Episode 066: Breast Cancer Series, Pt. 11-Metastatic HER2+ Breast Cancer

medicine

Jul 26

Written By TheFellowOnCall HemeOncPodcast

This week, we continue our discussion about metastatic breast cancer, focusing on HER2+ disease.

What is the general window for relapse in HER2 positive breast cancer after definitive local treatment?

There was a very well done prospective cohort study from Germany that looked at pattern of recurrence based on breast cancer subtype

Patients were defined as Luminal A, Luminal B, Luminal/HER2, HER2, or TNBC
Over 12,000 patients were analyzed from 2000-2016

Results:

It is very clear that, for HER2 positive and TNBC, a majority of relapses are occurring within the first 5 years and then leveling off after with very few late relapses
The figure also highlights the slow steady relapse that occurs with HR+ (i.e. Luminal subtype) of breast cancer at roughly 1% per year in the long term
It is important to note that therapies have changed significantly over the 16 years of this patient accrual but it is still illustrative of general relapse risk for these patients

How should we counsel her and what is the first line of therapy in metastatic HER2 positive breast cancer?

We don’t recommend simply using the median overall survival from clinical trials to give our patients a realistic estimate of prognosis. There are so many more factors that go into the equation.
If you look at several observational cohort studies looking at predictors of long term survival in breast cancer, we know that we are looking at a median of 3-4 years with about a third of patients living over 5 years
Brain metastasis is a poor prognostic risk factor with only 10-15% of patients living over 5 years
Representative studies:

What led to the dual HER2 blockade (trastuzumab + pertuzumab) with chemotherapy as the first line treatment in metastatic disease?

Important Phase III CLEOPATRA trial (Clinical Evaluation of Pertuzumab and Trastuzumab)

Looked at docetaxel (i.e. taxotere), herceptin (i.e. trastuzumab) and pertuzumab (THP) vs. TH + placebo
400 patients with HER2+ disease (IHC 3+ or FISH) enrolled in each arm
Median OS was 57 months for THP vs. 40 months so over 1.5 years better
Median PFS in THP arm was ~19 months so a little over 1.5 years without progression
Importantly there was no increase in CHF or heart disease with dual HER2 blockade

We talked about how we add carboplatin in the neoadjuvant setting to improve pathologic CR. Why not use the same strategy in the metastatic setting?

There was an older phase III trial from the BCIRG cooperative group published in 2011 that looked at this question

Compared TCH (docetaxel, carboplatin, trastuzumab) vs. TH
No difference in time to progression (a little less than 1 year) or response rate (~70%)

This is why CLEOPATRA is standard of care with THP

How do we approach second line treatment in the metastatic setting?

The current agent we recommend reaching for is trastuzumab-deruxtecan (Enhertu), but how did we get there?
In 2009, we found that there was a slight benefit continuing trastuzumab after progression in the second line setting with capecitabine (trial looked at capecitabine alone or with trastuzumab and found improved PFS by ~3 months)

Survival was still poor and CNS mets were an issue because of poor CNS penetration with trastuzumab and pertuzumab, so we developed novel smaller HER2 oral TKI therapies that could penetrate the CNS and also could overcome resistance to trastuzumab

Remember all TKI will end in -inib
We had lapatinib, neratinib, and tucatinib
Several trials looked at these in combination with capecitabine

A review of the TKIs for metastatic HER2+ breast cancer:

Lapatinib was the first kid and the control arm in many of the later trials

Mechanism is a reversible TKI
Initially approved 2nd line after trastuzumab in a trial that compared lapatinib + capecitabine vs. capecitabine monotherapy

Improved time to progression by 4 months but median time to progression was still just a little over 8 months in the lapatinib arm so not blockbuster

Another trial showed that it didn’t improve time to CNS metastasis in the second line setting for patients without baseline CNS mets

lapatinib + capecitabine vs. trastuzumab + capecitabine with primary endpoint of time to CNS metastasis

Currently available antibody drug conjugates include Trastuzumab emtansine (TDM-1 or Kadcyla) which we discussed in the neoadjuvant setting for those who didn’t achieve path CR based on the KATHERINE trial) and trastuzumab-deruxtecan (Enhertu). How do we pick one over the other?

TH3RESA study investigated T-DM1 in the 3rd line setting after lapatinib with a response rate of ~30% and median PFS of 6 months showing promising activity
EMILIA was phase III RCT looking at T-DM1 in the 2nd line setting

Looked at T-DM1 vs. standard of care at the time (lapatinib + capecitabine)
Improved PFS by 5 months (~9.5 vs. 4.6) and OS by 5 months (31 months in the T-DM1 arm)

MARIANNE Study compared TDM1 + pertuzumab vs. TDM1 alone vs. trastuzumab + taxane in the first line metastatic setting

Comment on study: Notably no pertuzumab in this control arm (which we discussed as SOC as per CLEOPATRA study)
No difference in PFS or OS

Now let’s turn our attention to the newer antibody-drug conjugate, trastuzumab deruxtecan. Is this any better?

Trastuzumab deruxtecan is a more powerful agent:

As discussed in our intro to pharmacology episode, higher drug-to-antibody ratio

For trastuzumab deruxtecan this is 8:1 compared to 3.5:1 for TDM-1
Trastuzumab deruxtecan also has tumor selective cleavable linkers unlike TDM-1 which was a more stable linker that requires internalization through receptor mediated endocytosis

This allows for more of a bystander effect on non HER2 expressing surrounding cells because of the larger drop off of chemotherapy

Keep the context in mind that the prior median PFS was ~9 months maximum as we get into the data here

Important phase II trial called Destiny-Breast01

Enrolled TDM-1 refractory or TDM-1 intolerant patients

Included 184 patients that all received trastuzumab and TDM-1 and 66% having pertuzumab so more representative of the standard of care treatment
13% of these patients had a history of brain metastasis so higher risk
The ORR of trastuzumab deruxtecan was ~79% with a disease control rate of an astounding 97%
At the 2020 data cutoff, the median duration of response was 20.8 months and PFS of 19.4 months - truly remarkable

Big AE: pneumonitis occurring in 15% of these patients with majority grade 2; however 9 deaths occurred due to pneumonitis

Now we get to the practice changing Destiny-Breast03 trial

Randomized trial comparing trastuzumab deruxtecan and T-DM1 in the 2nd line setting

Median PFS of trastuzumab deruxtecan was 28.8 months compared to 6.8 months
OS data maturing

Adverse AE:

Drug related ILD or pneumonitis occurred in 15% of trastuzumab deruxtecan compared to 3% in T-DM1 group without any deaths related to the toxicity
More LFT abnormalities in T-DM1 compared to trastuzumab deruxtecan but still common in both arms
More alopecia due to the deruxtecan linker

What are the options for the 3rd line setting?

At this point, you can always try T-DM1 but this has never really been tested in a clinical trial after progression on trastuzumab deruxtecan. Remember T-DM1 was initially approved in the 3rd line setting.
A more preferred option would be using the newest of the three TKIs that we mentioned which is called tucatinib + trastuzumab + capecitabine

You may be wondering about the other TKI neratinib (irreversible pan-HER2 inhibitor so think side effects)
Main difference is that tucatinib is selective for HER2 with very little off target EGFR side effect
Neratinib has lots of diarrhea and could an option in the 4th line setting

NALA Phase III trial: Approved with capecitabine after beating lapatinib + capecitabine by 2 months in PFS in the 3rd line setting (median PFS of 8.8 months vs. 6.6 months)
More diarrhea but had improved CNS control rates (~5% absolute improvement)

Tucatinib likely has better CNS response rates which is why it is preferred

Tucatinib as single agent in early phase trials showed great response rates

ORR 61%
CNS ORR 42% which was very impressive

Led us to the phase III trial called HER2CLIMB

Looked at tucatinib + trastuzumab + capecitabine vs. trastuzumab + capecitabine

Included 3rd line or greater patients
All of these patients had progression after pertuzumab, trastuzumab, and T-DM1…this is an appropriate control arm in terms of prior therapy

Median PFS improved by 2 months to roughly 8 months from 6 months
Also had significantly improved CNS-PFS in exploratory analysis for those with both stable and active brain metastasis suggesting good CNS penetration
Median OS improved close to 2 years from 1.5 years
ORR 41% compared to 23% so clearly more activity with tucatinib

What about later line settings after progression of disease?

Clinical trials are always an option!
Could consider neratinib at this point based on the NALA trial where it beat lapatinib, but if they have received tucatinib before, may not be effective
Trastuzumab + chemo (often trastuzumab+navelbine or gemcitabine) is an option
Lastly, let’s talk about the other new drug called margetuximab

Very similar mechanism as trastuzumab but it has been engineering to have improved binding and better antibody dependent cellular cytoxicity
SOPHIA phase 3 trial compared margetuximab + chemo vs. trastuzumab + chemo in the 3rd line or greater

Enrolled over 500 patients total
Improved PFS from 5 months to 6 months - very small one month benefit
Improved response rate of 25% vs. 14%
Exploratory analysis suggests there may be some benefit based on the Fc gamma receptor genotypes but this is still very early

Let’s put this all together (our approach based on the data):

At time of disease progression: Always re-biopsy
First line: Docetaxel + Trastuzumab + Pertuzumab (THP)
Second line: Trastuzumab deruxtecan
Third line: tucatinib + trastuzumab + capecitabine
Fourth line:
- Clinical trials
- Trastuzumab + navelbine
- Margetuxumab + Chemotherapy