This is our second episode of the Summer 23 season.  You might recall that a few months ago we introduced you to the new series  under the new brand #OMBCLShorts.    As the title implies, these are shorter episodes. Some will be the  outtakes of the amazing interviews that we had done, others brand new shorter interviews. We have so many incredible guests and we want to make sure that you hear what they have to say.

Unlike the  first short that featured Dr. Stephanie Graff in an outtake from an interview that Lynda Weatherby and Victoria Goldberg had done earlier in the season, this short feature with Dr. Erika Hamilton is the brand new material.

A couple of weeks after the 2023 Annual Conference of the American Society of Clinical Oncologists (ASCO), Victoria Goldberg met with Dr Hamilton to get her take on what were the biggest developments in MBC at ASCO this year. 

To her big surprise, Dr. Hamilton thought that the abstract that had stolen the show were the primary results of the Phase 3 NATALEE study ( NCT03701334) presented at ASCO by Dr. Dennis Salmon.

Monarch E, a similar early stage trial that tested abemacyclib was presented by Erika Hamilton at the same conference  Obviously these are early stage trials and their results do not affect us directly, but any positive trial of a drug that is a standard of care for most MBC patients will affect us indirectly and is always worth mentioning. So we talked about them,  the new findings on capecitabine,  and finally discussed a novel HER3-targeted ADC that shows promise. The results of a phase II clinical trial  were presented  by the study’s author Erika Hamilton on June 5th at the 2023 asco conference and they support the use of patritumab deruxtecan as a treatment option for HER2-negative metastatic breast cancer,

On June 12th 2023 just a few days before this conversation. Astro Zeneca issued a press release that announced that based on CAPItello-291 Phase III trial results the FDA accepted and granted priority review to their  first-in-class AKT inhibitor capivasertib  

This was an excellent opportunity to ask Dr.  Hamilton what it meant for us. What she has to say is always  Interesting and informative.    This episode is about 20 minutes long.

Studies discussed in this episode

CDK4/6 inhibitors in Early and Metastatic BC

CDK4/6 inhibitors block cancer cells’ ability to proceed through their growth cell cycle, thereby preventing cancer progression. They were developed as a treatment option in the event breast cancer cells become resistant to endocrine therapy. In 2015, palbociclib (Ibrance®) was the first CDK4/6 inhibitor to get FDA approval specifically for treating advanced hormone receptor (HR)–positive/HER2-negative breast cancer; other CDK4/6 inhibitors ribociclib (Kisqali®) and abemaciclib (Verzenio®) were approved shortly thereafter in 2017. Palbociclib was tested in early disease and those randomized trials showed no benefit. So it's not been approved for early disease. Abemaciclib has been approved, but it focused on the highest-risk patients in early breast cancer.

Researchers presented several clinical trials that may potentially change treatment strategies for both early- and advanced HR-positive/HER2-negative breast cancer—the most common type—in women of all ages.

Phase 3 NATALEE study ( NCT03701334): Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: Primary results

The NATALEE trial was designed to say, “Is this only going to work in the very high-risk patients?” and for that reason included the, stage II and stage III populations, so basically those that would be considered at intermediate risk, not just the highest risk, including node-negative patients

Trial results showed that ribociclib reduced recurrence risk by an additional 25 percent compared to treatment with an aromatase inhibitor alone. Further, the dose of ribociclib used in the study was found to be safe and well-tolerated by participants. These results support the use of ribociclib in this patient population and may soon give doctors an added option in addition to abemaciclib, which is currently being used in early-stage breast cancer. Ongoing studies are assessing the therapy’s overall survival benefit long-term.

Phase 3 Monarch E study ( NCT03155997): Efficacy and safety results by age in monarchE: Adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2-, node-positive, high-risk early breast cancer (EBC)

Almost half of breast cancer diagnoses occur in women older than 65, who often have a higher incidence of comorbidities and an increased risk for toxicities from treatments. Dr. Hamilton reported the efficacy and safety of abemaciclib (Verzenio®) plus hormonal therapy after surgery for early-stage HR-positive/HER2-negative breast cancer broken down by patient age.

The phase 3 monarchE trial showed that abemaciclib added to hormonal therapy reduced the risk of recurrence more than hormonal therapy alone across all ages. In addition, benefit was maintained beyond two years following treatment. But there was one notable difference: Older patients—especially those over 75—had more adverse side effects and tended to discontinue treatment. As Dr. Hamilton reported, results from monarchE can help guide care for older patients, and they suggest that early treatment and frequent surveillance may be key.

Metastatic BC

Phase 2 X7-7 (NCT02595320) Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer

Researchers are seeking new approaches to make the oral chemotherapy agent capecitabine (Xeloda®) more tolerable for patients with breast cancer. Once in the body, capecitabine is broken down into substances that interfere with the production of DNA, RNA, and proteins. While this hinders cancer cells’ growth and is effective for treating breast cancer, patients experience several side effects that impact their quality of life.

The FDA-approved dosing schedule for capecitabine is 14 days on and 7 days off, giving patients little time to recover. The X-7/7 clinical trial challenged this paradigm and tested a novel dosing schedule with seven days on and seven days off capecitabine. This study showed that this strategy was effective; it yielded a significant reduction in side effects while achieving similar overall and progression-free survival rates.

These findings are practice-changing and define a new strategy to ensure that patients receive the benefits of capecitabine therapy without compromising their quality-of-life post-treatment.

Phase 2  Study of HER3-T-DXd, HER3 ADC (NCT04699630) This study is to evaluate safety and efficacy of an antibody drug conjugate U3-1402 in patients with locally advanced or metastatic breast cancer (MBC).

A close relative of HER2, the HER3 protein is a newer target being investigated in breast cancer. Both are cell membrane proteins involved in cell signaling and, in fact, act in concert to promote HER2-driven breast tumor formation. Researchers have developed a HER3-targeting ADC by linking patritumab (which recognizes the HER3 protein) with the toxic drug deruxtecan (DXd) that’s already being used in breast cancer.

The results showed promise for patients with heavily-pretreated estrogen receptor (ER)–positive or triple-negative metastatic breast cancer. Overall, 35 percent of patients responded, and clinical benefit was observed in about 43 percent of participants.

Moreover, HER3-T-DXd had a manageable safety profile and patients responded regardless of their HER3 expression. The trial presented at ASCO is one of three, and investigators anticipate that these studies will support the introduction of HER3-T-DXd into the clinic for people with all types of metastatic breast cancer.

Phase 3 CAPItello-291(NCT04305496): Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer

At ASCO23 Dr.Hope Rugo reported a detailed analysis of side effects patients experienced in this study. Prior results from this trial provided support for the FDA to fast-track the therapy’s approval in January 2023 and grant a priority review in June 2023.

Study investigators concluded that the most common side effects associated with this regiment (capivasertib combined with fulvestrant) occur early in treatment and are generally low-grade and manageable.

Taken together, these results and previous findings from CAPItello-291 provide support for capivasertib’s approval as the first AKT inhibitor for treating breast cancer—an approval that will be especially important for metastatic breast cancer patients.

Meet the Guest of the Episode