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The Evolving and Transformative Role of Maintenance Therapy in the First-line Setting of HER2+ Metastatic Breast Cancer

Thank you very much.

[00:16:58]

Case: Patient With ER+/HER2+ MBC

I will start with a clinical case just starting from our clinical practice. This is a 62-year-old postmenopausal woman, who was diagnosed seven years ago with an HR+/HER2+ stage I breast cancer. She received a lumpectomy and then an adjuvant treatment according to the APT trial. Weekly paclitaxel for 12 administration, together with trastuzumab and then trastuzumab at completion of one year.

She received radiation therapy. Since HR+, she started an aromatase inhibitor. Unfortunately, since tolerance was not optimal, she stopped the aromatase inhibitor.

At the recent follow-up, almost three years after an aromatase inhibitor, she presented with progressive back pain and fatigue. We performed an imaging and there was multifocal liver mets with extensive bone mets. We did a biopsy and the tumor was ER+ 90%, and again immunohistochemical 3+ also with FISH amplification.

Cardiac function was normal, so CBC and comprehensive metabolic panel was within normal limits. This is a metastatic breast cancer patient that relapsed after three years of aromatase inhibitors.

[00:18:54]

Poll 3

My question is actually, in your current practice, which is actually your standard of care in this patient? It is:

A. THP, so the CLEOPATRA regimen;

B. Trastuzumab-deruxtecan and pertuzumab that has been formally approved by FDA recently;

C. Tucatinib-trastuzumab and capecitabine; or

D. Pembrolizumab and chemotherapy;

Please vote. I am very curious to understand if oncology practitioner in the United States still use the CLEOPATRA or go to the DESTINY-09 regimen.

Very interesting. We have still 22% of doctors that prefer to prescribe the CLEOPATRA regimen, but we have 36% trastuzumab-deruxtecan and pertuzumab. Of course, pembrolizumab and chemotherapy is not indicated because this is not a triple negative. Also tucatinib-trastuzumab and capecitabine is a second-line treatment. It is never a first-line. Almost 50% will go for CLEOPATRA or DESTINY-09 regimen.

[00:20:23]

Case Continued: Patient With ER+/HER2+ MBC

Let us go now to the second scenario in the same patient. After discussing with the patient all the available data, we decided to start the DESTINY-09. 36% of the oncologists decided also for this combination so trastuzumab-deruxtecan and pertuzumab.

We started with the treatment. After six cycles, we observed a partial response with an improvement of pain. As a side effect, the patient had a grade 2 diarrhea, neutropenia, and that there was no cardiac toxicity. Actually, there was an excellent activity of this regimen. The patient returns to discuss the next step in their treatment journey.

[00:21:21]

Poll 4

In your current practice, what are you going to do now?

A. To continue trastuzumab-deruxtecan-pertuzumab;

B. To switch to a maintenance therapy HP until progression; or

C. To switch to maintenance therapy with HP, palbociclib, and endocrine therapy since here we have an HR+ disease also; or

D. You switch to HP, tucatinib exactly like the HER2CLIMB-05.

Responsive disease after six cycles, we do not know if this was the maximum response selected between continue the same treatment; switch to maintenance HP; or switch to PATINA regimen; or HER2CLIMB-05. Please vote.

Very interesting. 28% decided to continue treatment. It means not to switch, but 45% proposed to stop and maintain with the PATINA, only 9% with HER2CLIMB-05 and 17% with the same maintenance, of course, of the CLEOPATRA regimen. Very interesting, but we have also 28% that decided to continue.

[00:23:02]

Case Variation: Patient With ER+/HER2+ MBC

Now we propose a case variation, and the case variation is the following. What if the patient, rather than starting a trastuzumab-deruxtecan and pertuzumab started the CLEOPATRA regimen, so trastuzumab-pertuzumab and paclitaxel, in this case docetaxel. In this case, after six cycles, there was exactly the same response. Minus 55% sum of diameters with the grade 1 neuropathy and grade 2 alopecia. Exactly now the decision point is, what if you have a response after six cycles?

[00:23:47]

Poll 5

The question is, whether:

1. You continue with the same treatment;
2. You switch to pertuzumab and trastuzumab maintenance;
3. You switch to maintenance therapy and you continue HP adding endocrine therapy; or
4. You maintain with the PATINA trial; or
5. The HER2CLIMB-05.

In this case, the patient received dual blockade plus chemotherapy. Who of you is going to continue or to switch to a maintenance. With dual blockade, the dual blockade endocrine therapy, or PATINA trial or HER2CLIMB-05. Please vote.

Let me see. Okay. Very interesting here. Almost 47% will stop and continue with the PATINA regimen. I believe that this was also my choice to be honest. I would stop THP and I would maintain with the PATINA regimen because we know perfectly that median progression-free survival is up to 44 months. This is, of course, respecting our clinical practice because the PATINA trial was explored exactly after the CLEOPATRA regimen, so after THP.

[00:25:28]

Guideline Recommendations for HER2+ MBC: First-line Therapy

Let us discuss now about guideline recommendations. Actually, in clinical practice guidelines, there are two proposed regimen. Still we have pertuzumab-trastuzumab and docetaxel and paclitaxel. The second option is trastuzumab-deruxtecan and pertuzumab based on the data of the DESTINY-Breast09 trial.

For THP, we have a prospective randomized trial demonstrating that the maintenance with trastuzumab-pertuzumab, or trastuzumab-pertuzumab AI and palbociclib is an optimal maintenance regimen because you can improve median progression-free survival up to 44 months.

In the second-line setting, if you received the CLEOPATRA regimen, we have two options or trastuzumab-deruxtecan that is preferred, or tucatinib-trastuzumab and capecitabine. Of course, if you received trastuzumab-deruxtecan and pertuzumab, we have no level of evidence to suggest a specific treatment. Of course, here we are in a free data zone, and we have to discuss what to do in this setting.

[00:26:50]

CLEOPATRA: Trastuzumab + Docetaxel ± Pertuzumab in Untreated HER2+ MBC

Just to remind to you the CLEOPATRA regimen. This was a prospective randomized trial, including patients with HER2+ metastatic breast cancer. Patients have been randomized to pertuzumab-trastuzumab and docetaxel vs placebo-trastuzumab and docetaxel. The primary endpoint was median progression-free survival per independent review. The HP was of course given to the patient until PD or unacceptable toxicity. Docetaxel was recommended for minimum six cycles.

[00:27:30]

CLEOPATRA: Survival With Pertuzumab, Trastuzumab, and Docetaxel as 1L Therapy in HER2+ MBC

In the CLEOPATRA regimen, there was an improvement of median progression-free survival from 12 months to 18.7 months, and an overall survival benefit up to 57 months. There are still patients alive in the CLEOPATRA regimen.

[00:27:48]

DESTINY-Breast09: T-DXd ± Pertuzumab vs THP as 1L Treatment for HER2+ MBC

In the DESTINY09, this was a prospective randomized trial comparing trastuzumab-deruxtecan-placebo, trastuzumab-deruxtecan-pertuzumab and THP regimen. Trastuzumab-deruxtecan and pertuzumab was continued until progression, and concurrent use of endocrine therapy was allowed for HR+ disease.

The primary endpoint of the study was median progression-free survival, comparing A vs B and B vs C. Finally, the interim analysis that we presented at ASCO is referred to arm B vs C, trastuzumab-deruxtecan-pertuzumab vs THP.

[00:28:40]

DESTINY-Breast09: Baseline Characteristics

These are the patients all HER2+ metastatic breast cancer. Some of them with brain mets at baseline. 54% of them were HR+. 46% were HR-.

[00:28:55]

DESTINY-Breast09: Previous Therapy for Breast Cancer

If we look at the data in terms of previous therapy, many of them receiving chemotherapy and then tier two therapy in the neoadjuvant and adjuvant setting, the majority of them.

[00:29:09]

DESTINY-Breast09: PFS (BICR)

The analysis demonstrated that the improvement of median progression-free survival from 26.9 months to 40.7 months. The combination of trastuzumab-deruxtecan and pertuzumab is FDA-approved as first-line treatment for patients with unresectable or metastatic HER2+ breast cancer. Still, we do not have any approval for this.

[00:29:43]

DESTINY-Breast09: Secondary Efficacy Endpoints

In the secondary efficacy endpoint, overall response rate was 85% in T-DXd and pertuzumab arm vs 78% in THP arm. Number of complete responses were 15% in the experimental arm vs 8% in the HP, and the rate of partial response was very similar across the two arms.

If we check median duration of response, we have 26 months for THP and 39 months for trastuzumab-deruxtecan and pertuzumab. The median progression-free survival is, I said, improved from 20 months to 40 months with an hazard ratio of 0.49, and the median progression-free survival 2 was not reached for trastuzumab-deruxtecan. Still we do not have data on overall survival. We need a longer follow-up.

[00:30:46]

DESTINY-Breast09: Most Frequent TEAEs and AESIs

The most frequent toxicity was peripheral sensory neuropathy in the THP arm, 28% vs 11%. Of course, we had nausea and diarrhea more prevalent in the trastuzumab-deruxtecan and pertuzumab arm, the nausea. A similar incidence for diarrhea. Of course, of interest we have to remember ILD that is a typical toxicity of trastuzumab deruxtecan that was observed in 12% of the patients receiving trastuzumab-deruxtecan and pertuzumab, vs only 1% in the standard of care arm.

[00:31:29]

Let's Revisit the Case

Let us now revisit the case.

[00:31:33]

Panel Discussion: IL Therapy for Case Patient

Let us try to discuss with Professor Karlinsky about our patient. This was a 62-year-old postmenopausal woman that received an APT adjuvant regimen, then three years of endocrine therapy. She progressed in the liver. We performed the liver biopsy, and finally there was an immunohistochemical 3+.

For Professor Karlinsky, what are you going to do in this patient who relapsed three years after APT? Are you going to propose the CLEOPATRA regimen, or are you going to propose the DESTINY-09 regimen, trastuzumab-deruxtecan and pertuzumab?

Dr Kevin Kalinsky (Winship Cancer Institute of Emory University): For this particular patient who is experiencing pain and fatigue, so she is symptomatic. She also has multiple liver metastases and is described as having extensive bone mets. I would start with T-DXd and pertuzumab based upon the data that you presented. I imagine for you it would be the same approach.

Dr Curigliano: Yes, absolutely, because you have a rate of partial response that is very high. Also, complete response. My question for you is, what are you going to do to continue until progression? Would you stop and maintain even if we do not have data after T-DXd and pertuzumab on maintenance?

Dr Kalinsky: This is where I wonder if you and I are going to slightly differ or be somewhat the same. As you mentioned, you can have some really nice responses. At the very least, we would have this as induction. If she has a really nice response with also improvement of her symptomatic disease. Her tumor is strongly ER+, and she had stopped her AI due to adverse events. I would consider something like PATINA that we would have the discussion about. Tell me more about why you did not tolerate the AI or should we think do a search? That would be a conversation that we would have in that particular case, something like fulvestrant.

One of the big questions that we face in this field now is, at what point should we pivot if we are going to pivot to a maintenance approach? Do we need an optimal response, also recognizing that with CDK4/6 inhibitors, you can also have nice response rate. It is somewhat of an unanswered question. For sure, if she was still symptomatic and those liver metastases were still very much present, I would continue. But the question is, when do you change if you are going to change at all?

I tend to "deescalate," but I am curious, Giuseppe, your take on it.

Dr Curigliano: For sure if I have a patient with a complete radiological response, of course, I will not proceed until progression. Let us assume that after six to nine cycles, you have a complete disappearance of liver mets, complete disappearance on bone scan of bone mets or not active. This is a type of patient where I will discuss eventually to stop and maintain, and then a potential to reconsider a rechallenge in case of new progression in the future.

Let us assume that this patient is receiving trastuzumab-deruxtecan and pertuzumab. Then you complete with an evaluation on complete response, you continue and then she progress, which is your second-line treatment in this patient.

Dr Kalinsky: In that situation, I would think about something that is tucatinib-based probably. I would also say, and I am curious what you think about this as well. We can see with HER2-directed ADCs, including with T-DXd, that you can have downregulation of the expression of HER2. If a patient is progressing, that is a circumstance where I might think about repeating a biopsy just to get a sense of what the biology looks like in that time. What do you think about that?

Dr Curigliano: I completely agree with you because sometimes in patients with the rapid progressive disease after T-DXd, you have really a downregulation. It is really important to recheck eventually.

Please submit your questions for the presenters at any times. I have another question for you before moving to the next case.

What you are going to consider if you have a patient first-line with brain mets?

Dr Kalinsky: That is one circumstance where I might really be inclined to continue the T-DXd. We know it has really good penetration. The other consideration here is let us say you have that patient and they are having a great response. They are having a great response in the CNS, but also systemically as well.

We will talk about the HER2CLIMB-05, but as we know, tucatinib has good CNS penetration. Do you feel like there is a world where you would think about pivoting and doing a maintenance strategy with tucatinib in that setting?

Dr Curigliano: Yes, absolutely. It is important to understand we cannot do in the first-line setting. If we analyze the data in the DESTINY-09 and there is a clear benefit from the combination of trastuzumab-deruxtecan and pertuzumab, we have also the data in the second-line of the DESTINY-12. When you have brain mets asymptomatic, you can also delay radiation therapy and starting with this combination.

[00:37:55]

Let's Return to a Question From Earlier

Let us return now to a question from earlier.

[00:38:00]

Posttest 2

Now I will give again the podium to you in a few minutes. But the first question I ask is, which of the following treatment is FDA-approved for the first-line treatment of patients with HER2+ metastatic breast cancer? Which are the regimens across A, B, C, and D approved in the first-line?

A. Margetuximab-trastuzumab;

B. Palbociclib-pertuzumab and trastuzumab;

C. Tucatinib-trastuzumab and taxane; or

D. Trastuzumab-deruxtecan and pertuzumab;

Please vote. Which one of these regimen is the first-line approved? Vote.

The first-line approved is trastuzumab-deruxtecan and pertuzumab, since palbociclib-pertuzumab-trastuzumab is only a maintenance. The correct answer was trastuzumab-deruxtecan and pertuzumab.

[00:39:19]

Novel Strategies in Maintenance Therapy in the First-line Treatment of HER2+ MBC

Let us move now to your section please. We go now to present a novel strategies of maintenance. Please, Kevin.

Dr Kalinsky: Thanks, Giuseppe. I am, as Giuseppe mentioned, going to be talking about maintenance therapy is talking about some of the data that we have seen. I am also going to focus on some ongoing studies as well.

[00:39:46]

Guideline Recommendations for HER2+ MBC: Maintenance

Giuseppe had mentioned this slide, but I just want to highlight. Again, I am going to be talking about maintenance, and maintenance can include just giving HP, or if it is HR+ HP plus endocrine therapy plus palbociclib, and I will also show some data with tucatinib.

[00:40:11]

PATINA: Palbociclib + Anti-HER2 + Endocrine Therapy in Previously Treated HR+/HER2+ MBC

These data we had seen at San Antonio a few years ago. These now have been published in the New England Journal of Medicine. This is the PATINA study in which patients received six to eight cycles of induction therapy. Again, as Giuseppe had mentioned, this is not T-DXd and pertuzumab. This was giving taxane or vinorelbine with HER2 monoclonal antibodies.

Then if patients did not have disease progression for at least six months after induction therapy, then they could be randomly assigned to receive endocrine therapy with HER2 monoclonal antibodies. It could be trastuzumab with or without pertuzumab. That was the control arm, and then the experimental arm also added in palbociclib with the dosing that we utilize in our patients with HER2-negative disease. 125 milligrams day one through 21 in a 28-day cycle.

[00:41:14]

PATINA: Baseline Characteristics

These are the baseline characteristics. Just to show you that the median cycles of induction were six cycles. The receipt of dual anti-HER2 therapy was high. It was greater than 90%. Around two thirds of patients had achieved a CR or PR with their induction therapy, a third stable disease. The majority received an AI. A little shy of 10% of patients had received fulvestrant.

[00:41:47]

PATINA: PFS and Interim OS

The primary endpoint was progression-free survival. You can see that the median, the point estimate for the experimental arm with palbociclib was 44 months, and with the control arm again without palbociclib, it was around 29 months.

I just want to call your attention to the Kaplan-Meier curve. If you look at the landmark analyses, you can also see the percent of patients. This is with 52 months of follow-up where if you look at five years, 43% of patients were still on the PATINA regimen and 30% were still on HER2 monoclonal antibodies plus endocrine therapy. Just again, highlighting when Giuseppe had showed the CLEOPATRA data that there are some patients that can remain on that front-line therapy for some time.

We also saw responses. As I mentioned, about a third of patients with measurable disease had an objective response with adding in palbociclib.

[00:42:54]

PATINA: Cumulative Incidence of CNS Progression/Death

These are the data in terms of the cumulative incidence of CNS progression. In the HER2-negative setting, we have some data with some of the CDKs about the potential penetration of the CNS with CDK4/6 inhibitors. Though these numbers are relatively small, when you look at absolute numbers that there was a lower rate of having CNS progression if you were in the palbociclib arm.

If you look at the cumulative risk of CNS progression or death, including at three years, that rate is lower in the palbociclib arm. Again, these are small numbers. You can even look at the confidence intervals and you can see that those are wide.

[00:43:46]

PATINA: Safety

I would say no real surprises with the addition of palbociclib to HER2 therapy monoclonal antibodies along with endocrine therapy, primarily neutropenia or other cytopenias then nausea and some fatigue. Then you can also see that there was some stomatitis that was also identified.

[00:44:13]

PATINA: Discontinuation, Interruptions, and Reductions

In terms of discontinuation of the palbociclib, the rate was about 18%. There were some patients who had grade 3 or higher. The majority of those were neutropenia. Again, I had mentioned some fatigue but also some stomatitis as well as diarrhea.

Then about 50% of patients did require a dose interruption. You can see in this table to the right that about a quarter of patients had one dose reduction, and about 30% of patients required going to the 75 milligram dose, so a second dose reduction.

[00:44:56]

Practical Endocrine Therapy Selection HR+/HER2+ First-line Maintenance

We see that this is an option that we might consider for our patients with HR+ disease. When you are thinking about this, questions to ask yourself include what prior adjuvant endocrine therapy did patients received? How quickly did patients progress on that adjuvant endocrine therapy if someone was on their aromatase inhibitor and then progressed on it? It would give me a little bit more pause or I might think about something like fulvestrant compared to somebody who might not have received adjuvant endocrine therapy or had a tumor that had progressed despite completion of it years later.

Also, patient preferences, discussing the risk benefits, including if you are thinking about something like fulvestrant coming in and getting those injections.

[00:45:49]

HER2CLIMB-05: Tucatinib vs Placebo Added to HP as 1L Maintenance for HER2+ MBC

I mentioned HER2CLIMB-05. This was presented at San Antonio, where patients with metastatic breast cancer had received THP for four to eight cycles. Then if they had not had a tumor that progressed, they were randomly assigned to HP with or without tucatinib.

Tucatinib dosing was standard, the 300 milligrams twice a day. The primary endpoint was progression-free survival.

[00:46:18]

          HER2CLIMB-05: Baseline Characteristics

This is the population. About half of the patients had tumors that were HR+. About 12% had prior existing brain mets. A little bit more than 50% of patients had visceral disease. Around 30% of patients had recurrent disease. You can see the rate of de novo disease was actually about two thirds.

Then the median induction HP cycles again was about six. In this study, about 9% had a complete response. Two thirds of PR and a little bit less not to do cross-trial comparisons, but around 20% to 25% of patients had stable disease as their best response to THP.

[00:47:06]

HER2CLIMB-05: Investigator-Assessed PFS (Primary Endpoint)

This showed an improvement in median progression-free survival. The hazard ratio was 0.6, and you can see the point estimates that are listed here.

[00:47:17]

HER2CLIMB-05: OS and CNS-PFS

It was an absolute difference of a little shy of nine months. As I mentioned previously, we know that patients can have CNS benefit when they receive tucatinib. The numbers here really are small, but I just want to call your attention to that bottom table to the right, where if you look at CNS, PFS in patients with brain mets at their baseline. When you look at the point estimate, again, like the confidence intervals are wide. You can see the number of events in each arm is around 25. There was a 4.2 improvement with the tucatinib arm, but again, small numbers.

[00:48:00]

HER2CLIMB-05: Safety Summary

In terms of safety, you can see. I just want to call your attention to the discontinuation rate due to treatment-emergent adverse events. You can see that about 13% to 14% discontinued study drug. In the tucatinib arm and the placebo arm, it was a little shy of 5%. In terms of the events that led to discontinuation, primarily hepatic events and diarrhea, which is what we see with tucatinib.

[00:48:32]

          HER2CLIMB-05: Hepatic and Diarrhea Treatment-Emergent Adverse Events

In terms of dose modifications, on the left is hepatic and on the right is diarrhea. If you look at the bottom, you can see that around 20% of patients needed to hold when they received the tucatinib had to dose modify, i.e., hold due to hepatic events and around 9% due to diarrhea.

[00:49:00]

Additional Investigational Strategies

I referenced at the beginning additional investigational strategies.

[00:49:06]

DEMETHER: Maintenance HP Following T-DXd Induction Therapy for HER2+ MBC

This is the DEMETHER study, which is a study that is looking at induction with T-DXd. Again, not T-DXd plus pertuzumab, but with T-DXd. Then patients go on to subcutaneous pertuzumab trastuzumab, and then they can stay up there up to three years. Then if they do not progress after three years, they can continue treatment outside of that. If they have a progression or discontinue, than they would continue to be followed up.

This study is really looking at the question of how do patients do if we do this induction approach and then give pertuzumab and trastuzumab?

[00:49:54]

SAPPHO: Sequential Therapy With Curative Intent in Newly Diagnosed HER2+ MBC

This is the SAPPHO study, which is an open-label, single-arm, phase II study. The primary endpoint for this study is looking at disease-free survival at four years. Again, this is a frontline study. It has different parts to it. Just note the difference in terms of how the induction phase is being described. Patients get THP for 12 weeks, then they go to T-DXd for 18 weeks, and then they go to T-DM1 plus tucatinib. Then they go on to a maintenance phase of tucatinib plus HP. This is a slightly different approach by extending the induction though, with different agents that we have in our armamentarium.

[00:50:34]

STOP-HER2: Trastuzumab Cessation in HER2+ MBC

This is the STOP-HER2 study, which is looking at, as we have already highlighted, we have a group of patients who really seem to do well on HER2 therapy. The question that we get for these long-term responders is, can we stop? Can we possibly stop HER2-directed therapy?

There are two cohorts. There is an observation cohort where we continue their anti-HER2 therapy. Then there is cohort B where patients stop their anti-HER2 therapy. Embedded in this is MRD and restaging scans to help address this question.

[00:51:17]

Let's Revisit the Case

Let us revisit the case.

[00:51:20]

Panel Discussion: Maintenance Therapy for Case Patient

Again 62-year-old postmenopausal woman diagnosed seven years ago with ER+/HER2+ stage I, had local therapy. Got paclitaxel and trastuzumab, radiation, three years of AI but stopped it. Then as we mentioned four years later progressed with back pain and fatigue in liver mets. Liver biopsy, ER strongly positive, PR 20%, and HER2 3+ and FISH amplified.

Giuseppe, with this in mind, any additional thoughts about if this was a patient who had HR- disease, would you think about a HER2CLIMB-05 regimen? That is question number one.

Then number two, if you are thinking about a maintenance approach, are you leaning more towards something like PATINA if they would be ER+ and then something more like HER2CLIMB-05, if they would be ER-?

Dr Curigliano: I would prefer of course the PATINA arrangement mainly for toxicity issue. Giving tucatinib-trastuzumab and pertuzumab can give a lot of diarrhea. There is a high discontinuation rate. I believe it is an excellent combination, maybe to be considered in HR- patients. Specifically for this patient, I really believe the optimal treatment is the PATINA regimen.

I am really convinced about this because you have a dramatic improvement in median progression-free survival when compared to the standard maintenance therapy and also tolerability in my opinion is very good.

Dr Kalinsky: Just as a reminder, please submit your questions so that we can have a Q&A. Feel free. You can see the Q&A feature at the bottom of your console. Giuseppe and I would be happy to answer your questions.

The other thing just to highlight here, and Giuseppe, I do not know if you have anything else that you would like to add to this. But this patient has a PIK3CA wild-type tumor. I do not know right now if this influences anything for you, but also just to highlight that we talked about different maintenance strategies that are being evaluated. There are ongoing efforts to evaluate PI3K agents in this setting if patients have PIK3CA mutant tumors. Also, we will see some of the novel endocrine therapies possibly getting into this space. Right now, just PIK3CA mutation status, does it have any bearing for you, including the duration of which you would continue T-DXd and pertuzumab?

Dr Curigliano: It is an interesting study in my opinion, because we know that having a PI3 kinase mutation maybe can reduce the activity of the dual blockade. The trial is actually active in my institution. We are giving to patients with PI3 kinase mutation, a randomization to inavolisib plus pertuzumab and trastuzumab vs placebo, pertuzumab and trastuzumab plus endocrine therapy in both arms.

We have to remember to add endocrine therapy if HR+. I do not expect, in my opinion, a superior outcome when compared to the PATINA trial. In the HR+ disease, my maintenance favorite is for sure the PATINA regimen and not the PI3 kinase one.

Dr Kalinsky: Agreed.

[00:55:08]

Posttest 1

Maybe we will do a few final questions and then we will open this up for any questions that you might have. Giuseppe, I will run through these questions then I will pass this off to you if that works.

For a patient with HR+/HER2+ metastatic breast cancer, has had a good response to THP, a switch to maintenance therapy with which of the following agents added to HP and endocrine therapy significantly improved PFS compared with HP plus endocrine therapy alone in trials?

A. Elacestrant;

B. Imlunestrant;

C. Palbociclib; or

D. Ribociclib;

[00:56:08]

          Posttest 1: Rationale

We have been talking about this, the PATINA study, palbociclib. Thank you for those that are responding. The majority had said palbociclib.

[00:56:21]

Posttest 3

For a patient with HR-/HER2+ metastatic breast cancer with no evidence of progression after 48 cycles with first-line THP, a switch to maintenance therapy with which of the following agents added to HP significantly improved progression-free survival compared with HP alone in a phase III study?

A. Pembrolizumab;

B. Ribociclib;

C. T-DXd; or

D. Tucatinib;

In this particular study, the question really was we are referencing the HER2CLIMB-05, which is tucatinib.

Dr Curigliano: We have some questions.

Dr Kalinsky: Good. I think I have one more. I am almost done.

[00:57:28]

Poll 6

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

A. Yes;

B. No;

C. Uncertain;

[00:57:45]

Poll 7

Then please take a moment to enter one key change you plan to make in your clinical practice based on this education.

[00:58:02]

Q&A

Dr Curigliano: The first question we have is, if you have a patient who received trastuzumab-deruxtecan-pertuzumab in the first-line, and then you perform the biopsy and there is a clear downregulation of HER2. What are you going to do as a second-line treatment?

Dr Kalinsky: He threw that out there.

Dr Curigliano: Assuming that there is a heterogeneity because I do not believe all the clones will be HER2-. In a patient like this, I would consider or tucatinib-trastuzumab and capecitabine but also trastuzumab, pertuzumab and taxanes, why not the CLEOPATRA regimen?

Dr Kalinsky: There are lots of ifs ands here, honestly. It depends. Let us just say you have a patient who is on T-DXd and pertuzumab and they are on this for several years, and then they have a tumor that progresses. You do a biopsy and it remains strongly HR+ and HER2 1+. Let us just say.

Depending upon the extent of disease, etc., this may be a patient that I would think about giving endocrine-based treatment in a targeted therapy, like a CDK4/6 inhibitor. The question that one may ask themselves is, should I continue HER2-targeted therapy?

But there are different permutations in terms of how this might look, just depending upon what is happening at that time of second-line. This would be a conversation with the patient, in particular about continuation of HER2-targeted therapy because historically, we have also had this circumstance where we have continued HER2-targeted therapy in patients who have HER2+ breast cancer. So there continue to be things we need to learn.

Dr Curigliano: Yes. Then we have another question. If you are going to do a maintenance after trastuzumab-deruxtecan and pertuzumab, which tier two regimen can I use? If you have HR+ or HR-, are you going to differentiate the use of the regimen?

Dr Kalinsky: Yes. I will say based upon what we had seen at San Antonio when HER2CLIMB-05 was presented, for the ER positives, I would utilize the PATINA regimen. If I am going to switch and do a maintenance approach for HR-, I was thinking more HER2CLIMB-05. Giuseppe, the same.

Dr Curigliano: Yes, I completely agree. Then there is an interesting question on the median cycles used in the DESTINY-09 for the combination of trastuzumab-deruxtecan and pertuzumab. We have this information. The median duration of treatment was 21 months for trastuzumab-deruxtecan plus pertuzumab, and 20 months for the CLEOPATRA regimen. This is the median number of cycles, 21 vs 20. It means that for more than one year these patients received the combination of trastuzumab-deruxtecan and pertuzumab. Do you have any comment on this, Kevin?

Dr Kalinsky: No. You are the expert in that study. I will absolutely just agree.

Dr Curigliano: Yes. Because finally, toxicity can be an issue, mainly nausea and vomiting, so we need to do an appropriate premedication in these patients in order to increase the compliance to the treatment. We have to be careful also to ILD. It is really important to have every two months CT scan.

Now we have a very interesting question. How long would you keep a patient on trastuzumab-deruxtecan and pertuzumab if responding well? Let us assume you perform a CT scan, every two months and you have still response. When would you switch to maintenance for HR+ and HR-?

Dr Kalinsky: This is tricky. One, I think that I can absolutely rationalize the idea of wanting to make sure that you have seen a response. The question that I still have is the degree of response that you need before thinking about making a switch. It is a conversation with the patient also recognizing that not everybody tolerates the combination of T-DXd. There is some patients still that are getting intravenous treatments and having fatigue. Often we are able to manage this, but it is a question of how well is the patient tolerating the regimen? How impacted are they by getting intravenous therapy because theoretically with the PATINA regimen, you can switch to orals and then give the pertuzumab and trastuzumab as a subcutaneous injection. Those are the conversations.

There is a discussion about trying to extend it to they have the best response. To me, at least how I have adapted this clinically is to the point where patients have had a response that they are not as symptomatic as they were. Then I have that conversation with the patient. Giuseppe, differing?

Dr Curigliano: Yes. This is what I do exactly. We have to be clear here. We do not have data on this stopping and maintaining in the DESTINY-09. I cannot guarantee that if you stop and maintain, and finally, you have exactly the same outcome for patients in terms of median progression-free survival. But as we said before, and if you have an excellent response with a good tolerability, in case of a complete response, potentially you can stop and maintain. Now what we need really are pragmatic trials in the real world.

I would like to mention to the audience that soon we will start a trial of Daiichi and AstraZeneca. The name is DESTINY-Breast Guide, and in this trial you receive trastuzumab-deruxtecan and pertuzumab. Then if for any reason you will stop the treatment for a complete response, or because the patient is tired, or because you had a toxicity, you can maintain with the PATINA trial and then you can rechallenge.

The comparator arm will be the arm of the DESTINY-09. This is, I believe, a very interesting, pragmatic trial that will give us the opportunity to really understand if we can stop and maintain or we should eventually continue on the approach.

[01:05:37]