This video features Lori J. Goldstein, MD presenting on HER 2+. This presentation was given at our January 19th 21st Annual Highlights of the 2022 San Antonio Breast Cancer Symposium in 2023.
Good evening. This is Lori Goldstein um Happy to be with you for the 21st annual san Antonio breast cancer. Symposium highlights. This is for 2022. And again my topic will be the her two positive breast cancer section. These are my disclosures and these are the topics we'll be discussing tonight from general session two we'll discuss the Destiny breast Oh to study which is T. D. X. D. Versus TPc and her two positive metastatic breast cancer. Second we'll discuss the second abstract from general session to which it is Destiny breast 03 trial of T. D. X. D. Versus T. DM. One in her two positive metastatic breast cancer. And then the last abstract will be the talent trial which is a neo adjuvant T. D. X. D. Plus or minus anastrozole in her too low early stage breast cancer. Now to start with you know what we've seen in her two positive breast cancer has really been remarkable. There's been no setting with more advances over the last 25 years in breast cancer. We've discovered how to give more optimal less toxic therapy with an increasing portfolio of targeted biological agents which has led to both clinical clinically and meaningful improvements in overall survival in terms of years for metastatic breast cancer patients. So this is the first study this is the Destiny breast oh to trial comparing T. D. X. D. Versus positions choice and patient with her two positive unrestricted ble under metastatic breast cancer previously treated with T. DM. One. And just to review with you T. D. X. D. It was designed with several important attributes. As you know, it's an A. D. C. Composed of three components a humanized anti heard to I. G. G. One monoclonal antibody with the same amino acid sequences transducer map which is co violently linked to a Tokyo. I summaries one payload via a tetra peptide based cleave a bill linker. It has a high potency payload. It has a high drug to antibody ratio. It has a payload with a short systemic half life which limits its toxicity. The stable linker uh to its payload. It has a tumor selective believable linker and it has a by standard anti tumor effect. So let me review first the evolution of treatments for her two positive metastatic breast cancer. We know that the standard of care in the first line setting is th p. Due to the cleopatra study Prior to Destiny breast 03. The Amelia study established that T. DM. One as a second line standard of care showing an improvement in progression free survival over the patented and Cape cited. Being based on the strength of the Destiny breast 03 trial the efficacy and safety data. T. D. X. D. Is now the recommended option in the second line setting. In the third line setting. T. D. X. State demonstrated robust activity in a post T. DM one phase two single arm study Destiny breast a one leading to regulatory approvals globally which led to the other destiny trials and breast cancer. The trial will be discussing today, breast 02 is a randomized confirmatory trial of breast 01. This is now a Phase three trial comparing the efficacy and safety of T. T. X. T vs. TPC treatment of physicians choice in patients with her two positive metastatic breast cancer previously treated with T. DM one. This is the schema for the Destiny breast 02 trial eligible patients had her two positive metastatic breast cancer that were previously treated with T. DM. One. The stratification factors included former receptor status, prior treatment with Pertuzumab and history of Israel disease patients were randomized to 21 to T. D. X. D. Versus treatment of positions choice TPC. The primary endpoint was progression free survival. The key secondary endpoint was overall survival. Other secondary endpoints included overall response rate, duration of response PFS and safety. This is the patient disposition and I showed this to you only to demonstrate that the time of the analysis, 23% of the patients on the T. D. X. D. R. Was still undergoing treatment versus 2.6% on the T P. C. R. Which is indication of better activity with T. D. X. State. These are the patient characteristics that are basically balanced in both arms but I just wanted to bring out that 18% of the patients had brain medicine, 58% of the patients were hormone receptor positive. The patients were heavily pre treated. You can see here the patients had multiple lines of previous therapy And here is the primary endpoint progression free survival showing the median progression free survival of T. d. x. d. was 17.8 months versus 6.9 months for treatment of physicians choice with a significant hazard ratio of .35. These are the key subgroups and you can see progression free survival favors T. D. X. D. And all subgroups including hormone receptor status, prior producing map treatment and baseline brain metastases. So here's the key secondary endpoint overall survival. Again showing superiority to T. D. X. D. With the median overall survival of 39.2 months versus 26.5 months. With a hazard ratio 0.65 with a p value of 0.1. Crossing the boundary of significance. In the TPC arm, 69% of the patients received a new systemic anticancer treatment and 25% of patients received T. D. X. D. In the post trial setting. Yet there still is a significant difference in overall survival. These are the secondary and exploratory efficacy. Endpoints again all favoring T. D. X. D. Over TPC including overall survival. Clinical benefit rate, duration of response and PFS by investigator. In terms of I. L. D. The median time to onset of adjudicated drug related I. L. D. Was 209 days. Any great I. L. D. Was 10.4% consistent with other studies using T. D. X. D. So there were no new safety signals in this area in the T. D. X. D. R. 4.5% of patients experience in LV dysfunction events versus 1.5% in the TPC arm. So in conclusion for this study and Destiny breast O. To T. D. X. D. Demonstrated statistically significant and clinically meaningful improvement and progression free and overall survival versus TPC. For patients with her two positive metastatic breast cancer previously treated with T. DM. One, the overall safety profile was consistent with the established safety of T. D. X. D. With no new safety signals observed thus supporting the favorable benefit risk profile. T. D. X. D. In patients with advanced her two positive metastatic breast cancer as previously demonstrated by Destiny breast 01. Next we'll move on to the second presentation which is T. D. X. D. Versus T. DM. One and patient with her two positive metastatic breast cancer. The updated results of Destiny breast 03. Uh We discussed the background in terms of the standard first line and second line therapies. Uh T. D. X. D. Was demonstrated to be significantly better in terms of progression free survival. Uh in the interim analysis that was published in the new England Journal in 2022 showing um the PFS had not reached its medium for T. D. X. D. Versus 6.8 months with T. DM. One with a hazard ratio ratio of 0.2 late. That was highly significant. So this is the updated overall survival analysis of destiny breast 03 patients that were eligible had metastatic her two positive breast cancer that had previously been treated with presses a map and a taxing in the metastatic setting or neo adjuvant setting with recurrence within six months. The stratification factors included the hormone receptor status. Prior treatment with riTUXimab and history of visceral disease. Patients were randomized 1212 T. D. X. D. Versus T. DM. One. The primary endpoint was PFS. The key secondary endpoint was overall survival. The secondary endpoints also included overall response rate, duration of response and safety. This is the key secondary endpoint as presented at San Antonio 2022 for overall survival at 24 months. The survival for the T. X. D. R. Was 77.4% and 69% for T. DM. One. As you can see here, neither arm reached medium which is really very good for our patients. That has a ratio of 0.64 with a significant p value that crosses the statistical boundary for significance. The anticancer therapies in the post trial setting included in the T. D. X. D. Arm, 35% received T. DM one and in the T. DM one arm 17% reached received T. D. X. D. Uh You might ask why only 17% and that is because many of the patients enrolled in this trial were from asia where T. D. X. D. Was not available at the time of crossover. This is the overall survival by subgroups. And one can see that T. D. X. D. Was superior to T. DM. One across all subgroups including hormone receptor status prior produce a mad visceral disease and based on brain metastases. This is the update of primary endpoint uh in terms of progression free survival. Again demonstrating that the progression free survival was superior for T. D. X. D. At 28.8 months versus T. D. At one at 6.8 months. To put it in a different context. The PFS was four times longer for T. D. X. Day compared to T. DM. One. The hazard ratio remains significant at 0.33. And again, these are the other confirmed secondary employment favoring uh T. D. X. D. Over T. DM. One including overall response rate, clinical benefit rate and median duration of response. In terms of post study anti cancer treatment, you can see the patients in both arms received a variety of different treatments post progression. And we're very fortunate that these were captured as part of the study. And as I mentioned, only 17% of the patients who progressed on the T. D. And one arm progressed and were treated with T. D. X. D. Because of availability of the drug here at the interstitial lung disease and pneumonitis data. Um You can see that the rate of T. Uh L. D. Was 15.2% longer treatment exposure and follow up the pneumonitis rate increased from 10.5% from the interim progression free survival analysis. 2 15.2%. There are four additional grade ones, eight additional grades tubes and no additional grade three events. The overall incidence of grade three events was 0.8% was the same as in the PFS interim analysis and there were no grade four or five events. So again T. D. X. D. Demonstrated clinically meaningful and statistically significant improvement in overall survival compared to T. DM one as well as continued PFS benefit in patients previously treated with trust us and they have been attacks seen. The consistent overall survival benefit was observed across all key pre specified subgroups for longer duration T. D. X. D. Continues to demonstrate a manageable and tolerable safety profile. This updated results demonstrate remarkable overall survival and progression free survival benefit with TTXT further supporting the use of this as the second line standard of care in patients with her two positive metastatic breast cancer. And this was simultaneously published and wanted. And the last abstract we'll discuss is the talent trial which is Neo Edmund. Uh There is T cam with or without a nast result for her too low former receptor positive early stage breast cancer. So her two testing is become another topic for discussion once again, you know, we spent almost a decade trying to validate the correct predictive test for the use of traces and I haven't heard too positive disease. And that this is how the test was initially established. Um But for terms of in terms of discussing her two testing in different categories operationally this is how we are categorizing things right now and this is how things were defined in terms of eligibility for these. Her too low uh studies. So her two testing is validated by I. H. C. If the I. H. D. Is three plus it's considered her two positive. If the I. H. C. Is zero is considered her to zero if the I. H. C. Is one plus is considered her too low which comprises about 45 to 65%. If the I. H. D. Is two plus this reflex ish testing if the issue is positive it's her two positive and the issue is negative. It's her too low. So her too low definition is either I. H. C. One plus or I say two plus with a negative ish. So TTxT has demonstrated present efficacy and metastatic her two low breast cancer. However efficacy and localized her too low breast cancer is not known. And we saw the remarkable data in her too low metastatic breast cancer and that was published in the journal in 2022 with an improvement in progression free survival over treatment of positions choice of 10.1 versus 5.5 months with the hazard ratio of 0.51. We also know that neo cycling, taxing based combination chemotherapy is often used to treat high risk localized hormone receptor positive breast cancer. However it can often be associated with very low pathologic complete response rates of 5-8% slightly lower in her too low. The radiological response rates about 50% is often does reductions and interruptions for toxicity. So this is an investigator initiated child designed to evaluate the efficacy of T. D. X. D. For patients with localized former receptor positive her two low breast cancer. And given the crosstalk between er and her two. They also evaluated whether the addition of endocrine therapy would improve the efficacy of T. D. X. D. In this setting. So this is the study design. The population included eligible patients with former receptor positive disease, her to low stage 2 to 3 operable breast cancer and then or pre opposed menopausal women. The stratification is included. Her two expression level one plus or two plus by I. H. C. And menopausal status patients were randomized to arm A. Which was T. D. X. D. Alone. 29 patients or RMB. Which was T. D. X. D. Plus in ashtrays all with ovarian suppression for premenopausal women and men and then they had surgery specimens were collected before uh before treatment. And at the time of surgery for Carlos science. The primary objective was to evaluate the pathological complete response rate and breast and lymph nodes. The secondary objectives were objective response rate, tumor biomarkers including change in her two and safety. The statistical design was a mini max. To stage study design. The 58 participants randomly assigned 1 to 1 of the two treatment arms. There was no formal statistical comparison between the arms And PCR less than 5% was used as a statistical benchmark. These are the baseline characteristics. They were balanced in both arms. You can see that over 50% of the patients were looking positive. Uh And you can see here that most of the patients were I. H. C. One plus her two status. In terms of low expression. These are the baseline characteristics. Um You can see that four patients had her to I. A. C. One plus by local assessment which was determined as I. H. C. Zero by central assessment. These are the objective response rates. Clinically based on imaging. For R. A. The overall response rate was 68%. There were 8% complete responses and 60% partial responses for R. And B. Which is a combination of T. X. D. Plus. The next result the overall response rate was 58% with 8% complete responses and 50% partial responses. The herd to I. C. Was measured from baseline to surgery with central review and 49% had a change in her to I. H. C. After T. D. X. Treatment of those who had to change the majority had a decrease in her to I. A. C. Expression. These are the pathological response data. You can see that in arm A. There was one path cr R. C. B. Zero and there were two R. C. B. One and R. And B. Of T. D. X. D. Plus nash resolve. There were three R. C. B. Ones. As the data cut off of 11 25 2022. The surgical outcomes were still pending for 24% of the patients in our May and 31% of the patients in R. And D. And therefore these data are somewhat immature to reach any significant conclusions. There were no new safety signals looking at the adverse events. One patient with grade two pneumonitis, no cases of cardiomyopathy. So in this study new achievement T. D. X. D. Demonstrated preliminary evidence of clinical activity and her two low former receptor positive localized breast cancer with a toxicity profile consistent with previous reports. The clinical overall response rate was 68% with T. D. X. D. Alone and 58% with T. D. X. D. With an astra zone. The R. C. V. 01 rate was 15% in both arts. But the surgical outcomes are pending 24% in our May at 31% in RMB. There were no new safety signals. The addition of endocrine therapy to TxT did not appear in the study to enhance efficacy because it needs to be exerted in strong conclusions given the small numbers and the immaturity of some of the data. There were dynamic changes in her to tissue expression noted after treatment with T. X. T. T. X. D. And of note this is a strong laboratory for continued translational studies given that they have specimens before and after treatment and will lay the groundwork for future trials. So just to give you all a perspective we still do this every year. But I think we've gained so much in the last 25 years in her two positive breast cancer. That it's worth taking a look back to go forward. We've got from THP in the first line to T. DM. One in the second line but basically transducer mob and chemotherapy and the third line in 2018 as the standards of care. And then in 2021 there were many new agents added in the third line setting with Catnip and Cape cited being frustrated or T. D. X. D. Martin. And the in the third line and now we have T. D. X. D. In the second line and it really is now considered the preferred treatment of choice for patients with her two metastatic disease And the second line treatment it is that as we see in the N. C. C. And guidelines. It is now referred to as referred regimen. And then T. DM. One is available for anyone for whom you will not feel that T. D. M. Uh T. D. X. D. Would be a safe option. This is the summary of the her two positive breast cancers abstracts from san Antonio 2022 the Destiny breast 02 trial T. D. X. D. Demonstrated statistically significant and clinically meaningful improvement and progression free and overall survival versus TPC for patients with her two positive metastatic breast cancer previously treated with T. DM. One in the Destiny breast 03 child. The updated results demonstrated remarkable overall survival and progression free survival benefit of T. D. X. D. Over T. DM. One further supporting the use of T. D. X. D. As a second line standard of care and her two positive breast cancer. The talent trial showed that the addition of endocrine therapy to T. D. X. D. Did not appear to enhance efficacy. And the neo as you've been setting for her to low breast cancer but caution needs to be exerted strong conclusions giving the small numbers and incomplete data. So I thank you And we'll be open to questions at the end of all of the talks. Thanks
