Sara M. Tolaney, MD, MPH

Sara M. Tolaney, MD, MPH, associate director of the Susan F. Smith Center for Women’s Cancers; director of Clinical Trials, Breast Oncology; and senior physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, discusses where she sees the treatment landscape evolving in the future for patients with hormone receptor (HR)-positive metastatic breast cancer.

There have been many advancements over the last several years for the treatment of patients with HR-positive metastatic breast cancer, but Tolaney believes there will be a shift towards combination therapy in the future. Current treatment options in the include the combination of endocrine therapy with CDK4/6 inhibition, while physicians may also consider mTOR or PI3K inhibition with endocrine therapy.

In terms of moving forward, Tolaney says 1 major consideration will be combination strategy, which is under exploration in several clinical trials today. These studies are aiming to move the use of CDK4/6 inhibition forward, as well as treatments in the adjuvant setting and treatment with mTOR and PI3K inhibitors as partners for combination strategies. Tolaney says there are many options and new directions for replacing endocrine therapy backbones and perhaps moving into the earlier disease settings. However, first robust data from monotherapy trials are needed.

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Sara M. Tolaney, MD, MPH, discusses where she sees the treatment landscape evolving in the future for the treatment of patients with hormone receptor-positive metastatic breast cancer.

Combination Strategy May Play Role in Treatment of HR+ Metastatic Breast Cancer

 [human epidermal growth factor receptor 2]–positive disease, they are still at an increased risk of recurrence compared with patients who have 

-negative breast cancers. Some retrospective series suggest that these patients have a risk of recurrence that ranges somewhere between 10% and 30%. The challenge had been that these patients had been excluded from the pivotal adjuvant studies. For example, they were not included in the NCCTG-N9831 and NSABP B-31 trials and were predominantly excluded from BCIRG 006.

We really didn’t have data to help us decide what to do with these patients. The APT trial looked at giving less chemotherapy to these patients. It really looked to see if giving a year of paclitaxel and trastuzumab was associated with a clinically acceptable event rate. With 7 years of follow-up, that trial has shown that the regimen is associated with a 7-year recurrence-free interval of 97.5%. This really demonstrates that very few patients with stage I 

-positive cancers will recur after giving the TH [docetaxel, trastuzumab] regimen.

The more recently presented trial, the ATEMPT trial, looked to see if we could potentially de-escalate therapy even further. This trial looked to see if we could give a year of T-DM1 [trastuzumab emtansine] instead of giving the TH [docetaxel, trastuzumab] regimen, and it looked to see if the year of T-DM1 [trastuzumab emtansine] was associated with a clinically acceptable disease-free survival. The trial also compared toxicities between T-DM1 [trastuzumab emtansine] and TH [docetaxel, trastuzumab]. With 3 years of follow-up, the trial demonstrated that a year of T-DM1 [trastuzumab emtansine] was associated with about a 98% 3-year disease-free survival. Only 2 patients in the trial of the 375 on the T-DM1 [trastuzumab emtansine] arm had metastatic recurrence. There were very few events in that arm, in general. However, when the trial then compared rates of clinically relevant toxicities between a year of T-DM1 [trastuzumab emtansine] and the TH [docetaxel, trastuzumab] regimen, it found that the rates of clinically relevant toxicities were actually identical in the 2 arms—46% in each arm.

While the studies suggest that T-DM1 [trastuzumab emtansine] is associated with a very good event rate and would be a very reasonable treatment regimen, technically it did not show that it had fewer toxicities than TH [docetaxel, trastuzumab]. However, it’s important to note that when looking at patient-reported outcomes, we did see that quality of life was actually better in those patients receiving T-DM1 [trastuzumab emtansine] compared with TH [docetaxel, trastuzumab]. There was less hair loss and less neurotoxicity.

There are differences in toxicities between T-DM1 [trastuzumab emtansine] and TH [docetaxel, trastuzumab], and it’s important to factor those toxicities in when making decisions for your patients who have stage I 

-positive cancers. For example, if you have a patient who has underlying neuropathy, you might want to consider a year of T-DM1 [trastuzumab emtansine] versus TH [docetaxel, trastuzumab]. But we have to acknowledge that 17% of patients didn’t complete a year of T-DM1 [trastuzumab emtansine] because of toxicities.

This is very similar to what we saw in KATHERINE. Those patients, at time of onset of toxicity, went on to receive trastuzumab. If we are giving T-DM1 [trastuzumab emtansine] to our stage I 

-positive patients, and they run into challenges with toxicity, we do need to think about shifting them to trastuzumab to complete their year of treatment.

Novel Approaches for Stage I HER2+ Breast Cancer

 [human epidermal growth factor receptor 2]–directed therapy—neratinib, a pan-

 tyrosine kinase inhibitor—for 1 year after patients had completed their 

-directed therapy with trastuzumab-based treatment. It’s important to realize however, that ExteNET was conducted when pertuzumab and T-DM1 [trastuzumab emtansine] were not being used in the early 

The trial did demonstrate that taking neratinib for 1 year after completing a year of trastuzumab did result in a reduction in disease-free survival events. There was about a 2.5% difference between the 2 arms. But what was really interesting is that this benefit seemed to be restricted to those patients who had hormone receptor–positive disease.

Where we saw that the difference between the 2 arms was about 4.4% in those patients with hormone receptor–positive disease, no difference was really seen in those patients with hormone receptor–negative tumors.

There was an interesting analysis that was done that looked at patients who had received preoperative 

-directed therapy and had residual hormone receptor–positive 

-positive disease. These patients had completed their year of trastuzumab and then had gone on to the ExteNET trial. There was a 7% absolute difference between those 2 arms, favoring a year of neratinib.

This suggests that in that population where we’re traditionally giving, for example, T-DM1 [trastuzumab emtansine], at this time those patients with high-risk residual disease do see an even larger benefit. The challenge is how to use these data in the current era, where we are giving pertuzumab and T-DM1 [trastuzumab emtansine] and don’t really have data on the efficacy of neratinib in this particular patient population.

In my general practice, what I say is that if a patient had a very high-risk hormone receptor–positive tumor—for example, a patient who had residual disease after preoperative therapy, and with multiple nodes involved—I do consider giving neratinib.

I acknowledge that we don’t have sufficient data to guide us and to know what the benefit is if someone had received previous pertuzumab and T-DM1 [trastuzumab emtansine]. But those patients are at high enough risk of recurrence, and extended therapy may potentially be of some benefit.

The ExteNET Study & Management of HER2+ Breast Cancer

 The KATHERINE trial was a study that looked at patients who had residual disease after receiving preoperative chemotherapy and trastuzumab and randomized them to receive 14 cycles of T-DM1 [trastuzumab emtansine] or trastuzumab in the adjuvant setting. Then they looked to see if T-DM1 [trastuzumab emtansine] resulted in fewer recurrences relative to trastuzumab. What was found was that there was a dramatic reduction associated with the use of T-DM1 [trastuzumab emtansine] instead of trastuzumab, with a hazard ratio of about 0.5. So there was a 50% reduction in recurrences from using T-DM1 [trastuzumab emtansine] relative to trastuzumab.

This trial was very exciting because it found benefit regardless of hormone receptor status and regardless of whether patients had received dual 

 [human epidermal growth factor receptor 2]–directed therapy in the preoperative setting versus not. Really, there wasn’t a subgroup that didn’t benefit from the use of T-DM1 [trastuzumab emtansine] relative to trastuzumab in this study.

One challenge, however, was that T-DM1 [trastuzumab emtansine] did not reduce rates of CNS [central nervous system] recurrence relative to trastuzumab. Rates of CNS recurrence were the same in both arms. I think this continues to be an area that we need to work on. We need to further explore ways to prevent CNS recurrence. Even though T-DM1 [trastuzumab emtansine] is doing a great job at preventing recurrence, in general, we’re not doing very well in regard to preventing those CNS events.

There is further work being done in this area. There is an arm of the COMPASS trial that is taking patients who have residual disease and is randomizing them to receive either T-DM1 [trastuzumab emtansine] or T-DM1 [trastuzumab emtansine] and tucatinib. We know tucatinib is a 

-directed tyrosine kinase inhibitor that does have CNS penetration and has had activity in the CNS in patients with metastatic disease. We’re hoping that adding tucatinib in this setting may also help prevent CNS recurrences. Certainly, there’s more to come in this area.

There was work done to look at patient-reported outcomes in the KATHERINE study that really showed there was no overall global deterioration in health in the T-DM1 [trastuzumab emtansine] arm relative to the trastuzumab arm. While there were some small changes in the T-DM1 [trastuzumab emtansine] arm with particular symptoms that were slightly worse than with trastuzumab, global health was maintained across both arms.

This is particularly important because we are giving 14 cycles of additional therapy. While T-DM1 [trastuzumab emtansine] is an antibody drug conjugate, technically it is chemotherapy. With prolonged exposure to treatment, we really want to make sure we’re able to maintain patients’ quality of life. In general, I think this shows that T-DM1 [trastuzumab emtansine] is generally well tolerated.

There were some patients who did need to discontinue T-DM1 [trastuzumab emtansine] early. In KATHERINE, approximately 18% of patients did not complete all 14 cycles of therapy. I think this was for a myriad of different reasons. There wasn’t 1 particular toxicity driving discontinuation. But generally speaking, T-DM1 [trastuzumab emtansine] has been very well tolerated. Again, the patient-reported outcomes show very good preservation in global health.

Adjuvant T-DM1 Therapy for Early-Stage HER2+ Breast Cancer

 The APHINITY trial was a randomized phase III adjuvant study that predominantly looked at patients with stage II and stage III disease, although it did include some patients with stage I 

 [human epidermal growth factor receptor 2]–positive cancer and randomized them to receive chemotherapy with trastuzumab, with or without pertuzumab.

We have previously seen data from this trial, where there was 45 months of follow-up. At a median follow-up of about 4 years, there was a 1.7% absolute difference between the 2 arms, favoring the pertuzumab arm, and the hazard ratio was around 0.81. At that time, we had seen that the benefit of adding pertuzumab was restricted to those patients with node-positive disease as well as hormone receptor–negative disease. There was really no benefit seen in node-negative and hormone receptor–positive patients.

However, at San Antonio [Breast Cancer Symposium], they did present the updated analysis that now had 74 months of follow-up. At this point in time, the difference did seem larger than what we had seen at the 4-year follow-up time point. At 74 months of follow-up, we’re seeing about a 2.8% absolute difference between the 2 arms. We are seeing benefit that is not restricted to hormone receptor–negative patients. Now, we also see a very nice benefit within those patients with hormone receptor–positive disease. There was an absolute difference of about 3% in that group of patients, with a hazard ratio of about 0.73. Whereas in the hormone receptor–negative cohort, the hazard ratio was about 0.83. We’re seeing with longer follow-up that the hormone receptor–positive patients also gained benefit from pertuzumab.

This may be related to the timing at which hormone receptor–positive patients recur, which tends to be a little later. Now with longer follow-up, you’re seeing that benefit come out. However, the benefit was still restricted to node-positive patients. There was no benefit seen in the node-negative patients. At this point, no overall survival benefit was seen, although there was a trend toward a little benefit in the pertuzumab arm.

I think we still need to see longer follow-up from the study, to see if the survival benefit would come out. But at this time, again, what we’re seeing is a benefit from pertuzumab in node-positive patients, and we’re seeing a benefit regardless of hormone receptor status.

In my general practice, I have been adding pertuzumab for all my 

-positive patients who are getting preoperative therapy, because I am giving preoperative therapy to all my stage II and stage III patients. In this setting I would add pertuzumab to chemotherapy and trastuzumab.

With longer follow-up from APHINITY, we have not seen any new safety signals emerge. They had continued to follow patients for potential cardiac toxicity, and the rates of cardiac toxicity were almost identical to what had been previously reported at the 4-year mark. It continues to add very minimal toxicity relative to trastuzumab alone.

The APHINITY Trial in Early-Stage HER2+ Breast Cancer

 The KRISTINE study looked to explore whether T-DM1 [trastuzumab emtansine] and pertuzumab would be as good as the TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] regimen. In this trial, patients were randomized to receive 6 cycles of TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] or 6 cycles of T-DM1 [trastuzumab emtansine] and pertuzumab, and then go to surgery. At the time of surgery, we did see that TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] was superior to T-DM1 [trastuzumab emtansine] and pertuzumab. We saw higher rates of pathologic complete response in patients getting TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] relative to T-DM1 [trastuzumab emtansine] and pertuzumab.

However, I think it’s important to note, there was less toxicity in the T-DM1 [trastuzumab emtansine]–pertuzumab arm. Interestingly, this study also followed patients after surgery. Patients on TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] continue on trastuzumab and pertuzumab, whereas patients who got T-DM1 [trastuzumab emtansine] and pertuzumab continued on that treatment. Then investigators looked at long-term outcomes. One interesting thing that was seen was that there were more patients on the T-DM1 [trastuzumab emtansine] and pertuzumab who experienced local-regional recurrences prior to going to surgery.

Interestingly, when you dug down into those patients who experienced local-regional recurrence, you can see that about two-thirds of those patients actually had 

 [human epidermal growth factor receptor 2] 2+ tumors. This suggested that patients with 

 heterogeneity are experiencing local-regional progression on T-DM1 [trastuzumab emtansine] and pertuzumab, which probably contributed to the differences we were seeing in terms of pathologic complete response rates between the 2 arms.

When you actually follow those patients long-term and look at invasive disease-free survival, the invasive disease-free survival is similar in the 2 arms, with the curves overlapping. Event-free survival was certainly better with TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] compared with T-DM1 [trastuzumab emtansine] and pertuzumab, but the invasive disease-free survival is actually quite similar. What this really tells me is that a patient without a heterogeneous 

-positive tumor may do just as well with T-DM1 [trastuzumab emtansine] and pertuzumab as they would do with TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab], regarding long-term outcomes.

This is quite important, because T-DM1 [trastuzumab emtansine] and pertuzumab is so much better tolerated than TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab]. If we could identify those patients who do not have HER2 heterogeneity, these are potentially the patients who could omit standard chemotherapy and do just as well with T-DM1 [trastuzumab emtansine] and pertuzumab.

There was also the PREDIX HER2 trial that compared THP [docetaxel, trastuzumab, pertuzumab] to T-DM1 [trastuzumab emtansine], and found very similar rates of pathologic complete response—45% and 47% in each arm. Again, this suggested that T-DM1 [trastuzumab emtansine] performs quite similarly to chemotherapy and trastuzumab and pertuzumab.

The THP [docetaxel, trastuzumab, pertuzumab] regimen is probably not quite as good as the TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] regimen that was looked at in the KRISTINE trial. In KRISTINE, we did see a higher pathologic complete response compared with T-DM1 [trastuzumab emtansine]. But I think the study just suggests that T-DM1 [trastuzumab emtansine]–based therapy can be very effective, even in early 

-positive disease. We really need to move forward trying to best select those patients who don’t have heterogeneous 

 positivity, because those patients may potentially be able to de-escalate from a standard chemotherapy regimen to T-DM1 [trastuzumab emtansine] in the future.

Sara M. Tolaney, MD, MPH | Authors

Articles

Combination Strategy May Play Role in Treatment of HR+ Metastatic Breast Cancer

Novel Approaches for Stage I HER2+ Breast Cancer

The ExteNET Study & Management of HER2+ Breast Cancer

Adjuvant T-DM1 Therapy for Early-Stage HER2+ Breast Cancer

The APHINITY Trial in Early-Stage HER2+ Breast Cancer

Neoadjuvant T-DM1 in Early-Stage HER2+ Breast Cancer