 Mark and Komal, will this data change your use of CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors? How are you going to apply this to your clinic?

 I like to look at this data from 2 different vantage points. One is clinical; from a clinical perspective, we now have level 1 evidence from a randomized, controlled phase 3 trial of an overall survival benefit that's statistically significant in the case of the first-line ribociclib plus AI [aromatase inhibitor] data. That is the gold standard for clinical decision-making: level 1 evidence, phase 3 trial, statistically significant OS [overall survival]. For clinical decisions, that's impactful to me. With the evidence we have available right now, that one is the surest bet and has the most robust OS data. The other perspective I like to look at this data set from is more from a scientific point of view. From that point of view, things are a little bit less clear. If you say that the null hypothesis is that palbociclib has no OS benefit in the first line, then looking at those curves and some of the relevant subsets like the planned analysis of PALOMA-1 plus PALOMA-2 data and the subset that has a longer disease-free interval, et cetera, when you look at the data from that lens and say, well, the null hypothesis is there's no impact on survival, no statistician would say that that's probably right. It doesn't rise to the level of statistical significance, to be sure, but that does not mean that there might not be an interaction, we just failed to demonstrate it in this trial—and there are so many variables as you rightly pointed out: geographic location of the patient populations in all the first-line studies that affects later-line therapy in ER [estrogen receptor]-positive disease. Different countries have different standards of care, and that could impact outcome. The crossover rates may differ from trial to trial. There are subtle differences between the patient populations, demographics, and pathology, etcetera, as well, so these things are not always clear. Finally, none of the trials had a 100% statistical power to detect an OS benefit if 1 truly exists. I think the data from Dr Richard S. Finn, University of California Los Angeles, in this presentation at this 2022 ASCO [American Society of Clinical Oncology] annual meeting, said the power for OS is about 80% in PALOMA-2 in the intensely treated population, so 1 out of 5 times you run that trial, you will probably fail to see an OS benefit statistically due to play of chance. That's also a possibility that we can't overlook from the scientific perspective, but the clinical data are in, and right now, I think ribociclib carries it there.

 It's an interesting question. One of the questions for you is, how does this affect your use of CDK4/6 inhibitors? How do you balance the adverse events from the different agents? We'll talk more about quality of life in a moment, but how do you balance that when you're making decisions?

 It is very important, and Mark pointed all the right things about how clinical decisions and how level 1 data are available. When we look at these trials, all of these trials, as we said, were powered for the primary end point of progression-free survival. If you look at those curves, they are nearly identical with identical hazard ratios. It's very frustrating in some ways to then go back and say, “OK, but now we're not seeing overall survival benefit in one study but we're seeing that in other; are there significant differences that can explain the difference between the 2 agents?” Certainly we do realize there are structural differences. There are differences in their CDK4 and -6 inhibition profiles and their toxicity profiles, but it's not very clear if that can translate into a significant clinical impact in terms of the difference in numbers and overall survival. Having said that, for me, it's going to have a patient in front of me, discuss the toxicity profiles as well, look at their comorbid conditions, see what kind of comorbidities that they have, what kind of medications they're already taking concomitantly; would that come in the way in terms of toxicity? For example, sometimes some patients are taking antidepressants, and that can have QTC prolongations. Would that come in the way of utilizing ribociclib? Or with dose reduction, would that not be an issue? Inflammatory bowel disease—that comes in the way for abemaciclib, so we must keep all of that in mind. Ultimately, quality of life, a good balance from tolerability, toxicity—quality of life for a patient and the efficacy data as we have—we can have a discussion with our patient.

 That is all really important. Aditya, would this data make you change somebody? Are you going to go back to work after ASCO and change a patient's CDK4/6 inhibitor?

 It's interesting whether PALOMA-2 is a practice-changing study from other perspectives in the sense that we should not use palbociclib. In patients who are currently on palbociclib, I would feel very comfortable continuing them on it. If there's a new patient with metastatic disease, be it de novo metastatic disease or someone who recurs after adjuvant endocrine therapy, the choice of CDK4/6 inhibitors, as Komal was discussing, whether premenopausal, postmenopausal, the comorbid conditions—it does increase the enthusiasm for ribociclib because you have overall survival data which is with level 1 evidence.

 A general question about how you treat younger women who have advanced breast cancer: do you always use ovarian function suppression in the first-line setting?

 In the first line, yes. I tend to use ovarian suppression plus an endocrine therapy like AI plus a CDK4/6 inhibitor. For someone who's premenopausal, my choice is ribociclib, given that we have level 1 evidence from MONALEESA-7.

 I agree. I tend to approach the premenopausal patients the same way. I think it's interesting that we're all debating this right now and just as we do this, the landscape is going to change. We have adjuvant CDK4/6 and who knows what that impact is going to be on overall survival with first-line CDK4/6 when the new metastatic breast cancer patient might have very well been exposed to 2 years of adjuvant CDK4/6. Just as soon as we continue to digest all this information and process it, things will be changing.

 How does the data and the discussions at ASCO 2022 this year change the way you're going to start the next patient on a CDK4/6 inhibitor?

 I think for me it's probably not going to be different. I agree with Dr Bardia about the premenopausal patients. That's been my practice pattern based on MONALEESA-7. I have had such great luck with palbociclib. I have patients that feel so well on it and have continued to do well for so long and I have many patients that travel to see us from a great distance. I practice in a rural state, so less monitoring is helpful as well.

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Taking into account all 3 available CDK4/6 inhibitors in HR+/HER2- breast cancer, experts consider how they’d select frontline therapy in this setting.

HR+/HER2- BC: Selecting a CDK4/6 Inhibitor in the Frontline Setting

 Now at this meeting, we saw updated data from the PALOMA-2 trial, the overall survival data, and then we also had seen some data published last year from the PARSIFAL trial looking at giving an aromatase inhibitor versus fulvestrant. We'd seen previous data suggesting there was a subset of patients who might do better with fulvestrant—really a unique group of patients who had no visceral disease, bone-only, had never received prior endocrine therapy. The PARSIFAL trial looked at a more real-world population. You had to be a year from your last AI [aromatase inhibitor] and you were randomized to take palbociclib with either an AI or fulvestrant. Initially, it was a superiority trial and then it changed to an equivalent trial. They didn't quite meet that confidence interval either, but the curves are right dead-on. That doesn't mean they seem to make any difference, which is intriguing. There's another study going on now, looking at getting letrozole first, with or without the CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor, and then you go to the fulvestrant with or without the CDK4/6 inhibitor, so that you find out whether you do better first or second. My bias on that is that you're going to do better if you get the better drug earlier because that's what we've always seen, but it's called the SONIA trial. With that in mind—and a lot of our trials had used palbociclib first-kid-on-the-block, we saw the long-awaited survival data from PALOMA-2 at ASCO [American Society of Clinical Oncology] 2022 with disappointing results. There was no difference in the intent-to-treat population and overall survival and long follow-up, but there were several unique characteristics of PALOMA-2 that are worth keeping in mind. One is it's the only trial in the first-line setting that included patients who had a disease-free interval from early- to late-stage disease of less than 12 months. That represented about one-third of the population. In that group of patients, when you look at a forest plot and divide the numbers up, they didn't clearly have a survival benefit, but the disease-free interval of greater than 12 months—the actual overall survival numbers are quite close to the other trial—that first-line ribociclib and AI trial in terms of the overall survival in the CDK group being well over 60 months. The first-line fulvestrant trial has the highest overall survival, but this is close to the AI trial. It's interesting that when you look at the population that are similar in the other trial, you still see this benefit. Of course, that wasn't the original plan of the study, so it makes it a little bit complicated. They also lost a lot of data, which is unfortunate and impossible to recoup. A lot of patients withdrew consent for reasons that are unclear, and so they just didn't have survival data on those patients, unfortunately. I'm interested in your guys' take on that. Let’s start with the Aditya; just your thoughts on the survival data from PALOMA-2.

 Absolutely. PALOMA-2 was the first large phase 3 trial evaluating CDK4/6 inhibitor-AI versus AI-placebo as first-line therapy. I think this was the trial—PALOMA-1—that opened the field of CDK4/6 inhibitors. Since then, we've had several studies. Now, in terms of why the results of PALOMA-2 were negative while we are seeing positive results from MONALEESA-2, MONALEESA-3, MONALEESA-7, as well as we've seen positive results with MONARCH-2, I think this could be differences in study populations [or other causes]. As you were saying, the disease-free interval was different. If you look at that subset, the results looked similar. The second possibility is what happened after the patients had disease progression on first-line therapy. That was not controlled, so there could be some imbalances in the placebo versus the palbociclib arm. The third possibility is that there are some differences in the drug; it's just impossible to know without head-to-head trial comparison.

 My feeling is that if we look at the entire PALOMA series, we see the dramatic efficacy of this drug; 10% of patients continue on palbociclib at 7.5 years. I certainly have a couple of patients in my own clinic that started the drug, really, in February of 2015 and remain on the drug today. Clearly, it's an effective agent. Of course, someone must be first; there's some difference in the populations, as you said. There appeared to be a little bit of an imbalance in the missing data, like a higher proportion of missing data in the placebo arm compared with the [INAUDIBLE] arm. If you look, I believe, Dr Richard S. Finn from the University of California Los Angeles, showed a forest plot of the subgroups where the missing data was balanced, and it favored an overall survival trend for palbociclib. There's a lot of nuances to this. Later we'll be discussing some real-world data with palbociclib that's encouraging as well.

Panelists share insight on clinical trial data behind use of palbociclib in the frontline setting of HR+/HER2- breast cancer.

CKD4/6 Inhibition in HR+/HER2- BC: Trial Data With Palbociclib

 Then we use CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors. Of course, there are 3 of them available, and we have seen a lot of recent data about the use of CDK4/6 inhibitors both in the first- and second-line setting. One of the updates that we've heard about is MONARCH 3 using abemaciclib in the second-line setting with Fulvestrant. Of course, other second-line studies as well. Then at this meeting, we presented data from a matched adjusted indirect comparison, looking at quality of life between the MONARCH 3 and MONALEESA-2 data in the first-line setting. Mark, what's your take and summary on this data and where we are now up until where we came to this meeting?

 I thought this was an interesting paper because biostatisticians have always taught us not to do cross-trial comparisons, and yet they come up with this novel technique of matched adjusted indirect comparisons, MAICs. They can do just that using quality-of-life data. In this case, they use the EORTC QLQ-C30 [European Organization for Research and Treatment of Cancer quality of life] metric as well as the BR23 [EORTC-breast-cancer specific quality of life] questionnaires. Using this statistical method, they were able to compare the difference in adverse event/patient-reported outcomes with these metrics between the 2 trials that you mentioned. They could compare abemaciclib plus an AI [aromatase inhibitor] with ribociclib plus an AI and really get some interesting findings. Perhaps it's not surprising to any of you who use these agents and have experience with them that what they found comes as no surprise. The overall results tend to favor ribociclib, on balance. There was less anorexia, certainly less diarrhea with ribociclib, a little less fatigue, and improved arm symptoms compared with abemaciclib. Having used these drugs, none of this comes as any surprise. It's gratifying to see that the patient-reported outcomes match the investigator-reported data that's already been published and approved by the FDA [United States Food and Drug Administration] for both drugs. The overall metric they used was this time to sustained deterioration of all of these various symptoms on these questionnaires. I thought it met what I expected, having used these drugs personally, and I treated patients with them and heard my patients tell me about their experience. That's gratifying, and I thought the methods were very interesting and novel to allow this kind of cross-trial comparison where a head-to-head trial is simply not available.

 MONARCH trials are kind of funny because they used the reverse numbers with MONARCH 2 for the second-line setting in MONARCH 3 for the first, whereas everybody else made their numbers go up through the progression. MONARCH 3, we're still waiting to hear. Survival data has shown a significant progression-free survival improvement, as have all 3 drugs. We've also heard some interesting data about ribociclib, and then recent updated data at ESMO [European Society for Medical Oncology] Breast Cancer 2022 meeting in May. The trials include pre- and perimenopausal women in the first-line setting, and then, of course, the second-line setting. They did a unique trial including the first and second-line group with fulvestrant, and then they have their first line trial, MONALEESA-2, in the postmenopausal women. We heard some updates that were quite interesting; some survival data at ESMO BC [Breast Cancer], and then we heard some data about dose adjustments in the first-line setting.

 Absolutely. I am happy to review the data from MONALEESA-3. Coming back to the numbers, it's more like MONALEESA-2.5, because it was a hybrid of first-line and second-line. The results from MONALEESA-3 overall demonstrated that there was an improvement in overall survival in patients who received ribociclib plus fulvestrant as compared with fulvestrant-placebo. At ESMO Breast, we saw the results of first-line. In the first-line setting, patients who got fulvestrant plus ribociclib had an overall survival of 67.6 months. That's more than 5 years—an overall survival we've never seen before—as compared with the control group, which was about 51 months. This corresponded to a hazard ratio of 0.67. Clear overall survival advantage seen with ribociclib plus fulvestrant in the first-line setting. Now, a question often comes up in clinic is we started 600 mg of ribociclib but if a patient has adverse events, should we dose reduce? If we dose reduce, would that compromise the efficacy? At ASCO [American Society of Clinical Oncology] 2022, we saw the results in terms of dose reductions and impact on survival. The bottom line was there was no impact. Even in patients who had a dose reduction, the outcomes are pretty much similar. This provides additional confidence that, for a patient who needs dose reduction, we should feel comfortable reducing the dose to 400 mg, and if needed, 200 mg as well.

 It's interesting with ribociclib. Of course, you have the packaging dosing. Although you're paying for all the pills, you can take less without getting a new drug dose; it's fairly easy. In fact, in the poster discussion at ASCO 2022, someone asked, ‘Why don't you just start at a lower dose? Why start at a higher dose, after all?’ They had something like 66% of the people who dose reduced. I thought, well, then why not just start at the full dose because you can dose-reduce so easily? I don't know what your thought on that is.

 I fully agree, because that's how the trial was done, and we have the results related to that. Unless we have randomized data, 400 mg versus 600 mg, I would not start with 400. I would start with 600 mg, but if a patient has an adverse event, particularly neutropenia, I feel comfortable reducing to 400 mg.

 There may be some pharmacogenomics that play a role there. Komal, you have a thought.

 I agree completely. There was a mention at the same discussion that perhaps there is a trial ongoing looking at the 400 mg versus 600 mg comparison. We know the adjuvant NATALEE trial is evaluating the 400-mg dose, but I agree with you. Not all patients get all adverse events, and it's something that we cannot predict for an individual patient. I see no harm in starting at the full dose because that patient might not need a dose reduction. We have the data, and we can easily dose reduce if we needed to.

 These are really important points as we think about using these agents in our patients with metastatic breast cancer.

Focusing on the frontline setting of HR+/HER2- breast cancer, panelists discuss clinical trial data with abemaciclib and ribociclib, respectively.

CKD4/6 Inhibition in HR+/HER2- BC: Trial Data With Abemaciclib and Ribociclib

®: “Therapy Options in Hormone Receptor-Positive HER2 Negative Breast Cancer.” I'm Dr Hope Rugo, and I'm a breast medical oncologist at the University of California San Francisco's Comprehensive Cancer Center. I'm joined today by a panel of my colleagues who treat breast cancer. I'd like to welcome Dr Aditya Bardia, who's at Massachusetts General Hospital in Boston, Massachusetts; Dr Komal Jhaveri, who is at Memorial Sloan Kettering Cancer Center in New York City; Dr Mark Pegram from the Stanford Cancer Center at Stanford University in Palo Alto, California; and Dr Anne O'Dea from the University of Kansas Medical Center in Kansas City, Kansas. I think we have a nice geographic representation of experts in breast oncology in the United States. We're going to have an exciting discussion today talking about hormone and receptor-positive, HER2-negative breast cancer. Let's get started on our first topic. Komal will talk a little bit about outcomes in patients with hormone receptor-positive breast cancer and how this has changed over the last couple of decades.

 Thank you, Hope. We have come a very long way in the treatment of hormone receptor-positive disease. Certainly, when we even think about single-agent endocrine therapy, if we look at the current phase 3 trials in the first-line metastatic setting, we're seeing a difference in the overall survival. The gain that we've got in overall survival—it's nearly over 4 years even with single-agent endocrine therapy—but what has really been a big paradigm shift and a big revolutionary treatment paradigm now is the addition of CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors with an endocrine therapy. In more recent trials from CDK4/6, which have read out the overall survival gains, we're seeing that over 5 years. For example, in the MONALEESA-3 trial, which had 2 cohorts, including both first-line and second-line, the first line being the endocrine-sensitive patient population overall survival with the CDK4/6, and endocrine therapy was about 67 months. We're seeing progression-free survival gains with other targeted therapies—maybe alpelisib, which is the alpha-specific PI3K inhibitor in patients who harbor 

 mutations; maybe with everolimus if we can use that. At this 2022 ASCO [American Society of Clinical Oncology] annual meeting, we heard the results for the DESTINY-Breast04 trial, antibody-drug conjugate, which has activity beyond HER2-positive disease and what we now define as HER2-low breast cancers, the majority of which are hormone receptor-positive disease. They have also had a progression via overall survival benefit—a lot of great gains.

 It's an exciting time to hear about the advances we're making in this most common subset of breast cancer, the most common cancer worldwide in women. Maybe we've done a little bit better job at identifying our receptors, so that we can identify more about which patients are hormone receptor-positive. We heard today about additional testing looking at genomic signatures that might help further. Now we’ve heard about the CDK4/6 inhibitors from Komal. Of course, we're all using those, but, Anne, in your practice, how do you select and order therapy for a patient who has hormone receptor-positive, HER2-negative disease? We heard about how many options they have. How do you vary that based on menopausal status?

 For me the most important thing I'm looking at is disease-free interval for these women. We're also looking at those patients that progress while receiving their adjuvant endocrine therapy. Of course, those patients have a much different biology than patients that have a 6-year or 7-year disease-free interval. Then we're selecting a first-line therapeutic option for them. I think that's the primary thing, and then we're looking at the patient's performance status. We're looking at their comorbid medical conditions, what their goals are, and certainly, volume of disease is a consideration as well. If you have a patient that has perhaps a single, solitary bone metastasis, that is very different from a patient that has visceral metastases. Those are sort of the things that I think through when I'm having this type of a discussion with a patient.

 When you do think through those, do you always give a CDK4/6 inhibitor first-line? And then, how do you choose an AI [aromatase inhibitor]or fulvestrant as the partner?

 The overwhelming totality of data that was described that really supports use of first-line CDK4/6. It's really a very rare patient in whom I'm not using that in the first line; perhaps an elderly patient in a skilled nursing facility where it's very cumbersome for her to have laboratory monitoring, or something like. However, outside of a situation like that, I’m really using it in all my patients. Typically, in terms of deciding aromatase inhibitor or fulvestrant, I'm really looking at that disease-free interval so those patients that are progressing on their adjuvant-AI, we're certainly going with fulvestrant for patients who have that very long disease-free interval. We're usually using an aromatase inhibitor.

Expert perspectives on the evolving treatment paradigm for patients receiving frontline therapy for HR+/HER2- breast cancer.

Frontline Treatment Strategies for HR+/HER2- Breast Cancer

Komal Jhaveri, MD, FACP, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses sequencing treatments for patients with metastatic HER2-positive breast cancer.

When a patient begins frontline treatment, Jhaveri recommends the use of trastuzumab (Herceptin), pertuzumab (Perjeta), and chemotherapy. Moreover, ado-trastuzumab emtansine (Kadcyla) can be used in the second-line setting, based on the results of the EMILIA trial, which showed a benefit over lapatinib (Tykerb) plus capecitabine, Jhaveria says. 

There are 3 drugs currently available that have been approved by the FDA to treat patients in the third-line setting, including fam-trastuzumab deruxtecan-nxki (Enhertu), tucatinib (Tukysa) with capecitabine and trastuzumab, and neratinib (Nerlynx) plus capecitabine.

The treatment landscape has become crowded in light of these approvals, although Jhaveri emphasizes that this is a good problem to have. Due to this, it's important for physicians to consider characteristics of each individual patients to make optimal treatment decisions; toxicity profiles should also be taken into consideration, Jhaveri concludes.

Dr. Jhaveri on Sequencing Treatments in Metastatic HER2+ Breast Cancer

Komal Jhaveri, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, discusses the potential for immunotherapy in the treatment of patients with triple-negative breast cancer (TNBC) based on results from the IMpassion130 trial.

Unlike in other solid tumors such as melanoma, lung cancer, and renal cell carcinoma, TNBC has not seen as much positive data with immunotherapy, explains Jhaveri. However, exciting data presented at the 2018 ESMO Congress suggest that immunotherapy may play a critical role in the treatment of certain patients.

In the phase III randomized IMpassion130 trial, patients with treatment-naïve metastatic TNBC were randomized to receive either standard of care nab-paclitaxel (Abraxane) or atezolizumab (Tecentriq) in combination with nab-paclitaxel. The primary endpoint of the study was progression-free survival in the intent-to-treat (ITT) and the PD-L1—positive subgroups. Overall survival (OS) was a planned analysis with hierarchal testing for OS in both subgroups, says Jhaveri.

Results indicated a hazard ratio of 0.8, reflecting a 20% reduction in the risk of progression or death with the combination. Patients also experienced a 25-month median OS. Although patients in the PD-L1—positive subgroup experienced a clinical meaningful benefit in OS, investigators could not claim statistical significance due to the hierarchal testing of that group. That being said, a 25-month median OS in the first-line setting is unprecedented for this difficult-to-treat, aggressive subtype of breast cancer, she stressed.

Dr. Jhaveri Discusses the Potential of Immunotherapy in TNBC

	Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is an aggressive type of breast cancer with an inferior prognosis. Trastuzumab, a human monoclonal anti-HER2 antibody, was the first targeted agent for this breast cancer subtype. However, de novo and acquired trastuzumab resistance does occur, resulting in the need for other HER2-directed therapies. One approach has been the use of antibody drug conjugates (ADCs), which are cytotoxic drugs connected by chemical linkers to monoclonal antibodies that are specific for a tumor-associated antigen. This results in the preferential delivery of a drug to cancer cells while minimizing exposure to normal tissues. Ado-trastuzumab emtansine (T-DM1) is a novel ADC that consists of trastuzumab bound via a thioether linker to the cytotoxic agent, DM1, a highly potent antimitotic drug. Currently, T-DM1 is approved for patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane, progressed on their most recent treatment in the locally advanced or metastatic setting, or are within 6 months of adjuvant trastuzumab for early-stage disease. It is currently being investigated in the neoadjuvant and adjuvant settings. This article provides a concise review of the clinical development, use, safety, and pharmacokinetics of T-DM1, as well as future research directions of T-DM1 in the field of HER2-directed therapies.

Human epidermal growth factor receptor 2 (HER2)-positive disease accounts for 20% to 25% of breast cancers, as represented by amplification of the HER2 gene and/or HER2 protein overexpression. This breast cancer subtype has an aggressive clinical course and inferior outcome.

 Trastuzumab is a humanized monoclonal anti-HER2 antibody that binds to the extracellular domain of HER2 and has significantly improved outcomes for patients with both early-stage and metastatic HER2-positive disease.

 Despite these significant advances, both de novo and acquired trastuzumab resistance occurs. Approximately 15% of women develop metastatic breast cancer (MBC) despite trastuzumab-based adjuvant therapy.

 This has led to the development of other HER2-directed therapies. Lapatinib, a potent small molecule dual tyrosine kinase inhibitor of HER2 and epidermal growth factor receptor (EGFR), was approved by the FDA in 2007 either in combination with capecitabine or trastuzumab for patients with HER2-positive MBC following disease progression on trastuzumab.

 In 2012, pertuzumab, a monoclonal antibody that binds subdomain II of the HER2 extracellular domain and blocks HER2 dimerization and signaling, was approved in combination with trastuzumab and docetaxel in the first-line setting for HER2-positive MBC (

 Most recently, the FDA provided accelerated drug approval for dual HER2 blockade in the neoadjuvant setting using pertuzumab and trastuzumab in combination with chemotherapy.

		Figure. Mechanisms of Action of HER2-Directed Agents for Breast Cancer

		Human epidermal growth factor (EGF) receptors HER1, HER2, HER3, and HER4 are receptor tyrosine kinases that are involved in the signal transduction pathways that lead to cell survival and differentiation. Each of these receptors consists of three components: an extracellular binding domain, a transmembrane lipophilic segment, and a functional intracellular tyrosine kinase domain (with the exception of HER3). When a ligand of an EGF receptor binds to the extracellular binding domain, the tyrosine kinase domains are activated by both homodimerization and heterodimerization. The HER2 receptor is an orphan receptor and does not require the binding of a ligand for activation. HER2 is also the preferential dimerization partner of other members of the EGF family, and dimerization can be induced by receptor overexpression and mutation. Homo- and heterodimerization of the HER family leads to phosphorylation of the tyrosine kinase domain and activation of downstream signaling pathway, including the PI3K-AKT-mTOR and the RAF-MEK-MAPK pathways. Downstream effects include survival, proliferation, and increased vascular endothelial growth factor (VEGF). Anti-HER2 strategies include: (A) Trastuzumab is a monoclonal antibody that binds to the extracellular domain IV of the HER2 receptor. (B) Lapatinib is a dual tyrosine kinase inhibitor against HER2 and EGFR (HER1). (C) Pertuzumab is a monoclonal antibody that binds to extracellular domain II of HER2 and inhibits the dimerization of HER2 with other HER family receptors, especially HER3. The HER2-HER3 heterodimer is a strong activator of signaling through the PI3K-AKT-mTOR pathway. (D) T-DM1 is a novel antibody-drug conjugate of trastuzumab and DM1, a derivative of maytansine and a highly potent antimitotic drug. The drug binds to the extracellular domain of HER2, allowing for the selective delivery of DM-1 to HER2-overexpressing cells.

One novel approach in the development of new HER2-targeted therapies has been the development of HER2-directed antibody-drug conjugates (ADCs).

 ADCs are cytotoxic drugs that are connected by chemical linkers to monoclonal antibodies specific for a tumor-associated antigen. ADCs are designed to preferentially deliver a cytotoxic drug to cancer cells while minimizing exposure to normal tissues, thus improving the therapeutic index.

 The use of ADCs in oncology first began with the development of gemtuzumab ozogamicin, an anti-CD33 antibody linked to the cytotoxic antibiotic, calicheamicin, for CD33-positive acute myelogenous leukemia (AML).

 Subsequently, brentuximab vedotin, a CD30-specific ADC, was developed and is approved for use in Hodgkin lymphoma and anaplastic large cell lymphoma.

Ado-trastuzumab emtansine (T-DM1) is an ADC that was developed to treat HER2-positive MBC. T-DM1 consists of trastuzumab covalently bound via a thioether linker, (N-maleimidomethyl) cyclohexane-1-carboxylate (MCC), to the cytotoxic agent, DM1, a derivative of maytansine. DM1 is a highly potent antimitotic drug that binds to microtubules in a similar way to that of vinca alkaloids.

 Vinca alkaloids have demonstrated synergy with trastuzumab.

 T-DM1 binds to the extracellular domain of HER2, and the complex is then internalized into the cell. The antibody is degraded by proteases and the active metabolite, lysine-Nε—MCC-DM1, is released into the cytoplasm (

 This metabolite is a charged molecule and is relatively membrane impermeable. This reduces the chance that DM1 can enter a neighboring cell and limits the possibility of nonspecific toxicity.19 T-DM1 also retains the effector functions of trastuzumab: inhibition of HER2-mediated signal transfusion and activation of antibody-dependent cellular cytotoxicity.

T-DM1 was initially evaluated as a single agent in a phase I dose escalation study in 24 patients with trastuzumab-refractory HER2-positive MBC (TDM3569g).

 Weekly and every-3-week dosing schedules were tested. The maximum tolerated dose (MTD) for the 3-week regimen was determined to be 3.6 mg/ kg. T-DM1 was well tolerated and the most common adverse events (AEs) were thrombocytopenia, elevated transaminases, fatigue, anemia, and nausea.

 In the 3-week regimen, the objective response rate (ORR) was 44% in patients treated at the MTD and was comparable to patients treated on the weekly regimen (40%). Subsequently, the every-3-week schedule has been utilized in the majority of subsequent studies, largely due to the convenience for patients.

T-DM1 monotherapy was then studied in two single arm phase II trials (TDM4258g and TDM4374g). TDM4258g evaluated T-DM1 at 3.6 mg/kg every 3 weeks for patients with HER2-positive MBC who had progressed on at least one line of HER2-directed therapy. A total of 112 patients with a median of 8 (range 2-19) prior anticancer agents in all settings were enrolled. The primary endpoint, ORR, was 25.9% (95% confidence interval [CI], 18.4% to 34.4%). Median progression free survival (PFS) was 4.6 months (95% CI, 3.9 to 8.6 months), and median duration of response (DOR) was not reached. In a post hoc exploratory analysis, the ORR in patients who had received prior lapatinib and trastuzumab was not significantly different than the overall ORR, suggesting that T-DM1 has activity after progression on prior HER2-directed therapies.

TDM4374g enrolled 110 patients who had previously received trastuzumab, lapatinib, capecitabine, a taxane, and an anthracycline for HER2-positive breast cancer and had progressed on at least two HER2-directed agents in the metastatic or locally advanced setting.

 This was in contrast to TDM4258g, which only required that patients had received and progressed on at least one prior HER2-directed therapy and had received at least one chemotherapy regimen in the metastatic setting.

 In TDM4374g, all patients were heavily pretreated with a median of 7 (range 3-17) anticancer agents in the metastatic setting. The ORR was 34.5% (95% CI, 26.1% to 43.9%) with a median PFS of 6.9 months (95% CI, 4.2 to 8.4 months) and a clinical benefit rate (CBR) of 48.2% (95% CI, 38.8% to 57.9%). This confirmed the single agent activity of T-DM1 in the metastatic setting.

T-DM1 was subsequently evaluated in several large, randomized studies. The pivotal EMILIA study was a phase III, international trial in patients with locally advanced or metastatic, centrally confirmed, HER2-positive breast cancer. Patients had previously received a taxane and trastuzumab and had progressed on their most recent treatment in the locally advanced or metastatic setting or within 6 months of completion of adjuvant trastuzumab for early-stage disease. A total of 991 patients were randomized 1:1 to T-DM1 (3.6 mg/kg every 3 weeks) or to lapatinib (1250 mg daily) and capecitabine (2000 mg/m

 days 1-14). The primary endpoints were PFS and overall survival (OS). Treatment with T-DM1 significantly improved median PFS compared with lapatinib plus capecitabine (9.6 vs 6.4 months; hazard ratio [HR] 0.65; 95% CI, 0.55 to 0.77; 

<.001). OS also favored T-DM1 (30.9 vs 25.1 months, HR 0.68; 95% CI, 0.55 to 0.85; 

<.001). ORR and DOR were superior in patients treated with T-DM1. Serious AEs were reported for 18% of patients in the lapatinib-capecitabine group versus 15.5% in the T-DM1 group. There were more grade ≥3 AEs in the lapatinib-capecitabine group versus in the T-DM1 group (57% vs 40.8%). The most commonly reported grade 3 or 4 AEs were diarrhea and palmar-plantar erythrodysesthesia in the lapatinib-capecitabine group and thrombocytopenia and elevated transaminases in the T-DM1 group.

 The results of the EMILIA study led to the FDA approval of T-DM1 in February 2013 for patients with HER2-positive MBC.

The TH3RESA trial is another phase III trial, which evaluated the efficacy and safety of T-DM1 in comparison with treatment of physician’s choice (TPC) in 602 patients with MBC or unresectable locally advanced/recurrent HER2-positive breast cancer who had received at least two prior HER2-directed therapies, including trastuzumab and lapatinib (NCT01419197).

 The first results from this trial, presented at the 2013 European Cancer Congress, showed that median PFS increased by nearly 3 months (6.2 vs 3.3 months; HR 0.528; 95% CI, 0.422-0.661; 

<.0001) in patients receiving T-DM1 compared with patients receiving TPC.

T-DM1 has also been evaluated in the first-line metastatic setting. The TDM4450g study was a phase II trial in which 137 patients with previously untreated HER2-positive metastatic or locally advanced breast cancer were randomized to T-DM1 or trastuzumab plus docetaxel. The primary endpoints were PFS and safety. PFS was significantly longer in patients receiving T-DM1 compared with those receiving trastuzumab plus docetaxel (14.2 months vs 9.2 months, HR 0.59; 95% CI, 0.36 to 0.97; 

=.035). Patients receiving T-DM1 had fewer grade ≥3 AEs compared with the trastuzumab plus docetaxel group (46.4% vs 90%). Of note, only 27.1% of the patients in the trastuzumab plus docetaxel group and 17.9% of the patients in the T-DM1 group had received trastuzumab in the neoadjuvant or adjuvant setting.

Encouraged by the synergistic activity noted in xenograft models, the combination of T-DM1 plus pertuzumab was then evaluated in a phase Ib/II clinical trial (TDM4373g). The safety and efficacy of T-DM1 plus pertuzumab in 67 patients with HER2-positive locally advanced or MBC was assessed. Patients received the combination either in the first-line or relapsed setting (defined as progression on prior HER2 therapy for MBC). All patients in the relapsed setting (n=46) had received prior trastuzumab and 75% had received prior lapatinib; of these 46 patients, 16 had confirmed responses. Interim results showed ORRs of 34.8% and 57.1% in the relapsed and first-line settings, respectively. The combination was deemed to be safe and tolerable.

Notably, the combination regimen did result in a 24% incidence of peripheral sensory neuropathy, and one patient was discontinued from the trial due to a decrease in left ventricular ejection fraction. However, the peripheral neuropathy was mild and it is not known if it was noted specifically in the patients treated with T-DM1 in the first-line setting versus those treated in the relapsed setting. In the 4374g phase II trial of single agent T-DM1, there was 18% incidence of peripheral neuropathy. However, these patients were heavily pretreated. The incidence of neuropathy will perhaps be further elucidated in the MARIANNE study.

The MARIANNE study is a randomized, 3-arm, multicenter, phase III study that is evaluating the efficacy and safety of T-DM1 with pertuzumab in patients with HER2-positive progressive or recurrent locally advanced or previously untreated MBC (NCT01120184). Patients were randomized to one of the three cohorts: T-DM1 with pertuzumab, T-DM1 with pertuzumab-placebo (blinded for pertuzumab), or trastuzumab combined with a taxane. This trial has completed enrollment and results are eagerly awaited later in 2014.

An additional phase 1b study of T-DM1 and paclitaxel with or without pertuzumab showed that the combination was feasible, and updated results regarding dosing schedules and safety are awaited.

					T-DM1 + capecitabine in HER2+ MBC and HER2+ locally advanced or metastatic gastric cancer (followed by phase II component)

					T-DM1 in HER2+ MBC and normal or reduced hepatic function

					Neoadjuvant T-DM1 with or without standard endocrine therapy vs trastuzumab with standard endocrine therapy for 12 weeks in patients with operable HER2+/HR+ breast cancer

					Pertuzumab + trastuzumab with or without chemotherapy both followed by T-DM1 in case of progression in patients with HER2+ MBC

					Pertuzumab + trastuzumab vs pertuzumab + trastuzumab + metronomic chemotherapy in the elderly HER2+ MBC population who may continue on T-DM1 alone following disease progression

					T-DM1 + pertuzumab + standard chemotherapy in women with HER2+ locally advanced breast cancer

					Assessing cardiac safety of trastuzumab vs pertuzumab vs T-DM1 in adjuvant or metastatic setting in patients with LVEF between 40% and 50%

					Cardiac events or asymptomatic worsening of cardiac function

					T-DM1 vs paclitaxel + trastuzumab for stage I HER2+ breast cancer

					T-DM1 in HER2+ locally advanced or MBC patients who have received prior anti-HER2 and chemotherapy-based treatment

					Adjuvant T-DM1 vs trastuzumab in HER2+ breast cancer with residual tumor in breast or axillary lymph nodes following neoadjuvant therapy

		DFS, disease-free survival; HR, hormone receptors; LVEF, left ventricular ejection fraction; MTD, maximum tolerated dose; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; pCR, pathologic complete response; PFS, progression free survival.

In addition to evaluating T-DM1 in the metastatic setting, T-DM1 is also being studied in the neoadjuvant and adjuvant settings. The I-SPY 2 study is evaluating T-DM1 and pertuzumab in the neoadjuvant setting.

 The KATHERINE trial is an adaptive trial design wherein patients with HER2-positive primary breast cancer with residual disease in the breast or axillary lymph nodes following neoadjuvant therapy are being randomized to T-DM1 versus trastuzumab.

Overall, T-DM1 is well tolerated with a relatively low rate of clinically significant AEs (

 A pooled analysis of toxicity data from 882 patients treated in seven clinical trials with single agent T-DM1 at 3.6 mg/kg every 3 weeks found that the most common AEs of any grade were fatigue (45.4%), nausea (42.3%), headache (28.7%), thrombocytopenia (28.7%), and constipation (25.5%).

 Grade ≥3 AEs occurring in ≥2% of patients were thrombocytopenia, increased transaminases, fatigue, hypokalemia, and anemia.

 It is important to note that up to two dose modifications (3 mg/kg and 2.4 mg/kg) are allowed with T-DM1 treatment. After two dose reductions, any further requirements for dose reductions should result in discontinuation of T-DM1.

The most common AEs of special interest are thrombocytopenia, hepatic toxicity, and cardiotoxicity. Thrombocytopenia is typically grade 1 or 2 and rapidly reversible, and has generally not been associated with clinically significant bleeding.

Platelet counts can start to decline as soon as 24 hours after dosing, nadir around day 8, and recover by day 15.20 In approximately 20% of patients, platelet counts do not completely recover to baseline after repeated dosing.

 Hepatic toxicity typically presents as transient and asymptomatic transaminase elevations.

 Serious hepatobiliary disorders, including two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported; as such, the prescribing information for T-DM1 includes a boxed warning for hepatotoxicity.

 Rare cases of nodular regenerative hyperplasia (NRH) have also been described (3 cases out of 882 treated patients).

 NRH is a rare liver disorder characterized by a widespread transformation of the hepatic parenchyma into small regenerative nodules and can result in noncirrhotic portal hypertension.

NRH can only be diagnosed by a liver biopsy, which should be considered in any patient receiving T-DM1 who develops signs and/or symptoms of portal hypertension.

		Table 2. Most Common Adverse Events (>20% incidence in at least one single agent trial) Reported in Clinical Trials of T-DM1

Patients were treated with 0.3-4.8 mg/kg every 3 weeks. This trial also included a separate cohort of a weekly regimen, which is not reported here.

 TDM4450g compared T-DM1 (n=67) versus trastuzumab plus docetaxel (HT) (n=70). Only the T-DM1 arm is reported here. 67 patients were enrolled in the T-DM1 arm but two patients in the HT arm mistakenly received a dose of T-DM1 and were included in the T-DM1 safety analyses.

 TDM4373g compared T-DM1 with pertuzumab. The AEs reported here are of the combination regimen.

EMILIA compared T-DM1 (n=490) versus lapatinib plus capecitabine (n=488). Only the T-DM1 arm is reported here. NR, not reported.

 One patient required a dose reduction for neuropathy but exact grade was not recorded.

T-DM1 should be discontinued if NRH develops.

 For both thrombocytopenia and hepatic toxicity, patients can typically continue on T-DM1 with dose modifications.

 Cardiotoxicity has been carefully studied in patients receiving T-DM1 because of the cardiac toxicity of trastuzumab, and a boxed warning for left ventricular dysfunction exists for T-DM1.

 In the pooled safety analysis, there were 13 cardiac AEs (1.5%) and all but 2 of the events were grade 1 or 2.

 Rare AEs of special interest include interstitial lung disease and pneumonitis, infusion-related reactions and hypersensitivity reactions, and peripheral neuropathy. T-DM1 is pregnancy category D and carries a boxed warning for embryo-fetal toxicity

The half-life of T-DM1 is approximately 3.5-4 days and there is no significant accumulation of T-DM1 when given every 3 weeks.

 The level of free DM1 in the plasma is very low (average of approximately 5 ng/mL) throughout the treatment cycle, which is likely related to the favorable toxicity profile of T-DM1. Pretreatment residual levels of trastuzumab have not been shown to influence the pharmacokinetics or clinical efficacy of T-DM1.

As the therapeutic armamentarium of HER2-directed therapies has expanded in the past decade, it has become imperative to identify patients who are most likely to respond to a specific agent or be resistant to it. The mechanisms that contribute to the frequent development of resistance to trastuzumab are only beginning to be understood.

 One mechanism of resistance to trastuzumab is the development of mutations in the phosphoinositide 3-kinase/protein kinase B /mammalian target of rapamycin (PI3K/AKT/mTOR) pathway.

 Preclinical studies have shown potent T-DM1 activity in breast cancer cells with PIK3CA mutations.

 T-DM1 inhibits the growth of lapatinib-resistant breast cancer cells with an activated PI3K pathway.

 A recent analysis performed on archival tumor tissue from the EMILIA study showed that patients with PIK3CA mutations who were assigned to the lapatinib-capecitabine arm had a shorter PFS and OS compared with patients with wild-type cancers in the lapatinib-capecitabine arm. However, patients treated with T-DM1 had a similar PFS and OS, regardless of the presence of a PIK3CA mutation.

 These results need further validation but highlight the need for identification of biomarkers of response to help identify which patients are specifically likely to benefit from T-DM1.

 Future steps also include identifying mechanisms of resistance to T-DM1. Currently, potential mechanisms include downregulating HER2 expression and upregulating expression of drug efflux pumps, such as multidrug resistance 1 (MDR1), and thus, reduction of intracellular exposure to DM1.

Overall, T-DM1, a novel ADC, is an attractive HER2-directed therapy given its favorable toxicity profile and clinical efficacy in the locally advanced and metastatic settings. Ongoing and future trials, as demonstrated in 

, will help elucidate the efficacy in the neoadjuvant and early disease settings. Research efforts are also focused on best selecting patients who are most likely to benefit from this therapy.

Given that there are now four approved agents in the field of HER2-directed therapy with various others under investigation, identifying biomarkers of response and/or resistance to these agents and determining the exact sequence of these promising therapies to best optimize the outcomes of patients is critical. Cost-effectiveness and toxicity profiles of these agents will come to play a significant role. Nevertheless, the future is bright and exciting, and evolving data bear further hope for the improvement of outcomes in this patient population.

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