The Latest Findings on Major Breast Cancer Trials

Industry investigators were on hand at the 2023 San Antonio Breast Cancer Symposium (SABCS) to report the latest findings on a range of cancer treatments and update several phase 3 trials.

Medscape Medical News presents a roundup of five studies that may be of particular interest to oncologists.

NATALEE (ribociclib)

The final disease-free survival outcomes from the NATALEE trial of ribociclib were reported at SABCS.

NATALEE randomized 1748 patients with early-stage II and III hormone receptor–positive, HER2-negative breast cancer to an adjuvant aromatase inhibitor (letrozole or anastrozole) for 60 months or more and 2549 patients to the aromatase inhibitor regimen plus 3 years of the ribociclib, a CDK 4/6 inhibitor.

In an interim analysis, the ribociclib-aromatase inhibitor combination demonstrated a significant invasive disease–free survival benefit over an aromatase inhibitor alone (hazard ratio [HR], 0.748; P = .0014).

At 3 years, the final analysis confirmed the benefit of adding ribociclib. The 3-year invasive disease–free survival was 90.7% with ribociclib add-on vs 87.6% without (HR, 0.749).

Three-year recurrence free survival (92.1% vs 89.1%) and overall survival (97% vs 96.1%; HR, 0.892) also favored those in the ribociclib group, but the overall survival results were not statistically significant.

Patients received 400 mg of ribociclib for 3 weeks each month, with 1 week off — a lower dose than the 600 mg approved for metastatic disease. This 400-mg dose led to lower adverse event rates. Still, 44.3% of patients developed grade 3 or higher neutropenia in the ribociclib arm, among other issues.

An audience member at the study presentation took issue with results in stage II patients. “You’d have to treat more than 50 patients for one patient to receive an IDFS [invasive disease–free survival] benefit.” At 3 years, invasive disease–free survival was 94.2% with ribociclib vs 92.6% without — a difference of 1.6%.

With a course of treatment costing about $500,000, “we are going to pay more than 25 million dollars per recurrence prevented. I really don’t think that’s sustainable for our healthcare system,” he said.

“How are we going to do a better job at identifying which patients should receive this expensive and potentially toxic treatment and which patients should not?” he asked.

This is “an important question,” said presenter and lead investigator Gabriel Hortobagyi, MD, a breast medical oncologist at MD Anderson Cancer Center, Houston, Texas. It is “not only true for this group of drugs but for all of the drugs we use for breast cancer.” We treat all patients to benefit essentially about 2%-10%. “That is a serious deficiency,” he said.

Part of the issue, Hortobagyi added, is that the effort to identify predictive biomarkers has not been fruitful to date. “Even our best biomarkers,” estrogen receptor (ER) and HER2 status, “are very weak” and useful only when negative.

However, he noted, that doesn’t mean we should stop looking for predictive biomarkers. In fact, “I think we should redouble our efforts,” Hortobagyi said.

KATHERINE (T-DM1)

The final invasive disease–free survival results from the phase 3 KATHERINE trial confirmed the benefit of adjuvant ado-trastuzumab emtansine (T-DM1) over standard trastuzumab in residual, invasive HER2-positive breast cancer following surgery.

The study randomized 1486 patients equally to either T-DM1 or trastuzumab after surgery.

The primary analysis, conducted in 2018, found patients receiving T-DM1 demonstrated a significant improvement in 3-year invasive disease–free survival (88.3%) vs those receiving trastuzumab (77%), but the overall survival data remained immature.

The final analysis, presented earlier this month at SABCS, reported 7-year invasive disease–free survival of 80.8% with T-DM1 vs 67.1% with trastuzumab. Overall survival rates at 7 years were 89.1% with T-DM1 vs 84.4% with trastuzumab, with the benefits from T-DM1 holding across subgroups.

Grade 3 or higher adverse events occurred in 0.4% of patients in each arm, with no new safety issues emerging and cardiac toxicity remaining rare in both arms.

An audience member asked why T-DM1 benefits were significant for patients with an immunohistochemistry score of 3+, indicating HER2-positive status (HR, 0.47) but not for those with a score of 2+, indicating borderline HER2-positive status (HR, 0.84; 95% CI, 0.56-1.25).

“This is a very important question,” said lead investigator and presenter Sibylle Loibl, MD, PhD, a breast cancer specialist at the University of Frankfurt, Frankfurt, Germany. “We need to investigate if this is a real effect and [if it can] be explained.”

APHINITY (pertuzumab)

The APHINITY trial found that patients with early HER2-positive breast cancer derive a benefit from adding pertuzumab to adjuvant trastuzumab plus chemotherapy regardless of ER and HER2 expression levels.

The exploratory analysis randomized 4804 patients equally to either pertuzumab or placebo with adjuvant trastuzumab and chemotherapy, which was most often anthracycline-based. Median follow-up was 73.6 months. Patients were categorized by HER2 status — a fluorescence in situ hybridization (FISH) ratio between 2 and 5 indicated HER2-low disease, while a FISH ratio of 5 or higher indicated HER2-high disease.

Patients with HER2-low, ER-positive disease demonstrated the greatest benefit, with a 30% reduction in the risk for disease recurrence, while patients with HER2-high, ER-negative disease experienced the smallest benefit (HR, 0.85; 95% CI, 0.59-1.25).

The fact that patients with HER2-low, ER-positive disease benefited the most is “surprising” given contrary results in other studies, said study discussant Jo Chien, MD, a breast cancer specialist at the University of California, San Francisco.

And, Chien added, “although these results are hypothesis generating,” for now “nodal status is the only factor that predicts pertuzumab benefit in early breast cancer for HER2-positive disease.”

KEYNOTE-522 (pembrolizumab)

Updated results from KEYNOTE-522 continued to show the benefit of neoadjuvant/adjuvant pembrolizumab over placebo for early-stage triple-negative breast cancer.

The trial randomized 1174 patients 2:1 to neoadjuvant pembrolizumab or placebo for eight chemotherapy cycles. After surgery, patients continued with an additional nine cycles of adjuvant pembrolizumab or placebo.

Overall, the 5-year event-free survival was 81.3% with pembrolizumab vs 72.3% with placebo. Among patients with a pathologic complete response (pCR) to neoadjuvant therapy, the 5-year event-free survival was higher (92.2% with pembrolizumab vs 88.2% with placebo), and without a pCR, 5-year event-free survival was lower (62.6% with pembrolizumab vs 52.3%).

The benefit of adding pembrolizumab held across programmed death-ligand 1 expression, nodal status, disease stage, and other subgroups.

The investigation will continue to determine how important pembrolizumab is after surgery and to see if the duration can be shorter than the 6-plus months in KEYNOTE-522.

EMBER (imlunestrant)

The EMBER study tested imlunestrant, a selective ER degrader being developed by Lilly, alongside abemaciclib plus or minus an aromatase inhibitor in patients with ER-positive, HER2-negative advanced breast cancer.

In phase 1 testing, 114 patients received imlunestrant monotherapy in doses ranging from 200 mg to over 600 mg, while 85 patients received imlunestrant 400-800 mg with abemaciclib plus or minus an aromatase inhibitor.

The combination therapy improved objective response rates, which ranged from 8% with imlunestrant alone to 62% with the addition of abemaciclib and an aromatase inhibitor. Similarly, 12-month progression-free survival ranged from 20.7% with imlunestrant monotherapy to 80% with abemaciclib and aromatase inhibitor add-on.

The most common grade 3 adverse events with imlunestrant monotherapy were fatigue (4%), nausea (2%), and diarrhea (2%).

Phase 3 testing is underway.

The trials were funded by the companies that make the various agents, and investigators reported ties to them and other companies. Chien disclosed grants/research support from Puma, SeaGen, Merck, Amgen, and Pfizer.

Alexander M. Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]