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New Insights in Breast Cancer: Independent Conference Coverage of SABCS 2020

Sara Hurvitz, MD, FACP
Joyce O'Shaughnessy, MD
Released: February 19, 2021

Additional EBC Studies

ExteNET: Neratinib vs Placebo After Adjuvant Trastuzumab in HER2+ EBC

Sara Hurvitz, MD, FACP:
The ExteNET trial was a randomized, open‑label phase III study that evaluated extended use of neratinib vs placebo for one year after completion of adjuvant trastuzumab in patients with HER2-positive EBC.[16,17] As previously reported, a significant iDFS benefit was associated with neratinib, especially in high‑risk patients with tumor hormone receptor expression.[18]

ExteNET: OS (ITT Population)

Sara Hurvitz, MD, FACP:
There was no OS benefit with the use of neratinib in the intention-to-treat population. In patients with hormone receptor–positive tumors, a nonsignificant 1.5% absolute benefit in OS was seen at the 8‑year time point.

ExteNET: Summary of Descriptive Analyses

Sara Hurvitz, MD, FACP:
An exploratory analysis was conducted suggesting an interesting OS benefit in highly select patients who had hormone receptor‑positive tumors, had residual disease after neoadjuvant therapy, and had completed adjuvant trastuzumab within one year of starting neratinib. Although these data show an almost 10% improvement in 8-year OS, it is important to point out that in a 2800‑patient clinical trial only 10% of the patients fell into this category. We should be careful with drawing conclusions from small subset analyses like these.

Also notable was a reduction in the cumulative incidence of central nervous system (CNS) recurrence with neratinib (1.3% vs 1.8% in the intention-to-treat population and 0.7% vs 2.1% within the hormone receptor–positive subgroup who started neratinib within 1 year of completing adjuvant trastuzumab). However, although these data are interesting, one does need to keep in mind that no one in the ExteNET trial was allowed to have received previous pertuzumab or ado-trastuzumab emtansine (T‑DM1), which are the standard-of-care therapies given now to the highest‑risk patients. Therefore, it is not clear what the incremental benefit achieved with neratinib would be if patients had received these agents.

ExteNET: Clinical Implications

Sara Hurvitz, MD, FACP:
In summary, extended adjuvant neratinib does reduce the risk of iDFS events, most clinically meaningfully so in patients with high‑risk, node‑positive, hormone receptor–positive/HER2‑positive breast cancer. It also reduces the chance of CNS metastases. That said, it is associated with a clinically important rate of grade 3/4 diarrhea in a substantial proportion of patients, it does not improve OS in the intention-to-treat population, and its benefits in patients who have received pertuzumab and T‑DM1 are not clear. Decisions regarding the use of this agent should take into consideration a patient’s risk of recurrence, hormone receptor status, comorbidities, other treatments given, and of course, the goals of care.

Joyce O’Shaughnessy, MD:
It is important to point out that with 1 year of neratinib therapy, the curves continue to separate in patients with hormone receptor–positive/HER2‑positive disease, particularly if they were within 1 year of finishing trastuzumab when they started adjuvant neratinib. There was an approximate 2% improvement in OS with neratinib in patients with hormone receptor–positive breast cancer who finished their trastuzumab within 1 year, but in those who had preoperative trastuzumab plus chemotherapy and did not have a pathologic CR, there was this 9% improvement in OS with neratinib. To me, this is very important. There was also a trend toward fewer CNS recurrences with neratinib, a site of metastasis we would expect in this high‑risk patient population.

Regarding the criticism of ExteNET that the patients had not had prior pertuzumab and/or T‑DM1, my response to that is that we see non–cross‑resistance of neratinib in the NALA trial in heavily pretreated patients, including those with previous pertuzumab and T‑DM1—it is still effective in improving PFS and in reducing progression of CNS metastases in those patients.[19] Tyrosine kinase inhibitors are generally non–cross‑resistant with antibody therapy. And patients who have either node-positive disease or large residual tumor burden after preoperative chemotherapy with docetaxel/carboplatin/trastuzumab/pertuzumab have a very high risk of recurrence. For example, in the phase III KATHERINE trial of T-DM1 vs trastuzumab for patients with residual disease after chemotherapy plus HER2-targeted therapy, at 3 years of follow-up, 12% of patients in the T-DM1 group had recurred, and that is a relatively short follow-up.[20] It is logical to predict that recurrence will be higher yet at 5 years. So, we need additional strategies for these patients and when I see a survival advantage, I must offer this to my high‑risk patients who have residual disease in their lymph nodes or considerable disease in their breast after neoadjuvant therapy. There is a great deal of synergy between blocking the HER family pathway with neratinib plus the estrogen receptor; if you give the neratinib with the ET for one year, the survival curves continue to separate for several more years in that high‑risk population, which I find impressive. Thus, I am an advocate for offering everything we can to these high‑risk patients who have a substantial risk of recurrence even after T‑DM1.

I-SPY 2: Neoadjuvant Ladiratuzumab Vedotin vs Paclitaxel in High-Risk HER2- Stage II/III EBC

Sara Hurvitz, MD, FACP:
Ladiratuzumab vedotin is a novel antibody–drug conjugate targeting the LIV-1 zinc transporter and that contains a microtubule poison payload. The adaptively designed multicenter phase II I‑SPY 2 study is evaluating the addition of a variety of novel agents to standard chemotherapy regimens as neoadjuvant therapy. The current analysis evaluated ladiratuzumab vedotin vs paclitaxel as neoadjuvant therapy in patients with high-risk HER2-negative stage II/III EBC (N = 387).[21] Patients who were hormone receptor positive had to have a high-risk molecular profile by MammaPrint. All study patients received 4 cycles of doxorubicin/cyclophosphamide after ladiratuzumab vedotin (4 cycles) or paclitaxel (12 weeks).

I-SPY 2 (Ladiratuzumab Vedotin): Pathologic CR

Sara Hurvitz, MD, FACP:
The study reported similar pathologic CR rates with ladiratuzumab vedotin and paclitaxel in each of the tumor subtypes.

I-SPY 2 (Ladiratuzumab Vedotin): Safety

Sara Hurvitz, MD, FACP:
Higher rates of grade 3/4 neutropenia, transaminase elevation, and hyperglycemia were observed with ladiratuzumab vedotin compared with paclitaxel, but paclitaxel was associated with more grade 3/4 neuropathy.

I-SPY 2 (Ladiratuzumab Vedotin): Clinical Implications

Sara Hurvitz, MD, FACP:
Ladiratuzumab vedotin remains investigational. However, there are ongoing clinical trials being conducted in the metastatic setting with this agent for multiple breast cancer subtypes.

Joyce O’Shaughnessy, MD:
I think where ladiratuzumab vedotin has shown its greatest promise is in the first-line metastatic TNBC population where, in combination with pembrolizumab—here they reported an impressive level of benefit.[22] We will wait to see if that moves forward into a randomized trial in the first line setting.

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