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Associate Professor of Medicine
Director, Breast Oncology Program
Division of Hematology-Oncology
Department of Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California
Sara Hurvitz, MD, FACP, has disclosed that she has received funds for research support (including editorial support) from Ambrx, Bayer, Daiichi-Sankyo, Dignitana, Genentech/Roche, GlaxoSmithKline, Immunomedics, Lilly, MacroGenics, Novartis, OBI Pharma, Pfizer, Pieris, Puma, Radius, Sanofi, and Seattle Genetics.
At the 2019 San Antonio Breast Cancer Symposium (SABCS), results from multiple key studies were presented that promise to further expand options for patients with HER2-positive disease. In this commentary, I discuss the HER2-targeted TKI tucatinib, the data that led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd), and the investigational HER2 antibody margetuximab. I also touch on the use of T-DM1 vs paclitaxel/trastuzumab in lower‑risk, stage I HER2-positive EBC and updated data from the APHINITY trial with neoadjuvant dual HER2-targeted therapy.
An important study presented at the 2019 SABCS was HER2CLIMB, a phase II study evaluating the addition of tucatinib to trastuzumab and capecitabine in HER2-positive metastatic breast cancer (MBC). Tucatinib is a novel HER2‑targeted TKI that is uniquely selective for HER2 compared with other HER2‑directed TKIs. The relative sparing of EGFR inhibition may result in less toxicity, such as diarrhea and skin adverse events (AEs). Early data with this agent showed quite promising response rates in heavily pretreated patients with HER2-positive MBC including patients with brain metastases.
The phase II HER2CLIMB study was aimed at confirming these early results. This was a randomized, placebo‑controlled trial comparing tucatinib plus capecitabine and trastuzumab vs placebo plus capecitabine and trastuzumab in patients with previously treated HER2-positive MBC (N = 612). The study met its primary endpoint of PFS: In the overall population, the median PFS was 7.8 months with the addition of tucatinib vs 5.6 months with placebo (HR: 0.54; P < .00001), corresponding to a 46% reduction in the risk of progression. In the subpopulation with brain metastases at baseline, the median PFS with tucatinib was 7.6 months vs 5.4 months with no tucatinib (HR: 0.48; P < .00001).
At the same time, results also showed an OS improvement, which is extraordinary at the first report of a study (in this case, after the first 410 patients were randomized to the tucatinib arm). To date, median OS is 21.9 months with the addition of tucatinib vs 17.4 months with trastuzumab plus capecitabine alone (HR: 0.66; P = .0048), corresponding to a 34% reduction in the risk of death.
The AE profile appears to be fairly tolerable with diarrhea as the most common AE in both arms. All-grade diarrhea was 81% with tucatinib (vs 53% with placebo), and grade 3 or worse diarrhea was seen in 13% with tucatinib (vs 9% with placebo). Diarrhea is not unexpected when pairing HER2‑targeted therapies with capecitabine. Hand–foot syndrome was also common in both arms, at 63% with tucatinib vs 53% with placebo. This is an expected AE of capecitabine; differences in rates of hand–foot syndrome between arms are likely due in part to longer duration of exposure in the tucatinib arm.
Overall, 41% of patients in the tucatinib arm had an objective response to treatment. Patients with HER2‑positive MBC and central nervous system (CNS) metastases represent a particularly challenging patient population to treat. In this study, approximately one half of the patients had baseline CNS metastases, so the fact that they also experienced improved PFS is pretty phenomenal.
Personally, I hope that this agent becomes available in 2020, as I believe many patients will be eager to have access to it, particularly those patients with brain metastases. I also am looking forward to participating in and seeing the results of HER2CLIMB‑02, which is a phase III study looking at T-DM1 plus tucatinib vs T-DM1 and placebo in patients with unresectable locally advanced or metastatic HER2-positive breast cancer who have had prior treatment with a taxane and trastuzumab (planned N = 460).
Another study that made a big splash at SABCS 2019 was DESTINY‑Breast01, a single-arm phase II clinical trial of the novel ADC T-DXd in relapsed/refractory advanced HER2-positive breast cancer. T-DXd pairs a HER2‑targeted monoclonal antibody similar to trastuzumab with a novel cytotoxic payload, a topoisomerase‑I inhibitor known as deruxtecan. Topoisomerase‑I inhibitors are typically not used in breast cancer, which means that the patients enrolled on this study were generally naive to this class of medication. This ADC is unique in that it has a high drug:antibody ratio of 8:1, meaning on average 8 molecules of the cytotoxic payload are attached to each antibody. By comparison, the ADC T-DM1 has a drug:antibody ratio of approximately 3.5:1 using the tubulin inhibitor emtansine.
In DESTINY-Breast01, 249 patients with heavily pretreated, relapsed, HER2-positive, unresectable or metastatic breast cancer received T-DXd every 3 weeks. Patients enrolled on this trial had a median of 6 previous lines of therapy, and all patients had received trastuzumab and T-DM1. This was a 2-part study, with doses tested from 5.4-7.4 mg/kg in Part 1 and then an expansion in part 2 to evaluate 5.4 mg/kg (n = 184). In the 184 patients treated at 5.4 mg/kg, the ORR was just over 60%, with 11 patients (6%) achieving a CR. The disease control rate was 97% and the median duration of response was nearly 15 months. Moreover, the median PFS was longer than 16 months (and more than 18 months in the 24 patients with brain metastases). Seeing this level of activity is extraordinary given that patients on this trial were so heavily pretreated (median of 6 prior lines of therapy for metastatic disease, range: 2-27). Median OS had not been reached at 11 months of follow-up.
The most common AEs were low-grade gastrointestinal and hematologic toxicities. The most concerning AE with T-DXd is pneumonitis or interstitial lung disease (ILD). A total of 25 patients developed ILD (13.6%), and 4 patients died as a result of this complication. It is thus imperative that clinicians monitor patients carefully and educate their patients about this potential side effect that can be life threatening. It will also be important to conduct future studies to better understand the pathophysiology of this clinically relevant AE.
Based on these data, the FDA granted accelerated approval for T-DXd in December 2019 for patients with HER2-positive MBC after ≥ 2 previous lines of HER2-targeted therapy for MBC. With this new approval, I will consider T-DXd for many patients with heavily pretreated HER2-positive disease. I am also eager to see the results of several ongoing randomized clinical trials that are evaluating this agent in earlier line settings.
If both tucatinib and T-DXd are approved, we do not have data to guide how to sequence these agents. In reality, most patients with pretreated HER2-positive MBC will ultimately receive both of these agents at some point. The CNS activity associated with tucatinib and its safety profile will likely make physicians more comfortable using it in the third‑line setting and possibly in earlier‑line settings to mitigate brain metastases. T-DXd has extraordinary activity, and clinicians who have a patient in need of an objective response due to symptomatic visceral metastases, for example, might turn to it before turning to tucatinib.
Results from the phase II ATEMPT study that evaluated adjuvant T-DM1 in patients with lower‑risk, stage I HER2‑positive early breast cancer (EBC) were also presented at SABCS 2019. In this study, 497 patients with stage I, HER2-positive EBC with N0 or N1mic disease were randomized 3 to 1 to either single-agent T-DM1 or the APT regimen of paclitaxel for 12 weeks concurrently with trastuzumab followed by maintenance trastuzumab to complete 1 year. The coprimary endpoints were 3-year disease-free survival (DFS) with T-DM1 (not to be compared against paclitaxel/trastuzumab) and a comparison of clinically relevant AEs between regimens.
Results showed an impressive the 3-year DFS rate of 97.7% in the T-DM1 arm. The study was not designed to compare DFS of T-DM1 against the standard paclitaxel/trastuzumab arm. That said, the 3-year DFS with T-DM1 was numerically higher than that achieved with paclitaxel/trastuzumab (92.8%). The number of distant recurrences was the same in each arm (N=2). Somewhat surprisingly, the incidence of clinically relevant AEs was not lower with T-DM1. Patients who received paclitaxel/trastuzumab had higher rates of grade ≥ 2 neuropathy (24% vs 11% with T-DM1) and neutropenia (13% vs 3%) while patients treated with T-DM1 had more thrombocytopenia (11% with T-DM1 vs 1% with paclitaxel/trastuzumab) and liver abnormalities. In addition, there was a higher discontinuation rate with T-DM1 (17% for any AE and 9% due to protocol-mandated AE).
In my opinion, T-DM1 can be considered as adjuvant therapy for select patients with small, lower‑risk HER2-positive EBC. I am looking forward to seeing longer follow-up from this clinical trial, as the event rate was quite low in both arms at this reporting. In my own practice, I would be tempted to use this for a lower risk patient who might not be able to tolerate cytotoxic chemotherapy, though it is not yet clear whether insurance will cover T-DM1 for this indication; it may be necessary for guidelines to list it as an appropriate medication before we are able to provide this to patients.
APHINITY is a randomized phase III trial comparing 1 year of trastuzumab plus pertuzumab vs trastuzumab plus placebo as adjuvant therapy for patients with HER2-positive EBC and no prior anticancer therapy. This is a very large study (N = 4805), which showed improvement in its primary endpoint of invasive DFS several years ago but did not suggest an OS benefit at that interim analysis. Pertuzumab was subsequently granted regular FDA approval in combination with chemotherapy and trastuzumab as adjuvant therapy for patients with HER2-positive EBC at high risk of recurrence.
At SABCS 2019, the second interim OS analysis from APHINITY was reported as were updated invasive DFS results. These updated data convincingly show improved invasive DFS with the use of pertuzumab. That improvement, however, appears restricted to patients with node‑positive disease: Overall, at 6 years, 90.6% of patients in the pertuzumab arm had not progressed vs 87.8% with placebo, only a 2.8% difference. By contrast, the rates were 87.9% and 83.4% in node-positive disease, a 4.5% difference in favor of pertuzumab. No meaningful differences in terms of benefit were seen based on hormone receptor status. Given these longer follow-up data, in my opinion, adjuvant pertuzumab should be restricted to those patients who have node involvement. At this time, there remains no significant OS benefit to pertuzumab, but long‑term follow-up may change that story.
At SABCS 2019, Rugo and colleagues presented updated OS results from SOPHIA, a phase III trial evaluating the HER2‑targeted monoclonal antibody margetuximab in HER2-positive MBC. Certain Fc receptor genotypes are associated with a weaker binding of the Fc receptor of one’s immune effector cells (NK, dendritic cells) to the Fc portion of an antibody. Patients with these genotypes are theorized to generate a less robust anti-tumor immune response to antibody therapy. Margetuximab is an antibody very similar to trastuzumab but with the Fc portion engineered to bind more tightly to Fc receptors, thus theoretically leading to enhanced antibody-dependent cellular cytotoxicity. This novel agent has increased affinity for the activating Fcγ receptor RIIIA (CD16A) and decreased affinity for inhibitory Fcγ receptor RIIB (CD32B) compared with trastuzumab.
In this study, the efficacy and safety of margetuximab plus chemotherapy was compared with trastuzumab plus chemotherapy in 536 patients with advanced or metastatic breast cancer who had received ≥ 2 previous lines of anti-HER2 therapy. SOPHIA was originally presented at ASCO in 2019, and now interim OS and updated PFS data are available (primary endpoints). To date, results have not shown a significant OS improvement, with median OS in both arms of approximately 20 months. Of note, there was a nonsignificant trend toward an OS improvement in patients who were CD16A-185 F carriers. In terms of PFS, again, most of the benefit from margetuximab appears to be in those patients who are F carriers. The safety profile of margetuximab is notably quite good with only a slightly increased risk of infusion related reactions compared to trastuzumab.
This study provides proof of principle, demonstrating efficacy especially in those patients who have an immune system that is less responsive to antibody-based therapy. Having said that, the absolute benefit of margetuximab compared to trastuzumab is relatively small in this study with relatively heavily pretreated patients. In my opinion, these results are not yet practice changing, but with longer term follow-up, if a significant OS benefit emerges, margetuximab could become a good option for select patients (F-carriers). It may be that this drug will be more effective in a less heavily pretreated patient populationI am interested in seeing studies evaluate this therapy in an earlier line setting and in combination with immunotherapy.
More SABCS 2019 Conference Coverage on the CCO Web Site!
These are just a few of the interesting and important abstracts selected by breast cancer experts from SABCS in 2019. Downloadable slideset summaries of these studies and more are available on our Web site, along with additional ClinicalThought commentaries.
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