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Department of Medicine
Medical Director, Breast Oncology
Samuel Oschin Comprehensive Cancer Center
Cedars-Sinai Medical Center
Los Angeles, California
Heather McArthur, MD, MPH, has disclosed that she has received funds for contracted research from Bristol-Myers Squibb and Merck and consulting fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Genomic Health, Merck, Pfizer, and Puma.
During the last 20 years or so, there have been considerable advances in the treatment of HER2‑positive breast cancer, including expanded options for patients with metastatic disease. Our evolving understanding of the role of the HER2 protein as the ongoing oncogenic driver of this breast cancer subtype has been key to the development of new findings and new drugs that ultimately have improved outcomes for these patients. The phase III CLEOPATRA and EMILIA trials established docetaxel, trastuzumab, and pertuzumab (THP) followed by trastuzumab emtansine (T-DM1) as the standard-of-care approach for HER2-positive metastatic breast cancer (MBC) in the first-line and second-line settings, respectively.
Despite these advances, HER2-positive MBC will ultimately progress, and to date, we have not had clear standard treatment options for patients who progressed following treatment with THP and T-DM1. However, following the reports of the single-arm phase II DESTINY-Breast01 trial of trastuzumab deruxtecan and the phase II HER2CLIMB trial of tucatinib at the 2019 San Antonio Breast Cancer Symposium (SABCS) in December 2019, we now have exciting new options for the treatment of HER2-positive MBC after THP and T-DM1.
Trastuzumab Deruxtecan, a HER2-Targeted Antibody–Drug Conjugate
Trastuzumab deruxtecan (DS8201a) is a new antibody–drug conjugate comprised of trastuzumab, a cleavable drug linker, and a novel cytotoxic payload, the topoisomerase‑I inhibitor deruxtecan. This antibody–drug conjugate is particularly exciting because it has the potential to overcome recurrence and resistance arising from tumor heterogeneity via a bystander effect: Not only does it deliver the cytotoxic drug to HER2-positive and HER2 low–expressing tumor cells, but its payload, once released, can easily cross the cell membrane to kill adjacent HER2-normal cells. This could address one of the challenges of treating HER2-positive disease, namely, tumor heterogeneity and the potential for recurrence due to adjacent HER2-normal or HER2 low–expressing tumor cells.
Trastuzumab deruxtecan was granted accelerated approval on December 20, 2019, by the United States FDA for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received at least 2 previous lines of anti–HER2-based regimens for metastatic disease based on the results from the single-arm phase II DESTINY-Breast01 trial. All 249 patients had previously received trastuzumab and T-DM1, and two thirds had previously received pertuzumab. The results with trastuzumab deruxtecan in this heavily pretreated population were outstanding—better than any we have seen for any HER2-targeted agent to date in this space. The ORR was 61%, with 6% achieving a CR; the disease control rate was 97%; and the clinical benefit rate at 6 months was 76%. Even more remarkable was the durability of the responses, with a 14.8-month median duration of response and a median PFS of more than 16.4 months. These results are particularly impressive given that patients in this trial had a median of 6 previous lines of therapy for metastatic disease (range: 2-27).
However, it is notable that these benefits were tempered somewhat by the toxicity of the drug. Notably, any-grade interstitial lung disease (ILD) was observed in 14% of patients. Fortunately, it was primarily grade 1 and grade 2 in severity, but 4 deaths were ultimately attributed to this toxicity. Thus, early detection of ILD will be critically important as we bring these drugs into our clinic as outlined below. Other common toxicities were mostly low-grade gastrointestinal and hematologic toxicities, which appear to be easily managed with supportive care.
Tucatinib, a HER2-Targeted TKI
Tucatinib is a novel, oral, HER2-targeted tyrosine kinase inhibitor (TKI) with enhanced HER2 affinity that generally spares inhibition of EGFR. This selectivity has been shown to cause fewer or less severe EGFR inhibition–related toxicities, such as diarrhea and rash, as compared with other HER2-targeted TKIs. Furthermore, the small size of HER2-targeted TKIs, including tucatinib, and their improved ability to penetrate the blood–brain barrier as compared with current standard-of-care antibody-based therapies for HER2-positive MBC has singled out this group of agents as a promising option for the prevention and treatment of brain metastases that, as we will see, was substantiated for tucatinib in the phase II HER2CLIMB trial reported at SABCS 2019. This is important because approximately 30% to 50% of patients with advanced HER2-positive breast cancer will develop brain and/or central nervous system metastases.
In HER2CLIMB, trastuzumab and capecitabine with either tucatinib or placebo was evaluated in 612 patients with previously treated HER2-positive MBC. Median PFS was 7.8 months in the trastuzumab arm vs 5.6 months in the control arm, with an HR of 0.54, corresponding to a staggering 46% reduction in the risk of progression. At 1 year, 33% of patients in the tucatinib arm and 12% in the control arm remained progression free. Furthermore, median OS was improved with tucatinib: 21.9 months in the tucatinib arm vs 17.4 months in the control arm, with an HR of 0.66, corresponding to a 34% reduction in the risk of death.
What was especially remarkable about the HER2CLIMB study is that it included 94 patients with known brain metastases, and these patients did extremely well on tucatinib. At 1 year, 25% of patients with brain metastases remained progression free in the tucatinib arm whereas none of the patients with brain metastases in the control arm remained progression free. Patients with HER2‑positive MBC and brain metastases represent an important area of unmet need, and this is an unprecedented clinical innovation in that specific clinical setting.
The most common adverse events in both arms of HER2CLIMB were diarrhea and palmar–plantar erythrodysesthesia syndrome, both of which could be ascribed as known adverse events of capecitabine that clinicians are familiar with managing.
Based on these results, tucatinib in combination with trastuzumab and capecitabine was granted breakthrough therapy designation by the FDA on December 18, 2019, for the treatment of patients with HER2-positive MBC, including those with brain metastases, after trastuzumab, pertuzumab, and T-DM1 and has now been submitted for FDA approval, which I anticipate it will receive in the coming months.
How I Plan to Use These New and Exciting HER2-Targeted Therapies in My Clinical Practice
In my practice, I would consider either agent for third-line treatment of patients with HER2-positive MBC after trastuzumab, pertuzumab, and T-DM1. I would use trastuzumab deruxtecan first in patients who do not have brain metastases, followed by tucatinib with capecitabine and trastuzumab when brain metastases occur, or as fourth‑line treatment upon progression on trastuzumab deruxtecan. For patients with brain metastases at the time of progression after both THP and T-DM1, I would reverse the order and administer the tucatinib combination regimen first and use trastuzumab deruxtecan in the fourth-line setting. However, because a taxane with trastuzumab and pertuzumab are currently approved for patients with HER2-positive early stage breast cancer based on the phase II NeoSphere study, the phase II TRYPHAENA study, and the phase III APHINITY study, and because T-DM1 is approved for patients with residual disease after neoadjuvant HER2-directed therapy based on the KATHERINE study, these novel agents may be increasingly used earlier in the course of disease when metastases occur.
As previously mentioned, we will need to be watchful for ILD in patients receiving trastuzumab deruxtecan so we can identify it early and manage it aggressively. Although the optimal surveillance and diagnosis strategy for trastuzumab deruxtecan–mediated ILD detection has not yet been elucidated, I anticipate that CT imaging in response to early, suspicious symptoms will be critically important, as will be early administration of steroids for those patients with radiographic or clinical suggestions of ILD. Similar to other drugs with a risk for this type of adverse event—for example, pneumonitis with immune checkpoint inhibitor therapy—education of oncologists, our multidisciplinary partners, particularly those in the emergency department, and patients will be critical. Because trastuzumab deruxtecan was only recently approved, a formal surveillance strategy has yet to be developed, but I anticipate that wallet cards that can be carried by patients could be a useful education tool in coming months and that supportive clinical guidance on monitoring and management will be forthcoming.
In light of the impressive clinical activity observed for both trastuzumab deruxtecan and tucatinib in combination with trastuzumab and capecitabine in the third-line setting for metastatic disease, there is interest in exploring these agents earlier in the course of disease. In the phase III DESTINY-Breast03 trial, trastuzumab deruxtecan is being compared head-to-head with T-DM1 in the second-line metastatic setting after progression on trastuzumab with taxane chemotherapy. I also expect that trastuzumab deruxtecan will be explored as adjuvant therapy, given the recent KATHERINE phase III data in support of T-DM1 over trastuzumab for patients with residual invasive breast cancer in the adjuvant setting. Tucatinib is being assessed in the neoadjuvant setting in the randomized phase II I‑SPY 2 adaptive platform trial, which is evaluating the addition of a variety of novel agents to standard chemotherapy regimens as neoadjuvant therapy for early or regional stage IV breast cancer.
Tucatinib in combination with trastuzumab and capecitabine is also being evaluated in a phase II trial for patients with HER2-positive MBC and leptomeningeal disease (planned N = 30). Leptomeningeal disease is an incredibly difficult disease to treat with a very poor prognosis and a space where we have no innovation whatsoever, so I look forward to seeing these results.
Finally, trastuzumab deruxtecan is being explored for HER2-low MBC in the phase III DESTINY-Breast04 trial, which is randomizing patients with previously treated, unresectable or metastatic breast cancer and low HER2 expression (defined as IHC 2+/ISH negative or IHC 1+ and ISH negative or untested) to trastuzumab or to physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel; planned N = 540).
It is an incredibly exciting time to be embarking on a new era of improved outcomes for our patients with HER2-positive MBC, now having 2 such efficacious strategies after progression on THP and T-DM1, a space where we have been lacking a standard of care. It is particularly exciting to see innovation in the treatment of brain metastases, which is a really challenging manifestation of breast cancer to treat. These are not small steps—these are huge leaps for the treatment of HER2‑positive breast cancer. Whenever we see such strong innovation in the palliative setting for metastatic disease, we try to apply those same strategies to earlier disease with curative intent. It is hoped that, with thoughtful application of these drugs earlier in the disease course, we will ultimately improve cure rates for patients with HER2‑positive breast cancer.
What are your thoughts or questions about the use of trastuzumab deruxtecan or tucatinib for patients with HER2-positive MBC and disease progression on standard-of-care HER-targeted therapies?
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