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Updates From Additional Clinical Trials in HER2-Positive Breast Cancer


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Jame Abraham, MD

Jame Abraham, MD

Here we present summaries of several additional clinical trials in HER2-positive breast cancer reported over the past year. Jame Abraham, MD, Chair of the Division of Hematology and Oncology at the Taussig Cancer Center, Cleveland Clinic, shared his perspective on several of these trials presented during the 2019 San Antonio Breast Cancer Symposium.

DESTINY-Breast 01

Results in metastatic HER2-positive breast cancer were reported for the novel antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) in heavily pretreated patients in the phase II DESTINY-Breast 01 trial.1 The results reported by Ian E. Krop, MD, PhD, were published simultaneously in The New England Journal of Medicine.2 On December 20, 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to T-DXd for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti–HER2-based regimens in the metastatic setting.

Ian E. Krop, MD, PhD

Ian E. Krop, MD, PhD

T-DXd is an antibody-drug conjugate with the same amino acid sequence as trastuzumab, linked to a payload of topoisomerase 1 inhibitor. With a much higher ratio of cytotoxic drug to antibody (8:1) than T-DM1, it is more potent against cancer cells, and given its greater ability to permeate cell membranes, T-DXd can kill neighboring tumor cells regardless of HER2 expression.

The study included 249 patients whose disease was resistant or refractory to T-DM1. In the heavily pretreated population (median of six prior lines), the objective response rate was 60.9% (95% confidence interval [CI] = 53.4%–68.0%), the disease control rate was 97.3% (95% CI = 93.8%–99.1%), the median duration of response was 14.8 months (95% CI = 13.8–16.9 months), the median progression-free survival was 16.4 months (95% CI = 12.7 months to not evaluable), and the median overall survival was not reached (95% CI = not evaluable). Measures of response were substantially higher than have been seen in other studies in this treatment setting.

Interstitial lung disease, however, was reported in 25 patients (13.6%), 4 of whom died. The investigators will monitor for this adverse event closely in future studies and are developing a management approach. Clinically significant cardiac toxicity was not observed in DESTINY-Breast01. Future phase III studies will compare T-DXd with T-DM1 and with chemotherapy.

Dr. Abraham: The promising data from DESTINY-Breast01 suggest the potential for a new standard of care in previously treated patients with HER2-positive advanced breast cancer. The response rate, clinical benefit rate, and waterfall plot (all but four patients showed tumor shrinkage) are impressive in this heavily pretreated population, especially after T-DM1 treatment. We eagerly await the results of the ongoing phase III DESTINY trials, which are looking at the role of T-DXd in the second-line setting in patients with HER2-positive disease. Studies of this drug in patients with HER2-negative or HER2–low-expressing metastatic breast cancer are also intriguing.

The drug is now approved by the FDA and offers an important treatment option for our patients, so it is important for clinicians to make an early diagnosis of interstitial lung disease and manage it promptly.

Of note, PD-L1 status was not associated with a tumor response in these early cancers—which is different from what is seen in metastatic breast cancer subjected to checkpoint inhibition. The investigators have hypothesized that the tumor biology in early disease may be less responsive to immune therapy. The use of immunotherapy in early breast cancer is still evolving, and there are many unanswered questions.

Phase III ATEMPT Trial

The antibody-drug conjugate T-DM1 failed to show improved safety when compared with paclitaxel plus trastuzumab as adjuvant therapy in patients with stage 1 HER2-positive breast cancer in the phase III ATEMPT trial presented by Sara M. Tolaney, MD, MPH.3

Sara M. Tolaney, MD, MPH

Sara M. Tolaney, MD, MPH

The ATEMPT investigators sought to determine whether T-DM1 would be a less toxic treatment option for patients with stage 1 HER2-positive breast cancer at risk of recurrence compared with paclitaxel/trastuzumab, which is associated with a 93% rate of disease-free survival. In this first report of the use of adjuvant T-DM1 for stage 1 disease, recurrences were few, but the preplanned endpoint of significantly improved safety was not met. The rate of clinically relevant toxicities was similar to, but not better than, that seen with paclitaxel/trastuzumab, and there were some individual differences in adverse events.

Although the study was not designed to compare disease-free survival between the two treatment arms, disease-free survival was 97.7% with T-DM1 and 92.8% with paclitaxel/trastuzumab. Clinically relevant toxicities were reported in 46% of patients in each arm. The only notable differences were a higher incidence of neurotoxicity with paclitaxel/trastuzumab (23% vs 11%) and more toxicity-related early treatment discontinuations with T-DM1 (17% vs 6%).

Dr. Abraham: Given the low event rate seen in this trial, T-DM1 may be considered an alternative treatment approach to paclitaxel/trastuzumab for select patients with stage 1 HER2-positive disease who are concerned about specific side effects and who understand the potential for T-DM1 toxicities. The rate of discontinuation of T-DM1 was high (17%), suggesting low-grade toxicities may be impacting patients’ well-being. It would be good to see a study of a shorter duration of treatment with T-DM1 followed by trastuzumab.

Another concern, however, is the cost of 1 year of T-DM1, which is about twice that of paclitaxel/trastuzumab. This “financial toxicity” is an important factor for some patients when making treatment decisions. The selection of this agent in stage 1 disease should clearly be individualized based on patients’ circumstances and preferences.

Residual Cancer Burden

After neoadjuvant chemotherapy, residual cancer burden can accurately predict disease recurrence and survival across all breast cancer subtypes, according to the findings of a pooled analysis from the I-SPY Clinical Trials Consortium encompassing 5,160 patients.4 The study examined the relationship between the continuous residual cancer burden index and event-free survival as well as distant relapse–free survival for four breast cancer phenotypes.

The residual cancer burden index categorizes patients with breast cancer into four groups (RCB 0–IV) based on the level of residual disease after neoadjuvant therapy and several other factors, as assessed by pathologists. The residual cancer burden calculator is available to all pathologists through an online calculator (www.mdanderson.org/breastcancer_RCB).

Fraser Symmans, MD

Fraser Symmans, MD

A pathologic complete response (RCB 0) was most likely to be achieved by patients with hormone receptor–negative/HER2-positive disease (69%) and least likely, by those with hormone receptor–positive/HER2-negative disease (11%). Pathologic complete response tracked well with long-term outcomes, and the residual cancer burden index values were associated with 5-year and 10-year event-free survival for all subtypes. For example, 5-year event-free survival rates were 80% for patients with triple-negative breast cancer who were RCB I but 28% for those who were RCB III; within the hormone receptor–positive/HER2-positive subtype, the 5-year event-free survival rates were 91% for the RCB-I group and 54% for the RCB-III group. The residual cancer burden index remained independently prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis, according to Fraser Symmans, MD.

Dr. Abraham: In a pooled analysis of I-SPY data, investigators found a generally linear relationship between residual cancer burden index value and log of risk, suggesting the potential to accurately calibrate an individual’s residual cancer burden index score to her prognosis. In the postneoadjuvant setting, being able to stratify patients is incredibly important for affecting outcomes and also for minimizing treatment (and toxicity) for patients who may have some residual disease but whose outlook is very good despite this.

The value of the residual cancer burden index is evident by the fact that, for 10 years, across 22 trial sites, the I-SPY basket trials have used it as a standard for evaluating residual disease. Dr. Symmans has standardized the process for how to evaluate the disease left after neoadjuvant treatment. This is not accomplished by examining one tissue section. It must be examined in a careful, specific way, and pathologists must be committed to using the online calculator and learning this approach. The website offers instructional videos, protocols, illustrations, and diagrams as resources for pathologists. We were told that the calculator receives about 16,000 visits per month, so it is being used. Let’s hope oncologists start asking for it, and even more pathologists start using it

DISCLOSURE: The DESTINY-Breast01 trial was supported by Daiichi Sankyo and AstraZeneca. The ATEMPT trial was funded by Genentech. Dr. Abraham has received institutional research funding from Pfizer, Daiichi Sankyo, Merck, and Seattle Genetics.

REFERENCES

1. Krop IE, Saura C, Yamashita T, et al: [Fam-] trastuzumab deruxtecan in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase II, multicenter, open-label study (DESTINY-Breast01). 2019 San Antonio Breast Cancer Symposium. Abstract GS1-03. Presented December 11, 2019.

2. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020.

3. Tolaney SM, Trippa L, Barry W, et al: TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage 1 HER2-positive breast cancer (ATEMPT). 2019 San Antonio Breast Cancer Symposium. Abstract GS1-05. Presented December 11, 2019.

4. Yau C, van der Noordaa M, Wei J, et al: Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis. 2019 San Antonio Breast Cancer Symposium. Abstract GS5-01. Presented December 13, 2019.


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