Top Picks From SABCS 2024: Part 1

Among the high-quality abstract presentations at the 2024 San Antonio Breast Cancer Symposium (SABCS), a few always stand out as particularly meritorious. Each year, The ASCO Post asks our Deputy Editor, breast cancer specialist Jame Abraham, MD, FACP, to give us his picks. Dr. Abraham is Chairman of the Department of Hematology and Medical Oncology at Cleveland Clinic and Professor of Medicine at Lerner College of Medicine. 

Jame Abraham, MD, FACP

AFT-38 PATINA Trial: Palbociclib as Maintenance Therapy

Late-breaking results of the phase III AFT-38 PATINA trial showed the value of adding the CDK4/6 inhibitor palbociclib to maintenance therapy in patients with hormone receptor–positive, HER2-positive metastatic breast cancer.¹ The combination yielded a statistically significant and clinically meaningful 15-month improvement in progression-free survival. Median progression-free survival was 44 months with palbociclib plus endocrine therapy and the monoclonal antibody trastuzumab or trastuzumab plus the monoclonal antibody pertuzumab vs 29 months with anti-HER2 therapy plus endocrine therapy alone (hazard ratio [HR] = 0.74; P = .0074).

PATINA enrolled 518 patients with hormone receptor–positive, HER2-positive metastatic breast cancer and no prior therapy in the advanced setting. After induction with anti-HER2 therapy and chemotherapy, patients without disease progression were randomly assigned to receive anti-HER2 therapy and endocrine therapy (fulvestrant or an aromatase inhibitor) with or without palbociclib. Almost all patients received dual anti-HER2 therapy and an aromatase inhibitor.

At a median follow-up of 53 months, the addition of palbociclib significantly improved progression-free survival by 26% compared with the control arm; benefit was seen in all stratification subsets. The objective response rate was 29.2% in the palbociclib arm vs 22.2% in the control arm, and the clinical benefit rate was 89% vs 81.3%, respectively. Though immature, median overall survival was not reached in the palbociclib arm and was 77 months in the control arm. The 5-year survival rate was 74.3% vs 69.8%, respectively.

Dr. Abraham: PATINA is a very important study. It is the first phase III trial to show the addition of the CDK4/6 inhibitor palbociclib to anti-HER2 and endocrine therapy is beneficial as first-line maintenance therapy in hormone receptor–positive, HER2-positive metastatic breast cancer. The strong scientific rationale—the potential synergy of these agents in combination—is reinforced by PATINA’s findings. The median progression-free survival of 4 years extends the time to chemotherapy by almost 1.5 years. It shows the durability and tolerability of this regimen and suggests that palbociclib may be overcoming resistance to endocrine and anti-HER2 therapy. The data support the potential of this maintenance approach to slow disease progression over the long term without impeding quality of life (as chemotherapy does), which is especially relevant in this more or less chronic disease population.

I think this is a potentially practice-changing study, but there are some caveats. A number of trials are looking at the role of other agents in the first-line setting, such as the antibody-drug conjugate fam-trastuzumab deruxtecan-mxki (T-DXd), which is being compared with the combination of docetaxel, trastuzumab, and pertuzumab. HER-2-targeted tyrosine kinase inhibitors such as tucatinib are also being evaluated, especially for maintenance. We will need to see how these agents all play out, but for now, the findings can be clinically applied in this population.

COMET: Some Patients With DCIS May Avoid Surgery

In the COMET trial, active monitoring in patients with low-risk ductal carcinoma in situ (DCIS) proved to be noninferior to guideline-concordant management (ie, surgery with or without radiation therapy).² After 2 years of follow-up, 19 of 473 patients assigned to active monitoring and 27 of 484 patients in the guideline-concordant care arm were diagnosed with invasive ipsilateral breast cancer, yielding rates of 4.2% and 5.9%, respectively, and meeting the standard for noninferiority. No significant differences were seen in subgroups.

COMET enrolled nearly 1,000 patients (aged 40 or older) with a new diagnosis of low-risk DCIS (ie, grade 1 or 2, hormone receptor–positive, HER2-negative disease with no evidence of invasive breast cancer). Active monitoring consisted of yearly bilateral mammograms interspersed with mammograms every 6 months for the DCIS-affected breast for 5 years. Surgery was recommended upon signs of progression to invasive cancer. Guideline-concordant management entailed surgery with or without radiation therapy. Radiotherapy was delivered to 7.4% of the guideline-concordant group and 26.6% of the monitored group. Lumpectomy was performed in 13.2% and 48.2%, respectively, and mastectomy was performed in 3.7% and 5.5%, respectively. All patients could have endocrine therapy if desired.

Almost half the patients assigned to guideline-concordant care declined surgery, so the investigators performed a separate per-protocol analysis of 673 patients who adhered to their assigned treatment. In that analysis, the 2-year rate of invasive ipsilateral breast cancer was 3.1% with active monitoring and 8.7% with guideline-concordant care, for an absolute difference of 5.6% favoring active monitoring. Among patients who received endocrine therapy, cancer developed in 3.2% of the monitored group compared with 7.2% of the guideline-concordant group. Health-related quality of life, anxiety, depression, worries about DCIS, and symptom trajectories were comparable in both arms of the study over 2 years of follow-up.

Dr. Abraham: For almost all patients with newly diagnosed DCIS, the standard treatment is surgery, often combined with radiation in patients who had lumpectomy and endocrine therapy for estrogen receptor–positive DCIS. But since nearly 80% of DCIS do not progress to invasive cancer, many such patients are overtreated. COMET is the first large randomized clinical trial in the United States to evaluate different management strategies for DCIS, including omission of surgery. The finding—that active monitoring does not compromise outcomes—is reassuring and serves as a first step in helping physicians and patients make informed decisions. It is important to realize that the results do not apply to all patients with DCIS—only to those meeting the low-risk criteria used to select patients for the trial. The results suggest that in the short term, active monitoring is a reasonable approach to managing low-risk DCIS; however, in my opinion, they do not change the practice recommendations until proven durable in longer-term analyses.

EMBER: Imlunestrant Improves Progression-Free Survival  

In the EMBER-3 trial, the next-generation oral selective estrogen receptor degrader (SERD) imlunestrant significantly reduced the risk of disease progression or death over standard endocrine therapy in patients with estrogen receptor–positive, HER2-negative advanced breast cancer.^3,4 As monotherapy, compared mostly with fulvestrant, imlunestrant reduced this risk by 38% in patients with ESR1 mutations—but not in the overall study population. The combination regimen of imlunestrant plus the CDK4/6 inhibitor abemaciclib, however, improved progression-free survival by 43% vs imlunestrant alone in all patients (regardless of ESR1 mutation status).

The 874 patients were randomly assigned to one of three groups:

• Group A: imlunestrant at 400 mg/d
• Group B: standard-of-care endocrine therapy (fulvestrant or exemestane)
• Group C: imlunestrant plus abemaciclib (vs imlunestrant alone).

Progression-free survival was compared between groups A and B in patients with ESR1 mutations and between groups A and B in all patients. Group C analyzed imlunestrant only if one of the imlunestrant vs standard-of-care endocrine therapy endpoints was significant. Median progression-free survival outcomes follow:

• Imlunestrant monotherapy vs standard endocrine therapy in ESR1-mutant: 5.5 vs 3.8 months (HR = 0.62; P < .001)
• Imlunestrant monotherapy vs standard endocrine therapy in the overall population (all-comers): 5.6 vs 5.5 months (HR = 0.87; P = .12)
• Imlunestrant plus abemaciclib vs standard endocrine therapy in ESR1-mutant disease: 11.1 vs 5.5 months (HR = 0.53)
• Imlunestrant plus abemaciclib vs standard endocrine therapy in the overall population (all-comers): 9.4 vs 5.5 months (HR = 0.57; P < .001).

The benefit of the combination of imlunestrant plus abemaclib was observed regardless of the presence of ESR1 mutations. For both the monotherapy and combination-therapy analyses, consistent benefits were observed regardless of the presence or absence of visceral metastases, prior CDK4/6 inhibitor treatment, or PI3K pathway mutation status. The safety data raised no concerns.

Dr. Abraham: Combining a SERD with a CDK4/6 inhibitor can be beneficial when metastatic breast cancer progresses on an aromatase inhibitor regimen, but the most commonly used SERD, fulvestrant, requires monthly injections, and the bioavailability of the fulvestrant injection may not be predictable. The novel orally available SERDs are expected to improve the patient experience, achieve higher drug levels, and be more effective against ESR1 mutations. EMBER showed a robust benefit for imlunestrant, especially when given with abemaciclib, and this was consistent across clinically relevant subgroups: patients who had received a CDK4/6 inhibitor previously, had tumors with or without an ESR1 mutation, or had a PI3K mutation. I believe the data for this highly effective oral SERD are practice-changing.

See a future issue of The ASCO Post for Part 2 of this article.

DISCLOSURE: Dr. Abraham has received research funding from Daiichi Sankyo/AstraZeneca, Pfizer, and Seattle Genetics and served as a consultant to ThinkBio.Ai.

REFERENCES

1. Metzger O, Mandrekar S, DeMichele A, et al: AFT-38 PATINA: A randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy vs anti-HER2 therapy + endocrine therapy after induction treatment for hormone receptor–positive/HER2-positive metastatic breast cancer. 2024 San Antonio Breast Cancer Symposium. Abstract P2-03-20. Presented December 10, 2024.
2. Hwang ES: Early oncologic outcomes following active monitoring or surgery (± radiation) for low risk DCIS: The Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET) study (AFT-25). 2024 San Antonio Breast Cancer Symposium. Abstract GS2-05. Presented December 12, 2024.
3. Jhaveri K: Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, for patients with ER+ HER2– advanced breast cancer, pretreated with endocrine therapy: Results of the phase 3 EMBER-3 trial. 2024 San Antonio Breast Cancer Symposium. Abstract GS01-1. Presented December 11, 2024.
4. Jhaveri KL, Neven P, Casalnuovo ML, et al: Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. December 11, 2024 (early release online).
5. Reimer T: No axillary surgery versus axillary sentinel lymph node biopsy in patients with early invasive breast cancer and breast-conserving surgery: Final primary results of the Intergroup-Sentinel-Mamma (INSEMA) trial. 2024 San Antonio Breast Cancer Symposium. Abstract GS2-07. Presented December 12, 2024.
6. Loibl S: Primary results of the randomised phase III trial comparing first-line ET plus palbociclib vs standard mono-chemotherapy in women with high risk HER2–/HR+ metastatic breast cancer and indication for chemotherapy: PADMA study. 2024 San Antonio Breast Cancer Symposium. Abstract LB1-03. Presented December 11, 2024.
7. Turner N: Circulating tumor DNA surveillance in ZEST, a randomized, phase 3, double-blind study of niraparib or placebo in patients with triple-negative breast cancer or HER2+ BRCA-mutated breast cancer with molecular residual disease after definitive therapy. 2024 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 13, 2024.
8. Meattini I: Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast cancer (EUROPA): Preplanned interim analysis of of a randomized phase 3 trial. 2024 San Antonio Breast Cancer Symposium. Abstract GS2-01. Presented December 12, 2024.