in what setting for that matter? Speaker 3 Yeah. No, I it's a great question and it's a little bit of a challenge of having three active options which is fantastic. I think in the setting of CNS disease we have the strongest data with the triplet of xeloda tucatanib trastuzumab longest follow up from the her two climb study that has certainly has its own challenges in terms of some side effect profiles. But the longest data, I think this data clearly shows that TDM one with tucatanib is also an option in patients who have early development of CNS metastasis. So if I had a patient who developed CNS disease after or during first line therapy, I would probably lean towards one of the two to cat nib based regimen regimens and decide on those two really based on side effect profile and and patient because we really can't compare the studies head to head and the follow up is is different. I think the TDXD data in the CNS is intriguing. I'm not sure about you all in in my patients where I've used it in later lines and patients who have perhaps had untreated brain metastases, I certainly have seen some responses and we have some early data from the tuxedo study. But I think until we see Destiny breast 12, which is led by Nancy Lynn, which is specifically looking at this question, you know we don't have that data quite yet for for patients with brain metastases and NTDXD. Speaker 1 Absolutely. I would actually like to emphasize 2 things here. One, the reason why we're even talking about this is her two positive breast cancer has the highest incidence of intracranial disease when we're looking at hormone receptor or her two or triple negative breast cancer. Second, when we're coming back to this particular study her two climb O2 we still have to wait for some of the granular data saying how many of these patients were with active disease versus treated. So I think that once we have that, this is going to get very exciting and we'll give more treatment options for our patients. Speaker 2 In addition, by that time, Destiny Breast 12 will be able to result some data as well. So it'll be exciting. Key Takeaways from HER2+ Breast Cancer Studies Ian, thank you so much for covering all these important and very relevant practice changing and practice informing studies. Each one of these studies and updates will continue to shape our daily practice for our listeners. Please stay tuned. For a quick recap, we have covered three studies in her two space from San Antonio Breast Cancer Symposium 2023 with for Daniel Stover from Ohio State University. Starting off with AFFINITY trial which is dual anti her two therapy in adjuvant setting which continues to show ongoing benefit even if there is hormone receptor positive concurrently present with her two positive disease. Speaker 1 We've also discussed the role of TDM one given its overall survival benefits seen at the eight-year update mark from Catherine trial. This update continues to reiterate TDM one being standard of care if there is residual disease after neoadjuvant treatment for her two positive disease. Speaker 2 The last we also discussed another potential option that might become available in metastatic space especially in intracranial involvement with R2 positive disease which was R2 client O2 study with TDM one and Tucatinib combination. Thanks for tuning in and supporting us. For more practice changing discussions that we need to keep up with our community settings, check out our podcast And we are the oncology brother.