I want Sara Tolaney to have the last word on this, with regard to use of platinum and maybe even the node negative patient, the T1c N0. What do you do, Sara, if they don’t have a pathologic complete response [pCR]? How do we define pathologic complete response and what do we do if we don’t have one?

: I think in terms of the platinum issue, I feel very similarly to others that I generally tend to use ACT [doxorubicin, cyclophosphamide, paclitaxel] for the larger tumors. I only use platinum if someone is not having a good response generally to the upfront AC [doxorubicin, cyclophosphamide]. Then sometimes I’ll tack on the platinum because I have been concerned about the toxicity. We saw in the CALGB 40603 trial that the people who got platinum, if they had to not complete all their taxane, actually did worse. I do worry about adding on toxicity when we don’t have data that are sufficiently powered for long-term outcomes.

In the T1c tumors, I think like others have expressed, if they’re usually under 1.5 cm, sometimes I’ll do TC [docetaxel, cyclophosphamide] times 4. Whereas, if they start getting over 1.5 cm, closer to 2 cm, then I start giving them ACT [doxorubicin, cyclophosphamide, paclitaxel] therapy. I tend to use size to help me judge how much treatment to give them. I think generally speaking, we do tend to approach most of our patients with larger tumors with preoperative therapy, with the reason being that we can tailor their therapy based on response to that preoperative treatment. That tailoring of treatment is really going to change their long-term outcomes.

What we’re looking for is are they achieving a pathologic complete response to their preoperative treatment, meaning is there no invasive residual disease found within the breast or lymph nodes at the time of surgery? We know that those patients who achieve pCR have better long-term outcomes, whereas we know that those patients who have residual disease do have a higher risk of recurrence. As Kevin had alluded to, we do have data to suggest that we can alter those long-term outcomes for those patients with residual disease based on data from CREATE-X.

We know that in patients with residual disease who are randomized to get capecitabine vs no capecitabine, we saw that giving the capecitabine had a statistically significant improvement in disease-free and overall survival. We saw that that control arm with no capecitabine actually doesn’t do very well with the 5-year disease-free survival that’s around 55%. Again, there was a significant improvement to their outcomes by giving them capecitabine. I do offer all my patients with residual disease the 6 months of adjuvant capecitabine.

Thank you. That’s a nicely put summary of that data. It highlights that if patients don’t get a pathologic complete response with triple negative breast cancer, their outcome is poor. It’s thankfully improved with the capecitabine, both disease-free and overall survival, as you strongly pointed out. Still, patients recur in spite of the capecitabine, and then patients still have a poor outcome if they don’t get a pCR. The pCR rates, correct me if I’m wrong, I would estimate that with an ACT [doxorubicin, cyclophosphamide, paclitaxel]-like regimen preoperatively, were in the 40%, 45% range. Then if you add the carboplatin, you’ll be in the 50%, 55% range, that’s probably pretty right, OK?

You get a little bit, 10% improvement, 13%, 16% in some of the studies specifically, but round numbers, it’s about 10 %. We’re pushing up around 55% with where we are, so that’s really good for those patients. But we have 45%, the number you said, who don’t get a pathologic complete response at 5 years; only 55% disease free is very concerning. We know what a huge issue this is in the practice. We’ve got an unmet need.

I think we’re all agreed that we would definitely have an unmet need. There is no question we have to do better in the curative setting.

Videos

Role of pCR in Early Stage TNBC Management

. I’m Joyce O’Shaughnessy from Baylor University Medical Center, Texas Oncology and US Oncology in Dallas, Texas. I’m really pleased to be joined here today for this virtual discussion with 4 of my colleagues, Dr Adam Brufsky from the University of Pittsburgh Medical Center; Dr Sara Hurvitz from the University of California, Los Angeles; Dr Kevin Kalinsky from Columbia University Medical Center in New York; and Dr Sara Tolaney from the Dana-Farber Cancer Institute in Boston.

Welcome, everybody. I’m so glad to be here with you today. Today we’re going to highlight a number of topics, mainly pertaining to triple negative breast cancer. First, we’re going to start by looking at some of the new data that came out from ESMO [the European Society for Medical Oncology Virtual Congress 2020] and putting that into the context of our day-to-day treatment of patients with earlier stage triple negative breast cancer. Then we’ll transition to the treatment of metastatic triple negative breast cancer, again focusing on the standard of care but also updating you on new data that came out from ESMO and putting that again in context. This ought to be a very interesting discussion because it’s always fun to look at the new data.

With that, let’s go ahead and get started. We’ll start with early stage triple negative breast cancer. Kevin, could you lead us off with a brief overview of some of the standards of care for early stage triple negative breast cancer?

: Thank you, Joyce. I think that increasingly for our patients with early stage triple negative breast cancer, we treat with neoadjuvant chemotherapy. I think that this is for a number of reasons, so that we could see how patients are responding to the treatments that we’re giving. But importantly, if patients have residual disease, then based upon the CREATE-X data, we follow that with oral capecitabine. For patients with triple negative breast cancer, commonly these are anthracycline/taxane-based regimens. We did see some data at ESMO, the GeparOcto study, in which patients had different sequencing of chemotherapies, and this really didn’t ultimately change therapy.

In this particular study, patients received anthracycline/taxane followed by Cytoxin as opposed to weekly doxorubicin and paclitaxel. But ultimately for patients with triple negative breast cancer, based upon the chemotherapy-alone ESMO data, this didn’t really change practice. One of the questions I think that keeps coming up for patients is what should be the utilization of a platinum? I think that this is something that we commonly argue about, whether we should be adding, for instance, carboplatin to the neoadjuvant setting, and whether there are any biomarkers that can help inform which patients should be receiving that treatment, given that it has additional toxicity, including hematologic toxicity.

Am I right that NCCN [the National Comprehensive Cancer Network] does not have preoperative carboplatin in its guidelines? Am I right about that? I know that historically, I want to make sure nothing had changed. It’s basically still ACT [doxorubicin, cyclophosphamide, paclitaxel], or for patients who can’t have an anthracycline, basically docetaxel, cyclophosphamide. But there are some platinum-based regimens, even docetaxel, carboplatin, from Priyanka Sharma, MD, and others. Kevin, when do you use platinum? Do you ever use platinum preoperatively?

: I think the jury is still out. A part of this is that there hasn’t been consistent findings in terms of improvement of things, including overall survival rate differences that we saw from the German study compared to the Alliance trial. Even though there are differences in how the studies were designed and whether they were powered to actually look at that end point, I think that this is something that we’re still trying to define in the operable setting. I will think about utilizing that if I have a young patient with a large tumor, perhaps somebody who has a germline 

I will also say that the data in the operable setting may not be as consistent as what we see in the metastatic setting. For instance, the TNT trial, the metastatic study for patients who have 

 mutations, where we saw that giving a platinum may be better than giving a taxane. Going back to the operable setting, I think the jury is still out. Identifying which patients really benefit from a platinum still is an ongoing question.

Thanks. For the most part, no, it sounds like, but the occasional high-risk younger or maybe germline 

patient. Let me get a couple of other viewpoints on that. Sara Hurvitz, how about you, do use platinum?

: I am compelled by Priyanka Sharma’s data. I try to avoid the use of anthracycline in a patient, for example, with node negative, triple negative breast cancer or 1 node positive. I want to use the neoadjuvant setting. I totally agree with Kevin in using the neoadjuvant setting to test the sensitivity of the tumor in vivoand see whether the treatment we’re deciding to use actually works. For the patients who have a robust response clinically and achieve a pathologic complete response with the taxane/platinum regimen, that’s a win-win because they’ve been spared the potential significant toxicities of an anthracycline.

However, on occasion we’ll have to change a patient to dose-dense chemotherapy with an anthracycline and/or give anthracycline on the back end if there is residual disease. It’s an area that is evolving. I think we have to follow the data and follow out the survival data, as Kevin mentioned.

Neat. We’ve got the East Coast and then the West Coast with the avant-garde getting us away again from anthracyclines as they did, correctly so we might add, in the HER2-positive setting. How about you, Adam, do you incorporate platinum sometimes into the preoperative setting?

 I personally don’t. There is a mixture in our practice, and I think that it reflects the whole uncertainty about the benefit of platinum and the toxicity of it. I think it is not a benign drug, especially if we give it weekly, or even every 3 weeks with weekly paclitaxel. You do get substantial thrombocytopenia, neuropathy, and neutropenia. That’s over and above the typical weekly paclitaxel we use, so it’s not a benign intervention. I agree with Sara that the data are quite mixed. If I’m going to give treatment to someone with node positive breast cancer, most of them will still get ACT.

I like the concept of going to TC [docetaxel/cyclophosphamide] and getting away from it, and eventually I will probably get there. I think node negative, I don’t usually do neoadjuvant therapy. They’ll all get TC times 4 anyway. Where I see the data is from the TNT trial, and I think a lot of what we see with the carboplatin may be explained either by 

-like disease that we just haven’t really uncovered yet. That’s where I tend to still use platinum. I agree with the chemotherapy sensitivity thing that Kevin said, that while I’ll try somebody out on AC [doxorubicin/cyclophosphamide] or something like that, and if they don’t really respond and they’re younger and could tolerate it, I’ll add the carboplatin to the Taxol, that’s how I usually do it, or the paclitaxel. I think we’re all saying the same thing, that we try to figure out what that patient selection is for carboplatin. We just don’t know who it is that’s really going to…

Now let me ask you, when you said you have a node negative patient who, let’s say, went to surgery first and she’s got node negative disease, T1C, you give 4 cycles of docetaxel and cyclophosphamide, or carboplatin?

 Docetaxel/cyclophosphamide, as we know, looking back from a year ago, we have great data on several thousand patients. You look at the TAILORx chemotherapy data that anybody with a recurrent score, and this is ER positive, but I suspect this could be the same. You have a 90% to 93% event-free survival at 5 years. I’d love to see data in node negative triple negative disease that anything beyond TC times 4 is a benefit. I know we use a lot of ACT, and we use a lot of TC times 6, whatever. But where are the data that are driving that? The head-to-head randomized data that can tell us that this extra chemotherapy is really doing clinically…I’m sure there’s going to be some benefit, but is it clinically significant?

Well, thank you. That’s why it’s not on NCCN guidelines, there’s just not a consensus that has come forward from the phase 3 trial data that we really need to have a uniform approach in clinical practice.

Standard of Care for Early-Stage TNBC

 This brings us into our question-and-answer period. The first question I have is actually for you, Dr Dang. Given your experience as the lead author on the weekly paclitaxel plus trastuzumab-pertuzumab paper and how it compared very favorably, both in terms of efficacy as well as a far better safety profile than a docetaxel-based dual-antibody regimen in first-line metastatic 

[human epidermal growth factor receptor 2]–positive disease, would you consider using your regimen with the subcutaneous formulation of the dual antibodies with weekly paclitaxel?

 I surely would. We’ve had so much experience with weekly paclitaxel and dual-antibody therapy and really saw virtually no rates of febrile neutropenia. That was a win for us, and it was well tolerated. Certainly, we would. And especially when they’re on the maintenance dual-antibody therapy, we certainly would support it. The answer is yes. We use weekly paclitaxel here much more than docetaxel, so it’s a natural chemotherapy for us.

 Joyce, you mentioned your experience on the PHranceSCa study and the study design of all the crossover from IV [intravenous] infusion of the dual antibodies over to subcutaneous administration. Was there any difference in reactions after the crossover to the subcutaneous administration, were there any other issues to be aware of, or did any of the studies measure antidrug antibodies, etc? Is there anything else you might be concerned about, theoretically even, by the switch from IV to subcutaneous?

 No. Thankfully, it was really good, but you’re bringing up an important point because it’s a very practical point in the clinic for our patients who are currently on IV, whether they’re finishing their chemotherapy and going on to maintenance and subcutaneous comes up as an issue. Or they may be in the metastatic setting and you just want to switch, you want to just save the time, save the chair time. That’s why it was so carefully looked at in PHranceSCa, and there just wasn’t anything. There wasn’t any additional toxicity. There are some injection site reactions that you don’t get when you’re using a port-a-cath for your IV dual antibodies. When you do the subcutaneous into the thigh for the 8 minutes, there are some injection site reactions, but they’re grade 1/2, mostly grade 1, at about 20% or so. That would be expected whenever you give it, whether you give it right from the beginning subcutaneous or whether you’re switching. There wasn’t anything. The pharmacokinetics are really no different between the IV and the subcutaneous, so no, there are just no concerns at all that were seen in PHranceSCa.

 Lastly, I’d just like to find out from both of you, what are you hearing from colleagues about the pricing of this subcutaneous dual-antibody formulation compared with IV? Now we’re in the biosimilar era of trastuzumab, for instance. Do you think this will be cheaper than a biosimilar trastuzumab plus IV originator pertuzumab, for example? What are you hearing from colleagues in industry, or just a gestalt?

 I’ll start out, Mark. I was curious myself. I went to my lead pharmacist to find out the cost is of subcutaneous trastuzumab-pertuzumab vs biosimilar trastuzumab and IV pertuzumab. The cost is very similar. If 1 is cheaper than the other, it’s by just a few dollars. It’s really very similar. I don’t like to discuss cost, but it was nice to see that the subcutaneous combination was not more expensive, and it boils down to saving time for patients and for the chemotherapy suites, that we can take care of more patients. It certainly makes sense to consider subcutaneous trastuzumab-pertuzumab over IV.

 There’s also the cost of the IV solution sets, all the IV tubing, and the piggyback solutions. Once you factor that in, it may very well be an advantage for the subcutaneous.

Like you, I predicted that biosimilar trastuzumab plus originator pertuzumab would be the benchmark target for cost considerations. I’m not surprised to hear your experience from your pharmacy. Joyce, do you have anything else to add about the pricing?

 No. All told, it’s going to be a win in terms of our current savings in the health care system when you put everything together. It’s going to be a favorable thing cost-wise, and then of course that will translate into the patients’ out of pocket as well. Mainly, it’s really the time saved that is quite costly these days in the COVID-19 [coronavirus disease 2019] era and the post–COVID-19 era as well.

 It seems to me in other areas of medicine even, that sometimes manufacturers expect you to pay for convenience, that it might cost actually more for a more convenient drug administration. In this case, it’s actually looking like it’s coming out a little less or at least a break-even scenario. That’s gratifying and reassuring to hear that you don’t have to pay a premium for that convenience.

In closing, this has been an excellent discussion. I want to thank Dr Dang and Dr O’Shaughnessy for joining me. We hope that you found this information that we’ve presented to be valuable in your clinical practice. Thank you for watching 

Q&A: Practical Considerations in HER2+ Breast Cancer 

 I’d like to discuss the potential benefit of having a subcutaneous dual 

-directed option for our patients. First, I’d like to discuss the label language, which stipulates that the fixed dose of trastuzumab and pertuzumab is indicated as neoadjuvant treatment of patients with 

positive locally advanced inflammatory or early stage breast cancer, adjuvant treatment of patients with 

-positive early breast cancer at high risk of recurrence, and use in combination with docetaxel for treatment of patients with 

-positive metastatic breast cancer who have not received prior anti-

 therapy or chemotherapy for their metastatic disease. This really illustrates how the FDA has similar label language for the indication statements for the fixed dose combination of trastuzumab and pertuzumab as the IV [intravenous] formulations. In fact, they’re identical indications. Given in totality all that we’ve talked about, the convenience, the safety, the randomized trial results, and patient-reported outcomes, when I consider what would I prefer and what I think my patients would prefer between the IV and the subcutaneous option, it boils down to an infusion time of about 2 hours, at best, if things are running on schedule in a busy infusion center, for an IV administration of these agents vs. 8 minutes for the injection. That’s, for many, a fairly easy decision because patients’ time is very valuable.

This brings us to our final segment, segment 3, which will focus on practice challenges and strategies for integrating the fixed-dose combination into clinical practice. First, I’d like to discuss the dosing schedule in a little more detail. The initial dose is 1200 mg pertuzumab and 600 mg trastuzumab, along with 30,000 units of recombinant hyaluronidase administered subcutaneously over approximately 8 minutes subcutaneous. Then every 3 weeks, this is followed by a maintenance dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units of recombinant hyaluronidase over approximately a 5-minute infusion into the subcutaneous space.

This fixed-dose combination subcutaneous formulation is for use in the tops of the thighs only. The subcutaneous injection site should be alternated between left and right thighs only. New injection sites should be at least 1 inch or about 2.5 cm from the previous site on healthy skin and never into areas where the skin may be red, bruised, or tender from prior injections. Don’t split the dose between 2 syringes or between 2 sites of administration. During the treatment course with the fixed-dose monoclonal antibody combination, other medications for subcutaneous administration should preferably be injected at different sites.

Next, I’d like to call on Joyce to discuss the potential benefit of an at-home administration of this combination to patients. Is that feasible or possible, and would medical professionals still be necessary to consider this as a home treatment?

 Well, it certainly would be a change from how we run our practices, where we have our highly trained oncology nurses who are doing our infusions and our oncology pharmacists are doing the mixing. We certainly have a high comfort level with all the documentation and all the ancillary medications in case there is an infusion reaction because that same amount of safety and rigor, of course, has to take place at home. It has to be a trained nurse with experience in training specifically in this fixed-dose combination subcutaneous, and obviously a nurse experienced in treating what could be an infusion reaction or a systemic injection reaction. The medications have to be there as they are in our infusion room.

That just is going to take a little time to get the registered nurses trained, and of course the documentation and where they’re getting the medication from—that chain of custody, if you will, of that medication—and then the safety of administering it at home. Of course, it’s very safe, so that’s thankfully very good. Then of course getting the documentation back to the clinic. There is a little bit of logistical effort there, but it’s certainly nothing insurmountable. As you said, Mark, the advantages for patients is many hours. If you put in commuting times, there can be a whole day basically, a whole day away from work, away from family obligations, etc. It’s a big time-saver for patients and convenience. I think it’s worth doing. It is just a new approach, however.

 Finally, Dr Dang, I’d like to ask you to discuss the importance of the recent FDA approval for this fixed-dose combination subcutaneous formulation with recombinant hyaluronidase and how you might consider it along with your colleagues there at Memorial Sloan Kettering Cancer Center. Where do you think you might use this? Do you think you might actually be able to do this in a home environment? I know at our institution, we’re having a site initiation visit for a clinical trial of home administration of this formulation on a clinical trial with home visiting nurses administering the agents, etc, per protocol. Of course, they’re trained on the protocol. They have all the drugs necessary to treat anaphylactoid reactions, etc, for the subcutaneous infusion of antibodies. I’m curious to know the environment at your institution and how you think this could be impactful to your patients.

 Sure. It is very impactful. I’ll start with the trial. We’re opening the same trial as you are, Mark, and I’m excited about it. I think in this peri–COVID-19 [coronavirus disease 2019] environment, even post–COVID-19, there are so many patients that we need to take care of, and we just don’t have enough space to take care of our patients properly. When we have a subcutaneous formulation that our patients can have at home safely, that’s the right way to go into the future, so we’re excited about this trial as well. In talking about standard of care with the fixed-dose combination, we actually had a discussion about it this past weekend.

We are certainly adopting subcutaneous delivery. As you said, the injecting is less than 10 minutes, 5 to 8 minutes. Wow, that is a time-saver for patients over the 60 minutes to 2 hours of being in the chair for that long. We would use it where it’s indicated in the neoadjuvant, adjuvant, and metastatic settings. Certainly, the first thought is if they’re on the maintenance dual-antibody therapy; that’s where it makes the most sense. If they’re on chemotherapy and they were getting intravenous trastuzumab-pertuzumab, certainly this is where we are switching over, and it’s just a mental switch because we’re so used to giving everything IV 1 after the other, and it’s more the clinician mental switch that now they can have the dual-antibody therapy in subcutaneous. We are adopting all those indications, and we’re looking forward to being able to take care of our patients in a more time-constrained setting because our clinic time is getting longer, because chemotherapy time is getting longer, because infusion times are so long. If we can cut it down, we strongly support it.

The Impact of Subcutaneous Option for HER2+ BC

 Joyce, can you please tell us about the safety outcomes reported in FeDeriCa? Also, because you’re the lead author on patient-reported outcomes from the PHranceSCa study at ESMO [European Society for Medical Oncology Congress], what can you tell us about the PHranceSCa study?

 The safety was very similar in the FeDeriCa trial with the IV [intravenous] and the subcutaneous. If you look down the list, you’d see the diarrhea, and it was very similar between the 2. With IV trastuzumab, you can get the very rare infusion reactions, systemic infusion reaction. With the subcutaneous trastuzumab-pertuzumab fixed dose, you can get a systemic injection site reaction. The occasional patient will have a systemic reaction, but it’s very similar on the IV and the subcutaneous. With regard to cardiac asymptomatic left ventricular ejection fraction declines were 2% with the IV pertuzumab-trastuzumab, and 4% with the subcutaneous trastuzumab-pertuzumab. That’s a very likely statistical similarity given the small numbers in the study. Truthfully, there really wasn’t anything else to look at in the FeDeriCa study, at least as I look at the safety data, to distinguish IV and the subcutaneous. 

That was very, very similar to the PHranceSCa trial. Now, the PHranceSCa trial that I was involved in is a patient-reported outcome trial, and it’s also a patient choice trial. It’s quite interesting. There were 140 patients in the neoadjuvant setting who were randomized to get 3 cycles initially of IV pertuzumab and trastuzumab with chemotherapy. They had actually finished. They had finished their preoperative therapy and had surgery, and most of these patients had a pathologic complete response. They were going to be finishing the year of trastuzumab and pertuzumab. They’re postoperative and they’re randomized to either IV or subcutaneous pertuzumab and trastuzumab, so the fixed-dose combination of the subcutaneous pertuzumab-trastuzumab or standard IV pertuzumab and trastuzumab.

One group got 3 cycles of IV, then switched to 3 cycles of subcutaneous, and the other randomized group got 3 cycles of subcutaneous first and then 3 cycles of IV. The patients then said which 1 they preferred, the subcutaneous or the IV. Furthermore, they were given the choice to finish the remaining year of the trastuzumab and pertuzumab, which 1 would they like to choose? Eighty-two percent of the patients said they preferred the subcutaneous to the IV, mainly because of less time in clinic and feeling more comfortable during the actual treatment. Then 84% of patients chose to finish the year with the subcutaneous formulation. Virtually all patients said they were very satisfied or satisfied with the subcutaneous formulation.

It also was interesting that switching patients from IV to subcutaneous was also very well received by patients who cross over, and there are really no safety signals at all. If you look at the safety in PHranceSCa between the IV and the subcutaneous, there’s really no difference whatsoever. Here there was no difference in cardiac toxicity whatsoever. About a couple of percentage points of patients got a systemic IV infusion reaction with trastuzumab, and a couple of percentage points of patients got a systemic injection site reaction with the subcutaneous. But it was very minor, nothing very serious at all. That was true even if patients had been receiving IV for a while, and they switched to 3 cycles of the subcutaneous with no safety issues at all. It’s very safe to cross over from IV to subcutaneous. It was very nice. It good to see the patient’s point of view and their patient-reported outcomes, and the subcutaneous was very well received.

Thank you, Joyce. Chau, can you help me understand how the safety data from PHranceSCa impacted your comfort level with subcutaneous administration with pertuzumab with trastuzumab?

 I was very comfortable with the safety data in reviewing it and seeing that there were really no safety signals in the subcutaneous or going from IV to subcutaneous. Just in reviewing the data a note that in terms of diarrhea, which is what Joyce had mentioned earlier on, that is a toxicity we pay attention to when patients receive dual-antibody therapy. It’s in the midteens, about 16% going from IV to IV and going from IV to subcutaneous; it’s about 15%. There was no worsening rate of diarrhea. That gain of the comfort that the patients were not going to experience worse gastrointestinal toxicity. What I find striking is that when they were going from subcutaneous to subcutaneous or staying with subcutaneous, the diarrhea rate was lower, less than 10%; that was also comforting. Outside local site injection that was noted in patients getting subcutaneous, bordering around 20%, the other toxicity rates were comparable. I think the data from PHranceSCa gave me much comfort that this is a safe combination.

Clinical Outcomes in HER2+ BC: FeDeriCa and PHranceSCa

 I’d like to lead us into segment 2 of our session to talk in more detail about subcutaneous formulation of trastuzumab and pertuzumab, and then talk about some of the clinical data. I’d like to lead off by talking about the formulation aspects of this combination treatment by catalyzing the hydrolysis of hyaluronan, a constituent of the extracellular matrix, hyaluronidase lowers to the viscosity of hyaluronan, thereby increasing tissue permeability.

Recombinant hyaluronidase, therefore, is used in medicine in conjunction with other therapeutic proteins or biologics, like monoclonal antibodies, to speed up their dispersion and delivery from the subcutaneous space of the injection site, into the vascular space and into the systemic circulation.

Let’s talk about the FeDeriCa study, which was a phase 3 neoadjuvant-adjuvant multicenter randomized, open-label, 2-arm study of subcutaneous administration of a fixed-dose combination of trastuzumab plus pertuzumab formulated with the recombinant hyaluronidase in combination with chemotherapy.

These data were presented at San Antonio [San Antonio Breast Cancer Symposium] 2019 this past December by Antoinette Tan and colleagues. Patients were centrally confirmed to have 

 [human epidermal growth factor receptor 2]–positive invasive breast cancer with tumors greater than 2 cm or node-positive disease with stage II to IIIC disease. Five hundred patients in total were randomized 1:1 to AC [doxorubicin, cyclophosphamide] times 4 followed by a taxane with HP [trastuzumab, pertuzumab], given either subcutaneously or intravenously.

Two chemotherapy backbone choices were dose-dense AC every 2 weeks for 4 cycles, followed by weekly paclitaxel times 12, or AC given every 3 weeks times 4 cycles, followed by docetaxel every 3 weeks times 4 cycles. The stratification variables for this randomized phase 3 study were hormone receptor status, chemotherapy backbone choice, and stage.

The dosing regimens for the fixed-dose combination, given every 3 weeks for the 2 antibodies were 1200 mg of pertuzumab subcutaneously; and 600 mg of trastuzumab subcutaneously as the loading dose; and 600 mg maintenance each. For pertuzumab given IV [intravenously] every 3 weeks was 840-mg loading dose, 420-mg maintenance; trastuzumab was an 8 mg/kg load and 6 mg/kg maintenance. This was followed by 42 weeks in the adjuvant setting of either the IV or the subcutaneous dose and schedule as noted.

The primary objective of the study was noninferiority of the predose, cycle 8, pertuzumab serum trough concentration. A pharmacokinetic end point with the fixed-dose combination subcutaneous vs. IV pertuzumab, trastuzumab, and chemotherapy. Key secondary objectives were total pathologic complete response [pCR] in the breast and axillae and safety, including cardiotoxicity. In terms of the demographics, the patient demographics and disease characteristics were well balanced between the arms in the intent-to-treat population.

In terms of the top-line pharmacokinetic primary end point result, the predose, cycle 8 pertuzumab serum trough concentration mean was 78.5 µg/mL in the IV arm and 93.7 µg/mL in the subcutaneous arm. Nearly 93.7 is noninferior to 78.5. Thus, this study met its primary end point, which is a pharmacokinetic end point, with statistical confidence.

Dr Dang, I’ll pass it over to you to discuss the clinical outcomes in FeDeriCa.

 In terms of the clinical outcome, testing for the pathologic complete response between the 2, we saw that the pCR rates were nearly identical with subcutaneous versus IV formulation bordering on 60% with subcutaneous vs. IV. These data are very consistent with the other neoadjuvant studies, mainly TRYPHAENA and BERENICE. In TRYPHAENA study patients were receiving anthracycline followed by taxane, that’s FEC [fluorouracil, epirubicin, cyclophosphamide]–docetaxel with trastuzumab-pertuzumab, starting with anthracycline and all the way through, or FEC followed by docetaxel-trastuzumab-pertuzumab.

The third arm was the nonanthracycline arm that’s docetaxel-carboplatin-trastuzumab-pertuzumab. It was a full chemotherapy regimen with dual-antibody therapy, with a pCR rate of 60%. The FeDeriCa study had a pCR rate of 60% in both arms, which is very similar to TRYPHAENA. The BERENICE study showed similar results with a pCR of 60%, and that’s dose-dense AC followed by weekly paclitaxel with a dual-antibody therapy, or FEC followed by docetaxel and dual-antibody therapy also leading to pCR rates of about 60%.

These data are very consistent with one another, but I do want to highlight that in NeoSphere, as Joyce had mentioned, the pCR rate was about 45%. I think the reasoning why that was a little lower is because the chemotherapy and dual-antibody therapy in combination was shorter. It was 12 weeks, 3 months as opposed to the other regimens that were studied full chemotherapy of about 5 to 6 months. The take-away from the FeDeriCa study is that we saw no differences in pCR rates with full package chemotherapy with trastuzumab-pertuzumab, whether given IV or subcutaneously.

Efficacy of Fixed-Dose Subcutaneous Therapy for HER2+ BC

Next, I’d like to describe some of the issues surrounding administration of dual 

 [human epidermal growth factor receptor 2] therapy in the neoadjuvant or adjuvant settings and the need for more convenient and equally effective approaches.

You both know that being a patient can be very challenging. For example, just obtaining appointments for our clinical visits can be difficult. You have to listen to Muzak or leave voice mails and wait for returned phone calls. Then you have to schedule appointments for the infusion visits in addition to the clinic visits, laboratory tests, imaging tests, port placement, echocardiography, etc. All of this can be daunting.

At Stanford Women’s Cancer Center a few years ago, we put up all these things on a whiteboard just to walk our way through what a patient actually goes through in our clinic for a diagnosis of early stage breast cancer. At the end of the session, the board is completely filled with sticky notes. It is absolutely incredible what we ask patients to go through.

Even for regimens given every 3 weeks, though this may not sound like often, but consider the patients may have to travel great distances, particularly here in the West, and many face grueling commutes due to horrible traffic conditions in and around major metropolitan areas. When the patients finally get to our clinics, they have to battle for a parking space, queue up at the front desk, queue up in the lab, wait for test results, wait for the pharmacy that makes their medications, wait for the nurse to access their IV [intravenous], finally start an intravenous drip, and then finally—almost an anticlimax—they get the infusion of their medicine. Infusions can sometimes be lengthy. Many are just 30 or 60 minutes, but some can be 3 hours, and that’s for each drug. For a routine infusion with a multiagent regimen, this can easily take a half day, start to finish, or more. A faster process for treatment, like a subcutaneous treatment approach, would dramatically shorten the amount of time spent in the treatment centers.

Moreover, subcutaneous treatment has become a preferred route of administration that mitigates against theoretical transmission risks for the coronavirus. Medical clinics are of course considered high-risk spaces. In my own clinics, 4 of our staff became infected with the virus. Considering patient risk factors for COVID-19 [coronavirus disease 2019] mortality—age, diabetes, hypertension, use of immunosuppressive drugs—many of our patients are being comedicated with steroids, for example, chemotherapy is immunosuppressive, and MTOR inhibitors can be. The shorter amount of time spent in the infusion centers should theoretically reduce exposure risk and mitigate against viral transmission. Not to mention the fact that for reasons I mentioned earlier, it’s simply more convenient.

Administration of Dual HER2-Targeted Therapy in BC

 Dr O’Shaughnessy, Dr Chau Dang set the stage for this discussion by introducing the concept of dual 

 [human epidermal growth factor receptor 2]–targeted antibody therapies, both in the first-line metastatic setting in the case of the CLEOPATRA trial but also in the adjuvant setting for early stage for 

-positive breast cancer in the case of the APHINITY trial.

Can you drill down on those 2 studies in just a little more detail? Talk about the long-term follow-up from the CLEOPATRA study, for example, and talk a little about the safety data from this dual-antibody approach and how these have changed practice in terms of the landscape of therapy for both early and late-stage breast cancer.

 Sure, I’d be happy to. That was a great summary there, Chau—a really lovely, complete summary. The dual targeting with trastuzumab and pertuzumab, both of those antibodies were aimed at 

 can certainly be amplified and often is. It can heterodimerize but also homodimerize, but it can also heterodimerize and can be ligand-driven with heregulin, which binds to 

. The trastuzumab-pertuzumab combination with them binding to different domains of 

 with pertuzumab binding at the heterodimerization domain of 

, it stops not only homodimerization but also heterodimerization, which is very important in 

It made a great deal of sense to take this forward into the metastatic setting, as Chau said. In the CLEOPATRA trial, patients with first-line 

-positive metastatic breast cancer were randomized to docetaxel and trastuzumab with placebo vs. docetaxel, trastuzumab plus pertuzumab, and first-line metastatic. The results, as Chau said, were very striking in terms of very important improvement in progression-free survival but also a 15.7-month improvement long-term in overall survival. I don’t think we’ve really seen that kind of a survival delta really any time in 

-positive breast cancer, likely in any of our metastatic breast cancer settings. This was an amazingly large improvement in overall survival.

That really set the stage of course to bring this combination into the high-risk curative setting, as Chau said. Initially, in the preoperative setting with NeoSphere and TRYPHAENA, which led to pathologic complete response rates that were in the 45% range with ER-positive disease, they were in the 80% range when you gave the anthracycline preoperatively along with taxane, trastuzumab, and pertuzumab. There were very big improvements in pathologic complete rates. That led to the conditional accelerated approval of the combination preoperatively until the data from APHINITY were available, where the physicians had a choice of a taxane, carboplatin, trastuzumab plus-or-minus pertuzumab regimen, or an anthracycline regimen followed by taxane-trastuzumab with or without pertuzumab. There were a couple of different chemotherapies. About half of patients received anthracycline and half received nonanthracycline chemotherapy.

The trial was largely node-positive patients. There were a proportion of patients that were node negative, but then they closed that cohort down to enroll a much higher-risk population. We had recent data of a 6-year update, the mature data from APHINITY. Patients received either the trastuzumab chemotherapy with placebo or trastuzumab-pertuzumab with chemotherapy. The chemotherapy—when that was stopped, they finished then the year of the trastuzumab placebo or trastuzumab-pertuzumab. A year of therapy.

When you look at the intent-to-treat population at the 6-year follow-up, it was a 2.8% improvement in disease-free survival that was statistically significant. Interestingly, pretty much all the benefit was in the node-positive population. There was a 4.5% improvement in disease-free survival, which is certainly a clinically meaningful 4.5%. The toxicity, thankfully, with the addition of the pertuzumab both in the metastatic setting and in the curative setting, is highly manageable.

The main thing is diarrhea when the pertuzumab-trastuzumab is combined with chemotherapy. Once the patient stopped the chemotherapy, whether in the metastatic or neoadjuvant setting, then the diarrhea basically largely abates with the pertuzumab. It’s actually very manageable. I must say, these days of course, in practices for the higher-risk patients, we’re treating them preoperatively with chemotherapy, pertuzumab, and trastuzumab. If they have a pathologic complete response and they were high-risk to start off, we continue the pertuzumab and trastuzumab to finish the year. If they still have residual disease, they get the T-DM1 [trastuzumab emtansine] for the KATHERINE trial, as Chau told us.

Diarrhea is definitely an issue in some grade 3 diarrhea that can be running in 20% or more. Certainly with the proactive use of loperamide, what I do is 2 loperamide after the first loose stole of each day, and then 1 loperamide after each subsequent loose stool that day. Within a couple or 3 doses, it shuts down. Once the patients get a few days beyond that, usually the diarrhea abates. Then it usually goes away once they finish the chemotherapy, and they’re finishing their year of pertuzumab and trastuzumab if they had a pathologic complete response.

There was no additional cardiac toxicity in the CLEOPATA trial with the addition of the pertuzumab. There was a very small increment in cardiac toxicity in the APHINITY trial, with the addition of pertuzumab. Other than that, you can get some rash with pertuzumab, but it’s not usually very substantial. It’s mainly diarrhea, which we’re all very used to using it at this point. It’s basically to just take a proactive approach with antidiarrheal medicine.

Dual HER2-Targeted Approaches in Breast Cancer

® presentation. Today’s discussion will be focused on systemic therapy for early 

 [human epidermal growth factor receptor]–positive breast cancer.Joining me today in this discussion are my esteemed colleagues: Dr Chau Dang, chief of the medical oncology service at Memorial Sloan Kettering Cancer Center’s West Harrison Outpatient Center in West Harrison, New York; and Dr Joyce O’Shaughnessy, chair of breast cancer research and the celebrating women chair in breast cancer at Baylor Scott & White Charles A. Sammons Cancer Center in Dallas, Texas.

During the next 45 minutes or so we’re going to navigate through some data for a novel subcutaneous dual 

-directed treatment and the challenges and benefits of integrating this approach into clinical practice. Our program will be divided into 3 segments: segment 1, dual HER2-targeted therapy in breast cancer; segment 2, a data review on subcutaneous trastuzumab plus pertuzumab; and segment 3, practical challenges and strategies to integrate this new information into clinical practice.

Let’s get started on our first topic. Dr Dang, I’d like you to begin with segment 1. Can you please provide a historical perspective on the treatment of 

Thank you, Mark. Thank you so much for inviting me tonight. Over the last 2 decades I’ve seen a dramatic improvement in our patients with 

-positive breast cancer, in both the metastatic and early stage settings. Starting with the approval of trastuzumab in 1998 in combination with chemotherapy, namely paclitaxel for the frontline treatment of patients with 

-positive metastatic breast cancer. It was also approved as a single agent in patients who have been previously treated with chemotherapy.

For a long time, patients were given taxanes and trastuzumab, and we’ve seen a significant survival gain for about decade and a half until the publication of the APHINITY trial, which showed a significant improvement in progression-free survival and overall survival of docetaxel in combination with trastuzumab and pertuzumab over docetaxel and trastuzumab and placebo alone. This was a huge trial that led to a paradigm shift in treating our patients with metastatic 

-positive cancer in the frontline setting.

I also want to highlight that there were other trials in between that led to the approval of several other drugs—namely apatinib, T-DM1 [trastuzumab emtansine] in the metastatic treatment of patients, and more recently, fam-trastuzumab deruxtecan and neratinib, as well at tucatinib. These other targeted therapies need to be highlighted as well.

Moving on to early stage breast cancer, in 1998, when trastuzumab was approved in the metastatic setting, 4 large studies were launched: N9831, B-31, HERA, and BCRG006 testing trastuzumab in combination with chemotherapy for the treatment of patients with high-risk early stage breast cancer. We saw that at ASCO [American Society of Clinical Oncology Annual Meeting] 2005, that the combination of trastuzumab and chemotherapy led to a significant improvement in disease-free survival and overall survival. This was the first time we saw such a significant gain in combining agents together. With the median follow-up of about 10 years now, our patients are doing very well with a median survival of 85%.

Along the way, pertuzumab was combined with trastuzumab in the adjuvant setting in the APHINITY trial in patients with high-risk 

-positive breast cancer. We’re seeing that the combination of trastuzumab-pertuzumab-chemotherapy led to an improvement in disease-free survival, but most notably in patients with node-positive breast cancer. I also want to highlight the other key trials that are worth noting, namely the new adjuvant studies, NeoSphere, TRYPHAENA, and others testing the combination of trastuzumab-pertuzumab and chemotherapy, showing a significant improvement in pathologic complete response.

In 2013, pertuzumab-trastuzumab-chemotherapy was approved to be given to patients being treated in the neoadjuvant setting with high burden disease, namely stage II/III breast cancer with a tumor size of greater than 2 cm, or node-positive breast cancer, or inflammatory or locally advanced breast cancer. This is another indication for pertuzumab added to trastuzumab.

What’s also worth noting in the early setting is the KATHERINE study that was reported very recently showing that T-DM1, given in the adjuvant setting for patients with a residual disease after neoadjuvant treatment led to significant improvement in disease-free survival over trastuzumab. In the modern era, patients are given T-DM1after neoadjuvant treatment if they have residual disease.

Lastly, I also want to mention the neratinib story. Neratinib was also studied in the adjuvant setting from the ExteNET study, and this is a study that is also worth highlighting. This is a study where patients with high-risk breast cancer were given chemotherapy and trastuzumab. At the end of their trastuzumab treatment, they were randomized to neratinib or not. We’ve seen a significant improvement in disease-free survival in our patients, most notably in patients with hormone receptor–positive breast cancer. It’s noted here that we have a plethora of options for our patients for 

-positive breast cancer, both in the early stage in metastatic cancer settings, and they do so well.

Joyce O'Shaughnessy, MD, Baylor-Sammons Cancer Center

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