Chapters Transcript Video Human Epidermal Growth Factor Receptor 2 (HER2) Positive Disease Update Back to Symposium Good evening. I'm Lori Goldstein and we're convening again for the 19th annual san Antonio breast cancer symposium. And again my topic will be her two positive breast cancer. And I'll be discussing some summary and highlights. These are my disclosures and these are the topics that will be reviewing. There's been no setting with more remarkable advances of the last 20 years and her two positive breast cancer that isn't how to optimize and give less toxic therapy to early stage disease. And all the new agents that have resulted in improvements and overall survival with clear and meaningful benefits to our patients for the achievement of neo adjuvant topics will be discussed in the optimization of therapy including the attempt trial, the Catherine trial, the affinity trial, the X. Inet and optimal duration for metastatic breast cancer. Will be reviewing the her to climb study of nicotine and versus placebo, the destiny trial, the Sofia trial and Perathoner. Um but we won't be discussing but that I wanted to bring to your attention because it may be affecting your practice and has been uh up on your formulary is probably in the last couple of years and out of the biosimilars combined trust is um Evan produce a map and subcutaneous administration In terms of optimizing therapy in stage one Her two positive breast cancer. We know that from the Syria data, stage one represents 34-41% of her two positive breast cancer. So it's frequent in the A. P. T. Trial, 90% of the tumors were stage one, even though it allowed up to three centimeter tumors. And the seven year relapse free and overall survival were 93 97% respectively. Which was quite quite good. The attempt trial looked at TDM one versus traces a map and tackle tax hole and while the disease free survival was the same, it was really similar to the A. P. T. Trial because it was not a direct comparison. And then I'll show you the proposed attempt to two point oh trial of 3 to 1 randomized study of T. D. M. One time six versus th. So this is the study design of the attempt trial which stage one her two positive breast cancer patients were eligible. They were N0 and one micro left that adequate left ventricular ejection fractions with no prior invasive breast cancer and less than or equal to 90 days from past surgery patients were randomised in a 3 to 1 ratio to T. D. F. One versus th. They will co primary endpoints of with a three year disease free survival and T. D. And one arm. And to compare the incidents of clinically relevant toxicities between the two arms. This is a disease free survival of 97.7 At three years, which was quite excellent. And this is the disease free survival. My hormone receptor status. And you can see the DFS was excellent for both hormone receptor positive but negative. And regardless of tumor size when there was less than one centimeter or greater than one centimeter, This is the recurrence free interval as if I'm to include invasive, local regional recurrence, distant recurrence and death from breast cancer. Again showing a 33 year relapse free interval of 99.1%. There were only two distant recurrences for the patients who received the TDM one and you can see that the clinically relevant toxicity was slightly different between the two arms. So with more neuro toxicity for the thr And we're toxic. You require early discontinuation in the TDM one TDM one arm, A TDM one may be considered in select patients with stage one her two positive breast cancer are concerned about certain toxicities. However th remains the standard for these small no negative. Her two positive breast cancers. Mm. So one of the interesting things I'm very fish will be very happy and delighted that we've been discussing this and I hope the surgeons are paying attention is the question of whether if we're doing so well with 99% disease free survival at three years for some of these small tumors. Can we omit surgery and highly selected patients. And this was Shown in the LP's trial design which is ongoing. And it selected patients who had small her two positive with her two was enriched by Pam 50 that was clinical T. One C. And zero. All the patients received THP times 12 weeks If they achieve a pcr defined by a clean M. R. I. And a vacuum assisted core biopsy then they received no surgery and then are followed. So this is pretty exciting. We've gone from radical mastectomies to modify mastectomies to lumpectomies, radiation and axillary number two. Section two sentinel lymph nodes. And now we're talking about no surgery. So this is really an interesting uh study. And we all look forward to these results for these highly selected patients. Now. What about optimizing therapy for stage two and three or two positive breast cancer? About 40 to 50% of her two positive breast cancer is stage two and three. We know that transducer map improves disease free and overall survival from the N. 98 31 N. S. A. P. P. B. 31. Combined analysis we know that tracks changes in the map and produce a map from the affinity trial improves invasive disease free survival and with no positive patients, Probably the trial that's changed our treatment paradigm more so than any other study in the last few years is the Catherine trial, which demonstrated the TDM one, improved disease free survival post neo adjuvant therapy with residual disease. And the excellent study also showed that in rats have improved disease free survival post neo achievement residual disease and won't go through some of the highlights of these studies. So this is the affinity trial and this is an average of in trial for her two positive breast cancer, comparing chemotherapy plus translucent mad plus Pertuzumab versus chemotherapy, translucent plus placebo with the primary endpoint of invasive disease free survival. And here you could see the invasive disease free survival of 19.6% vs 87.8%, favoring the producer Matt Bomb at six years. This was an absolute difference of 2.8 Here, you can see the overall survival of 94.8% vs 93.9%. Not statistically significant. If we look at the benefit in terms of cohorts, the benefit really is for the lymph node positive patients. There is no benefit in the negative patients. And what we saw last year when this was updated was that the benefits of produce a magazine, they all look no positive patients, regardless of formal receptor status. So to summarize the affinity trial, we know that the clinical benefit of produce a map and hurry to positive early stage breast cancer is strengthened and positive patients With a hazard ratio .7 to a six-year invasive disease free survival of 87.9% vs 83.4% was an absolute difference of 4.5%. And there is no criticism that benefit in the no negative population and there were no new cardiac signals. Next moving on to the Catherine trial. And then, as I said, this is the trial That really has changed our treatment paradigms especially has affected a workflow for our multidisciplinary teams. So this study took patients who had clinical T. 124 and 0 to 3 and our presentation. They excluded very small tumors of T. One A. And B. Her two positive. The patients all received neo adjuvant therapy which must have consisted of a minimum of six cycles of chemotherapy with a minimum of nine weeks of taxing anthro cycling's and operating agents were allowed all chemotherapy was prior to surgery and a minimum of nine weeks of trespass a map and a second her to target agent was also allowed. The patients also had to have residual invasive tumor in the breast or exploring those to be randomized and randomization was with within 12 weeks of surgery and the patients were randomised in a 1 to 1 ratio to TDM one versus trans Susan matt. And here you can see the remarkable invasive disease free survival improvement favoring the TDM one. The hazard ratio was .5 with a highly significant p value. The three year invasive disease free survival was 77% for the transfusion mob in 88.3% for the TDM one. Similar benefits we're seeing in terms of distant recurrence with a hazard ratio 0.6. The three year event free rate was 83% for the trust, Osama Bin 89.7% for the T. D. M. Month and again significant. The overall survival was numerically higher. For the transfusion map for the TPM one excuse me. Um With a P Value of point oh eight. So this did not meet the boundary for significance but clearly numerically favor the T. D. In one arm. So the adjuvant TDM one demonstrated both statistically significant and clinically meaningful improvement invasive disease free survival compared with trash. Susan map with a hazard ratio 10.5. That was highly significant. Three year invasive disease free survival rate improved from 77 to 88.3%. With an absolute difference of 11.3%. This was this benefit was consistent across all key subgroups, including hormone receptor status, extensive residential invasive disease, single or dual her to targeted neo adjuvant therapy. The safety data were consistent with the known effects of TDM one. So there were no new signals. An additional follow up is necessary to determine the effect on overall survival. And this really was a new standard became a new standard of care um and was approved by the FDA. Next is the retina has extended adjuvant therapy. This is the excellent trial that looked at her two positive breast cancer patients received prior a german traces um absence chemotherapy. They will look no positive or negative or residual disease after neo adjuvant therapy and was stratified by nodal status, former receptor status and concurrent versus sequential transfusion map. And the patients were randomized one to launch in the raton and versus placebo for one year. The primary endpoints were invasive disease free survival. There are many parts of the study but eventually after many years the study was presented and published and there was a benefit in the hormone receptor positive patients Of about point about 4%. But really overall there's only about a 2% benefit in the neurotic arm. So this is recommended to random for early stage her two positive breast cancer at high risk for recurrence. The absolute benefit is 2.5% of the overall population. But the benefit is primarily seeing the ear positive patients that have been an absolute difference of 4.4% this year. As san Antonio update revealed that there was no difference in overall survival except in the very high warmer receptor positive patients who fail to achieve a path cr and numerically there were fewer CNS events with the red versus placebo. This has given following edge of interest is a map based therapy. However, there are no prospective data at this time for patients treated with produce a map or G. D. M. One. So it's hard to definitively determine the role of directive for patients at this point to produce a map or G. D. M. One in the early stage setting. and of course one of the toxicities it needs to be managed as diarrhea. But what about the optimal duration of transfusion? That this is another way of trying to optimize things for patients? The standard Uh therapy for tresses. A map in terms of duration is one year. The forest study is one of several studies that compared six months to one year in non inferiority designs. And most of them did show that six months was in period to 12 months of transducer mob in the adjuvant setting and therefore one year is the standard. Based on the fin. Her study, the short hair study was done of nine weeks versus one year of Tres Osama Bin. The study the patients did all receive entry, cycling's and taxing. So it's hard to look at this in comparison to some of the other studies, but it did show that there was no different scene in disease free survival with short versus long term traces. A map therapy but a significant decline in cardiovascular events was observed with shorter duration of transfusion man. So as I said, the standard duration is one year. But for those patients for whom the risk of cardiovascular disease is high and have low risk disease. Certainly a short of course may be entertained or for those patients for cardiovascular reasons you are unable to complete a year of therapy knowing that you can get at least nine weeks in is pretty good for the patients and basically some traces. A map is better than no translucent have. Yeah. So the current uh N. C. T. N. Cooperative group trial that's going on now for her two positive breast cancer is a compass trial. Those patients are eligible includes stage two or three A her two positive breast cancer. T. 2 to 3 and zero patients receive THP and the neo adjuvant setting as paclitaxel. Or those attacks are with translucent map and produce a man. They go on to have surgery. If they achieve a path cr they complete one year of HP and the indicated radiation. And the therapy is appropriate if they do not achieve a path cr they received uh TDM one or TDM one. Uh Plus I believe it's two catnip um Capeside to be and um trust is a map. So there's a part two of this study. So I try to keep it simple for you and um really synthesize the current recommendations for the treatment of early stage breast cancer. And I broke it down into two groups to keep it simple. But of course all the details for this can be found in the N. C. C. And guidelines For tumors that are less than equal to two cm and clinically no negative. These patients have surgery. If they're found on stage one Pathologic Stage one of surgery they can receive th and clinically indicated TDM one. If that surgery they're found to have pathological stage two or three they should receive tch with P. Or a C. T. H. P. If there are no positive they should receive produce a man and then being considered for neurotic after that for high risk lives no positive hormone receptor positive tumors. If patients have tumors greater than two centimeters on a clinically no negative they should receive based on the Catherine results T. C. H. P. Or a C. T. H. P. And the addition of produce a map in the neo adjuvant setting here is not because of increased overall survival because we know the producers did not achieve that. But it's really to increase the pathologic complete response rate because we know dual her to inhibition, increases the pathological complete response rate. And then the patients have surgery after neo adjuvant therapy. If they achieve a path cr they continue with th if they do not achieve the paths er then they should have the standard therapy of TDM one. And then again we don't have data in this situation for patients who've had produced a map and TDM one but for very high risk patients will let no positive Palma receptor positive one might consider adding you're adding them afterwards. So the conclusions for her two positive early stage breast cancer or is that her to targeted agents have improved clinical outcomes for her two positive breast cancer, the affinity child determined that german Pertuzumab improves disease free survival, lift no positive tumors regardless of former receptor status. The attempt trial showed that Adam and TDM one was associated with very few recurrences and her two positive breast cancer. We also are learning that individualizing therapy based on response and to biology is the future of her to treatment. The shared decision making is essential. Uh And current studies are now aimed at identifying patients for whom treatment can be optimized and more research is needed. Now moving on to metastatic breast cancer. This was our 2018 treatment algorithm for her two positive metastatic breast cancer. In a simplified form were in the first line patients received THP second line TDM one based on the Amelia trial. And then it was Fielder's choice of a pack plus Capeside of being trust. Susan Matt plus the Patner trust. Susan Matt plus Capeside of being trusted plus, literal being etcetera. And then you ran through your combinations here depending on the patient's co comorbidities and toxicities from prior treatment. Now I'm going to show you some of the data that we've seen over the past year and how this algorithm has changed first. We'll review the her to climb trial. I know I presented this to you last year the the evening was late and while the studies home run I really had to drive it into you. So I'm going to review this again with you because I'm sure you're all trying to use this for your patients at this point. So this is the her to climb trial For her two positive medicine of breast cancer. Prior treatment with tries to Zermatt Pertuzumab and T. D. And lung eco performance status had to be zero along. And what was novel about the study design is that Brain MRI was done at baseline and patients who are eligible if they have previously treated stable brain mints untreated brain mints not needing immediate local therapy. Previously treated process. Progressive brain mets not needing immediate local therapy and no evidence of payments. And the stratification factors included rain, meds, peacock status and region. The patients were randomized into 21 fashion to take a keen interest to some advocates side of being versus placebo trust. Isn't that Ben Capeside of being? And this was a randomized double blind placebo controlled global trial, the primary employees BFS. And just to remind you that a Cabinet was an investigational oral T. K. I. That is highly selected for the kinase domain of her too, with minimal inhibition of E G F. R. So this is a progression free survival as a primary endpoint with the hazard ratio of .54 of the highly significant p value for the median PFS of 7.8 months versus 5.6 months favoring the cabinet arm. The overall survival show that has a ratio .66 also significant, With the median overall survival 21.9 months for the cotton um Arm vs 17.4 months for the control arm. Mhm. In terms of patients with brain mets again, their favor favorite, the Cotton farmer, the hazard ratio of 0.48 That was highly significant. The median progression free survival was 7.6 months for the to Cotton farm versus 5.4 months for the control arm. In addition, there was almost a doubling of the confirmed objective response rate of 41% for the ticket in the barn versus 23%. So in some rate to catnip in combination with tractors amendment capeside being reduced the risk of death by one third, reduced the risk of progression or death by half and nearly doubled the confirmed objective response rate. And what was really amazing is that this benefit also was seen in patients with brain mets, which is a very important issue to deal with For patients with her two positive breast cancer, the Cabinet was beneficial in all subgroups consistent with the overall outcome and the primary secondary endpoints and most of the adverse events were a blue grey. The study was simultaneously published in the Journal of Medicine and approved by the FDA in April of 2020. Next one, we'll move on to the tracks. Susan Derek D can DS 82 oh one and her two positive breast cancer. This is the destiny of one study and this is an A. D. C. With a payload of Tallboy summaries, one inhibitor with a high potency uh has a high drug to anti money ratio approximately eight with a payload with short half life as a stable linker payload that has a tumor selective people will linker and then bring permeable payload. And they had very promising results from a previous Phase one study the Destiny breast to one study uh including patients with her two positive breast cancer who received prior TDM one and excluded patients with a history of institutional lung disease. The primary endpoint was overall response rate and the secondary endpoints included overall response rate. D. C. R. D. O. R. CBR progression free survival, overall survival PK and safety. So the patient characteristics, you could see that 13% of the patients had a history of brain metastases. And this is the primary endpoint showing a confirmed overall response rate of 60.9%. And this was a very heavily pre treated group of patients with a median prior line of therapy of about six lines. You could see that the objective response rate was a scene across all subgroups, including the brain metastases group, The progression free survival. At the time, the initial report was 16.4 months and the median survival had not yet been reached. Of note, the median progression free survival in the 24 patients with brain metastases was 18.1 months. But you can see here that one of the concerning adverse events of special interest into social lung disease. What 13.6%. So this is not to be dismissed. We need to monitor closely for this. We need to hold the agent and start steroids as soon as I. L. D. Is suspected. So, in terms of the conclusions for the Destiny trial, the T. D. X. D. Demonstrated confirmed overall response rate of 60.9% and durable benefit and very heavily pre treated patients. The median duration of response was 14.8 months At San Antonio 2020. The update showed that the progression free survival increased to 19 months. The responses were consistent across all subgroups and the SAn Antonio 2020 update also showed the overall survival of 25 months. Again, we need to be concerned about interstitial lung disease monitor and treat appropriately. And there were three other studies and her two positive expressing breast cancer that are ongoing. The Destiny presto to trial is um TTXT versus standard of Care After TDM one in her two positive breast cancer, the 03 trials versus TDM wanted her two positive and a very interesting study is the oh four trial which is comparison to chemotherapy and her too low patients. So we're looking forward to the results of these trials since the report out and again this study was simultaneously published and then FADA approved in December 2019. And the last uh drug that I want to talk to you about randomized data are is the severe trial which uses margin to margin versus translucent Annapolis chemotherapy. Again, patients with metastatic her two positive breast cancer with greater than equal to two prior anti heard two therapies including Pertuzumab. The chemotherapy is an investigator's choice. Okay, so I have been a regular gym side of being a bit of well being in a 1 to 1 randomization with sequential primary endpoints of PFS and OS. So March to choose a mob is um engineer for increased affinity of activating FC receptors and decreased affinity for inhibitory uh Fc receptors to optimize its activity. And you can see here that the investigators spfs showed a 29% reduction in the risk of disease progression with a median progression free survival of 5.7 versus 4.4 months. But the hazard ratio 7.71 that was significant. You can see here the objective response rate was 25.2% from architects. A man versus 13.7%. Fortress does a man and this was also significant. You can see the second interim overall analysis showed the median overall survival 21.6 months versus 19.8 months has a ratio .89 and not significant but numerically improved. And you can see here that these drugs had similar overall safety profiles. So there were no major safety signals. So marshall toxin map increases affinity for activating and decreased activity for inhibitory fC receptors. The intent of the Fc engineering is coordinated engagement of both innate and adaptive immunity. The combination marshall toxin samples, chemotherapy, improved PFS overall response rate and clinical benefit clinical benefit rate Compared to transfuse Annapolis chemotherapy. There was no difference in overall survival but the data immature with acceptable toxicity. Similar transfuse um um And the FDA approved This combination in December 2020 just recently so I just wanted to show you a couple of other things to get excited about. This is not practice changing. But we know the CNS disease is a critically important area of her two positive breast cancer and trying to manage these patients is really very challenging. So this is a phase two study of karate in um and her two positive breast cancer with frame it's this is A. T. K. I. A. Pan hurt T. K. I. The study was performed and nearly diagnosed untreated metastatic breast cancer with brain mets. There were 61 patients enrolled, 89% had prior translucent MAb. And the cNS overall response rate was 76%. So quite good. Um And the toxicity included what we expect from T. K. On his diarrhea and PP. In addition, one might ask what the role of Iowa is and her two positive metastatic breast cancer. This area is still relatively immature, but this was one poster that was presented uh comparing uh combining trust is um Abdal decorative cab two plus an Ebola ma'am. There are 52 patients enrolled and included her two positive and her too low patients have five fire lines of therapy. The response rate for her two positive patients with 59% and then 37.5% for the herd to low. Uh This is a non randomized trial so we cannot isolate the benefit of the I. O. But we know that with the TTxt Um the response rate was 60%. So it's hard to know anything about this combination at this time but it's certainly interesting to look forward to other studies. Um So this is now I showed you the 2018 treatment algorithm beginning this metastatic discussion. Now this is the 2021 algorithm and you can see everything in red is completely new compared to what we met last year. So the first line is THP second line with the TDM one and then third line would be to catnip plus capeside of being translucent mob or translucent abdic derek can or masochism apples chemotherapy and or the rat nip. And I didn't show you that but that's also now on the list. And then they would go over to combination transducer mob and chemotherapy depending on toxicities and comorbidities. What we don't know is whether we can go in the red box from from one new T. K. I. To the other or one new antibody to the other. And of course we'll learn that as we go forward. But certainly having four new treatments in one year is really remarkable for these patients with metastatic her two positive breast cancer. This is a study we have a Fox Chase Cancer center I. R. B. 17 10 10. This is a phase two combination trying to protest, lose a map and combination of paclitaxel translucent map and produce a map and her two positive breast cancer. So if you have these patients please send them over, we'd love to enroll them on the trial. So the summary for her two positive metastatic breast cancer is a to catnip landscape side of Being and transfused mm improves PFS. Os and overall response rate, including brain metastases. The Destiny trial demonstrated confirmed overall response rate of 60.9%. But we need to monitor for I. L. D. And margin took some and plus chemotherapy and Cruz improves PFS overall response rate. Clinical benefit read but no significant change in overall survival. So I want to stop there and thank you very much. I wish you all a very safe and healthy 2021. Created by Related Presenters
