Debasish Tripathy, MD identifies the latest therapeutic options for HER2+ metastatic breast cancer and provides treatments for the advanced disease.
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it's now my pleasure to introduce our next speaker. Dr Deborah. She's Tripathi. Dr. Tripathi is a professor of medicine and chair of the Department of Breast Medical Oncology at the University of Texas M. D. Anderson Cancer Center. Dr. Tripathi will be speaking to us on how to prioritize the many therapeutic options for her two positive metastatic breast cancer. If you have questions for Dr Tripathi, please use the ask a question chat function, and we'll collate questions for the panel discussion. Please, everyone Welcome Dr Tripathi. Hello, I'm Deborah Tripathi from M. D. Anderson Cancer Center, and I am in the department of Breast Medical Oncology. It's a pleasure to be here today. I'm going to be covering the topic of her two positive breast cancer and the treatment of advanced disease. The her two oncogene is a clear psychogenic driver, and it's targeting has been a critical component of treatment for over 20 years. Now the field is moving very rapidly, and I'm going to be presenting the latest updates. Uh, shown here are my disclosures. The her to oncogene is a growth factor receptor that signals a pretty strong growth signal as well as other Vienna types. Numerous ways to attack this receptor to dampen its effect have been achieved with several different drugs summarized here antibodies such as trashed Osama bin pertuzumab and activate the receptor or modulated in a way to diminish its signaling but also activate, to some extent the immune system immuno conjugate such as TDM one and Iraq stick, and our antibodies that are similarly internalized into the cell. But bring with it a powerful toxin. Coyness inhibitors work on the intracellular aspect of the Selva pat nib Narayana been to catnip, and each of them have distinct roles in the treatment of breast cancer, and much a progress has been achieved over the last several years. If you look at the top set of bars, this is in first line treatment. You can see how the initial treatment with trash twosome AB alone with chemotherapy published by Dennis Slamon and colleagues have improved outcomes compared to chemotherapy alone. But in successive decades, different additional therapies or substitution of therapies have further extended survival toward now to where now the median survival is around five years. Similarly, kinase inhibitors and other drugs have produced similar improvements in later lines of therapy. As you can see, the field is very crowded. Many drugs are still in trial. In green are the drugs that are already approved, and I'm going to spend most of my time talking about these drugs. Uh, and in red are drugs that were approved just in the last year, so you can see how quickly things are changing. Currently first line therapy for patients with metastatic breast cancer. And this includes patients that are newly diagnosed with metastatic breast cancer as their initial diagnosis, which now accounts for 20 to 30% of cases as well as patients who earlier had early stage her two positive breast cancer and now recur with metastatic disease as long as there, uh, last treatment with age of interest is a mob is more than a year. We consider them all as first line therapy, and typically they are treated with Does attack cell, along with dual antibody therapy with Christ Osama bin Pertuzumab. And this is on the basis of an important study which has recently been updated shown here, comparing it to the old standard which used to be chemotherapy, either dose of taxol or paclitaxel with trash twosome AB alone and the addition of criticism have shown in the red Line now confers a clear survival as well as disease free benefit. Now you can see again, as I pointed out that the median survival with the pertuzumab combination is of surpassing five years, and to date we have not been able to distinguish a clear feature that tells us who may or may not respond. This is an example of one of the molecular subcategories, uh, pick three C a mutation status, which is seen in about 25% of all cases showing that while the outcomes are a little bit worse in the P I three kinds mutated cases, the benefit of parties may have still persists in second line therapy. TDM one, the antibody drug conjugate, which combines tries to use a map with them Tansy in a very potent micro tubules inhibitor, has now become the standard second line. And this is on the basis of truth to trials, one of which I'm showing here the Amelia trial, which compared to what used to be the prior standard second line therapy of Capeside a bean and patent, it and um, Tanzania now shows a clear improvement not only in progression free survival but overall survival, which is the figure I'm showing here, of course, in the second line, setting the median times to progression or shorter. They go from 6.42 96 with the use of TDM. One other other drugs, such as kinase inhibitors, are a critical part of therapy as well. The her to kindness share some home ology with other kindnesses. I've shown in the kind of country on the left side here lot Pat nib and rat nib are her two kinase inhibitors, but they're also her one kinase inhibitors. That's the epidermal growth factor receptor, whereas to catnip is a more pure her two kinase inhibitor. Not exclusively her, too, but much more selective Nurettin ib more more potent. Her one and her two kinase inhibitor had been approved earlier in early stage breast cancer, but was used also in metastatic breast cancer to some extent but was formally FDA approved for this indication last year on the basis of a trial that compared the old standard of la Patna with Cape Side of being too neurotic nib in Capeside of being because neuron um is a more potent kinase inhibitor, particularly for E g f R. One of the side effects diarrhea. So low Pyramid was given as prophylaxis in this particular trial. 621 patients were randomised on this trial, and this did show an improvement in progression free survival, crossing the threshold that was needed to define this as a positive trial. With an improvement of about 2.2 months and a small difference in overall survival. That's not yet statistically significant. Kinase inhibitors penetrate the blood brain barrier to a greater extent than antibody based therapies. And the incidents of CNS metastases has been found to be lower in some of the trials comparing kinase inhibitors to antibody and in this particular study, comparing a more potent kinase inhibitor to a less potent 11 also sees that the incidents of CNS metastases is a little bit higher, higher in the weaker kinase inhibitor low patented shown on the upper right corner. As I mentioned, the toxicities of the kinase inhibitors include diarrhea to a greater degree with narrative, and you can see here that diarrhea was seen more frequently in the narrative in Capeside of being armed Capeside. I mean, of course, on its own does have some diarrhea. As a side effect, however, it has been shown in other studies that gradually stepping up the dose of Neurontin have over the course of a month can mitigate some of the diarrhea side effects. They tend to be problems, especially in the first month or two of therapy. After that, the incidence of diarrhea wanes somewhat. Nora Nib also has the distinction of being effective in her two mutant cancers, which really doesn't fit into the category of her two positive cancer, because these are generally her two negative by standard essays. But her two mutation is detected with next generation sequencing, and this drug is active. It's not quite yet FDA approved. It's under, um, submission to the FDA pending a small randomized trial that is ongoing. But I just wanted to include this really more out of biological relevance as we are finding more and more her two mutations as we sequence, uh, these cases more, particularly in patients who have been on endocrine therapy for prolonged periods of time, a more specific her two kinase inhibitor to catnip has recently been tested and approved on the basis of interesting data in the Phase one trial which I'm showing here, Uh, this drug is given in combination with Capeside A bean and Krista's mob. And the responses that you can see in the waterfall plot on the lower left side have motivated this to be studied in larger randomized trials. Also, in these early trials, responses were actually seen in untreated CNS metastases has shown in the lower right panel. Therefore, a randomized trial was conducted in patients with metastatic her two positive breast cancer who had already received treatment with, um prior treatment with trashed Osama bin TDM one. In this particular trial, patients with brain metastases were allowed and uh, if they had been previously treated, they were allowed. But also, if they had asymptomatic or minimally symptomatic, active, untreated brain metastases, uh, they also could be treated, and about half of the patients had a brain metastases in these in this trial. So the overall progression free survival reported all patients with and without metastases is shown here. Uh, the endpoint was clearly met with a reduction of about half of the number of recurrence events, uh, compared to placebo again all patients received Capeside of being pressed to the map with either to catnip or placebo. Overall survival was also improved. In the initial analysis has shown here, about one third fewer mortality events were seen, with the median survival going from 17.4 months to 21.9 months with two captains. Patients with intracranial metastases were also, uh, found to have a benefit. You can see here the progression free survival and overall survival were both improved in the subset of patients that had CNS metastases. Uh, in fact, about a quarter of patients had partial responses uh, in, uh, brain metastases. So this is a good option for patients that may have either untreated or previously treated brain metastases as they heard two kinase inhibitors. Some degree of G I, uh, and hand foot syndrome is also seen, uh, with this drug not as great as we see with narrative. But you can see that diarrhea, hand foot syndrome, uh, nausea and fatigue or the more common side effects. However, grade three or higher were not seen as frequently as shown in the dark blue part of the bar. Let me now move to the antibody drug conjugate. These are exciting new class of drugs that are being tested in multiple tumors and multiple subtypes of breast cancer. This particular one is targeted toward her to using the trash to Zermatt backbone bound to a drug called directs T can. This is a synthetic Tokai summaries one inhibitor. These congregants are typically bound to the antibody through a linker that is then broken. Wants the antibody drug conjugate is internalized into the cell. The toxin can actually be released back into the tumor micro environment, which can help, uh, inactivate or kill cells that are maybe her too low that are part of the tumor mass. Uh, so these, uh, drug more eighties are also being tested in her too low cancers that are actually her two negative but expressed her to a one or two plus level and are showing some activity in these drugs. This trial destiny one was in patients who had had multiple lines of therapy. All of these patients had previously received trash twosome have and TDM one and about two thirds of them had also received pertuzumab. And so, for a very heavily pre treated group of patients, these results were really astounding. You can see the waterfall plot here that shows the depth of responses. And of the patients treated, 61% of patients actually demonstrated a partial or complete response. And the progression free survival and overall survival was very impressive for this heavily pre treated group of patients. You can see here the 95% confidence intervals for both of these endpoints, with a median duration of response to 15 months and also median survival of survival. Median survival has not even been reached yet. Adverse events of this drug include, uh, some of the side effects we expect to see with Tobias Andres one inhibitors like nausea and fatigue and alopecia. But there are also rare events of interstitial lung disease shown in the right side of the slide. And in the lower panel, you can see the cumulative probability of developing interstitial lung disease. This is something that needs to be monitored carefully. In fact, in this trial, 2% of the events were fatal, so patients who develop shortness of breath definitely need to be evaluated. Uh, sometimes these were picked up a symptomatically with interstitial changes on the lung ct And for those patients, treatment should be interrupted. And for those that have symptomatic grade two or higher pneumonitis treatment should be permanently discontinued. And these patients should be treated with steroids. Ongoing investigation with this, um, you know, conjugate is ongoing. Uh, TDM one is being tested against, um has a definitive trial to lead to permanent approval. The FDA did grant a accelerated approval on the basis of the phase two data that I just showed you. But the final approval will away to the results of the destiny. Oh, to trial that is comparing. Trust us. Um, Abdou rocks t can too. Chemotherapy of investigators choice along with crossed us a map that could be their capeside of being or low patting him or like pattern of Capeside a bean. And the Destiny three trial is for the next line of therapy comparing TDM one which is now second line standard treatment. Compared to trust us, um, Abdo rock stick. And so both of these trials are ongoing and recruiting patients. And as I mentioned earlier, this drug is effective in her too low, and a randomized trial is ongoing for this group of patients as well comparing chemotherapy. A physician's choice to the antibody drug conjugate transpose may have drugs. Tekin other antibody drug conjugate its are in testing. There are actually several of these her to targeting antibody drug conjugate its and this is just an example of one of them for which a, uh phase 23 randomized trial has recently been completed. Although the results are not out yet. These are data from the earlier Phase one study showing responses in 33% of patients again heavily pre treated patients. This one has a different set of side effects because it really depends on the payload, the toxic payload. This one is a micro tubules inhibitor payload and fatigue and conjunctivitis and other ocular symptoms are the primary side effects seen with this drug very few grade three events. But the ocular complications are seen frequently. A great one in two levels some degree of stone mastitis and nausea as well with this can't see it. And this is the randomized trial now that has been completed and we await follow up results of this. Yeah, and the most recent drug to be approved just a couple of months ago is Margaret tucks a mob, which is an antibody that has been engineered to have the FC portion of the antibody more avid or with a higher affinity to the FC three gamma receptor. We've known for decades now that patients that inherit a low affinity version of the FC receptor may have diminished responses to therapeutic antibodies, such as trashed Osama bin Rituximab in the case of lymphoma and B cell malignancies. So this antibody is engineered to have a higher affinity and therefore should activate the immune system both moral and T cell immunity, with a greater degree of activity. So this trial was designed to compare chemotherapy of the physician's choice about a group of therapies chemotherapies with trash twosome as compared to market takes a map with the same chemotherapy. And, uh, primary endpoint was progression free survival. Um, at the second interim analysis, one can see that progression free survival was improved by, um, 1.3 months, but it was statistically significant, and maybe a hint of, uh, survival of improvement, although not statistically significant at this time now, in the group of patients that had an inherited low affinity, uh, genotype for the receptor for the FC receptor, either hetero Ziegesar, Hamas, I guess for the low affinity, they had a bigger benefit, and you can see that overall survival in this group of patients was improved to a greater degree with a 4.3 month difference. So how do we put all of this together in making choices? It's great to have a wealth of options as we care for these patients. Uh, and I would propose the following model, obviously with some flexibility, but for first line therapy, So this includes patients. DiNovo. These are patients who initially present as their first manifestation of breast cancer with metastatic disease are those that recur more than a year from having received, as of interest, us a. Mob or crest Osama bin Pertuzumab. For these patients, first line therapy with a taxing the best data is with Does Attack Cell. But weekly paclitaxel has also been studied with Trust us a mob and pertuzumab with the chemotherapy component given for 6 to 8 cycles or four cycles. If there's problems with cholera bility and then followed by maintenance antibody therapy with both prostitution have been produced map until progression or until any side effects from the antibody. And during the maintenance phase, we do add endocrine therapy for those cases that are positive for estrogen or progesterone receptor. One of the questions, really. We know that in patients with her two positive cancers that we control their systemic disease to a greater extent. Now with these drugs. But especially with antibodies that don't cross the blood brain barrier, brain metastases are more common. In fact, in her two positive metastatic disease, up to 50% of patients may develop brain metastases at some point in their clinical course. We don't routinely screen patients with MRIs if there are asymptomatic, although some argue that we should. We don't know if early detection makes a difference, but we do know that our threshold should be lowered to screen these patients. I just wanted to add that as an aside in second line, then we or or in first line for a patient who has completed achievement antibody therapy. Within a year, those patients would be treated with a standard second line therapy with TDM one or two tracks tourism have enhancing the antibody drug conjugate, and then in third line or after we have options. Uh, the approval of two catnip crass to somatic. In Capeside, a bean is the one that was approved on the basis of phase three data with a survival advantage. So I put that first, and maybe that would be preferred for patients with a history of CNS disease or even small active metastases that may not be symptomatic. This may spare them having local treatment up front with either neurosurgery or with steri attacked IQ radiosurgery, um, and then in fourth line drugs, trash to zmapp drugs, T can or ttxt, as it's called, Um, and you could potentially use it in third line and someone that has very aggressive disease because the response rates are high. Uh, and so I think that these could be used in in either sequence and then beyond that, all those lines of therapy. Many patients are still have a good performance status and are still candidates for ongoing therapy. So, um, I have listed here some additional, uh, options for patients and later lines. Market tucks. A mob, of course, is now an FDA approved option. And then trust us. Um, Abdullah Pat nib Capeside of being granted Capeside of being let Pat nib venereal being which can also be active and several other side a toxic drugs that I have listed down here at the bottom and the bottom bar can have also shown activity and phase two studies with trash two's a mob. So many, many options for these patients. Um, we've really expanded the armamentarium, and this is one of the few cancers in which, even upon the development of resistance, that we still use the same target, and her to really continues to be important in these patients. Now. I should also emphasis that as we treat these patients when they recur and have progressions in areas where we can feasibly and safely get a biopsy, that we should be doing that to check the her two status. Because sometimes you get clonal selection of cells that evade treatment because there is some heterogeneity and the tumor mass and the subset of cells that may have lower her to expression could be the ones that proliferate. And sometimes patients actually switched their her two status from positive to negative. The hormone receptor status can change as well, so it is important to periodically check this in patients also as we go forward. There's a lot of exciting new areas that remain to be studied. I had mentioned to you that one of the reasons that antibody therapy may be so successful in her two positive cancers, with some patients having lived now two decades since we first started using trust us a map with metastatic disease and still under control maybe that it has the capacity to activate the immune system. Uh, the antibodies R I G one antibodies, which are able to activate antibody dependent cellular side of toxicity, and that could explain these prolonged remissions. So this is being studied further with the addition of immunotherapy for patients. A large randomized national study is ongoing now with plus or minus of textualism AB. Other immune checkpoint inhibitors are also being tested. Her two vaccines are being tested as well. Also, the role of cycling dependent kinase inhibitors, which have been very successful in hormone receptor positive disease, are being tested in the subgroup of patients that have her two positive and hormone receptor positive disease. Some interesting data from one of the monarch studies showing that one can get enhanced activity, um, with trust us a map and her two positive and hormone receptor positive setting. About one quarter of patients with her two metastatic positive breast cancer have mutations in the Pick three c, a catalytic unit of the P I three kinase enzyme. So treatments with Pi three kinase inhibitors are being tested in the maintenance phase to ongoing studies. Now are looking at different three kinase inhibitors. Um, the re use of immuno congregates. I mentioned that there is a real plethora of her to immuno congregates and testing, and, uh, these probably can be used in sequence because they have different payloads and different toxic, different toxic varieties. The re use of pertuzumab and later lines of therapy has recently been shown to be a benefit as well. And then finally, the whole notion of personalizing therapy based on biomarkers and genomics is something that is being studied more. There are some cancers that are her two negative by standard, uh, Communistic, chemical and fish essays. Yet the her to pathway is turned on and these might respond to kindness inhibitors, and this strategy is being tested as well. So really many advances and much more to go going forward in the treatment of her two positive breast cancer. Thank you very much for your attention. Uh, and I look forward to answering any questions in the panel discussion and question and answering setting, so thank you again for your attention.
