Updates From Selected Clinical Trials in Breast Cancer

‘Best of SABCS’ From Jame Abraham, MD, FACP

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Jame Abraham, MD, FACP

Jame Abraham, MD, FACP

Each year, following the San Antonio Breast Cancer Symposium (SABCS), The ASCO Post asks Jame Abraham, MD, FACP, to offer his picks of the most important and most clinically relevant research presented at this meeting. The following are summaries of studies that caught Dr. Abraham’s attention from the 2020 SABCS, followed by his comments.

Dr. Abraham is Chair of the Hematology/Medical Oncology Department at the Cleveland Clinic and Professor of Medicine at Cleveland Clinic College of Medicine.

RxPONDER: Adding Chemotherapy for Node-Positive Disease

The SWOG S1007 RxPONDER trial evaluated the benefit of adding chemotherapy to endocrine therapy in 5,015 pre- and postmenopausal women with hormone receptor–positive, HER2-negative, node-positive breast cancer (one to three involved nodes) and a 21-gene recurrence score of up to 25.1 It found no benefit for chemotherapy in postmenopausal women, but a 46% reduction in the risk for 5-year invasive disease–free survival in premenopausal women, as reported by Kevin Kalinsky, MD.

Kevin Kalinsky, MD

Kevin Kalinsky, MD

The findings echo somewhat those of TAILORx, which sought to identify subsets of patients with node-negative disease who might fare well with endocrine therapy alone. It has been unclear whether its results could be extrapolated to a node-positive population.

In RxPONDER, at a median follow-up of 5.1 years, no association was shown between chemotherapy benefit and recurrence score between 0 and 25 for the entire population (P = .30). Further analysis by menopausal status found a 5.2% absolute benefit for chemotherapy in premenopausal women, although none in their postmenopausal counterparts.

The 5-year invasive disease–free survival was 91.6% with endocrine therapy alone vs 91.9% with endocrine therapy and chemotherapy (hazard ratio [HR] = .097; P = .82) in postmenopausal women and 89.0% vs 94.2%, respectively (HR = 0.54; P = .0004), in premenopausal women. Despite limited follow-up, a 1.3% absolute benefit in overall survival was also seen in the premenopausal subgroup (HR = 0.47; P = .032), though not in the postmenopausal group.

Dr. Abraham: RxPONDER is the first large, randomized trial seeking to determine whether some women with hormone receptor–positive, HER2-negative, node-positive breast cancer can also safely avoid chemotherapy. The findings clearly indicated no benefit to adding chemotherapy to endocrine therapy in postmenopausal women with one to three nodes. This suggests that node positivity, although an important prognostic marker, is not a predictive marker of chemotherapy sensitivity. The findings also point to a subset of postmenopausal patients who may safely avoid chemotherapy.

In premenopausal patients, however, a different result was obtained, and the reasons for this are not entirely clear. Most premenopausal patients received tamoxifen, whereas today, the standard approach would be ovarian suppression plus either tamoxifen or an aromatase inhibitor, both of which have proved to be superior to tamoxifen alone. Since adjuvant chemotherapy may cause ovarian suppression, the patients in the study actually underwent ovarian suppression post-tamoxifen.

Thus, the question is whether the benefit in the premenopausal group was due to the endocrine effect of the chemotherapy, ie, chemotherapy-induced amenorrhea. Future clinical trials in this setting will answer that question.

KEYNOTE-355: Pembrolizumab Plus Chemotherapy

In the front-line setting, pembrolizumab plus chemotherapy conveyed a benefit across key subgroups of advanced triple-negative breast cancer, in the phase III KEYNOTE-355 trial of 847 patients presented by Hope S. Rugo, MD.2

Hope S. Rugo, MD

Hope S. Rugo, MD

The combination provided a statistically significant and clinically meaningful improvement in progression-free survival vs chemotherapy alone in patients with expression of PD-L1 with a combined positive score (CPS) ≥ 10 (HR = 0.65) and a CPS ≥ 1 (HR = 0.74). Of note, this was true regardless of the chemotherapy partner: weekly nab-paclitaxel, weekly paclitaxel, or gemcitabine/carboplatin.

Anecdotally, the analysis of pembrolizumab plus paclitaxel vs paclitaxel alone resulted in the greatest benefit in the CPS ≥ 10 group (HR = 0.33), the CPS ≥ 1 group (HR = 0.46), and in the intent-to-treat population (HR = 0.57), as compared with other chemotherapy partners. However, the study was not powered to compare efficacy across the regimens.

Response rates and disease control rates rose along with increasing CPS level. PD-L1 enrichment was also correlated with greater differences in median duration of response, reaching 19.3 months with pembrolizumab vs 7.3 months with chemotherapy in the population with CPS ≥ 10.

Dr. Abraham: KEYNOTE-355 was the basis for the approval of pembrolizumab in the first-line setting for advanced triple-negative breast cancer with a CPS ≥ 10. This update essentially confirms our enthusiasm for adding immunotherapy to chemotherapy in this patient group.

With Dr. Rugo’s report, we have more granular information on the chemotherapy backbones, showing a benefit across regimens in patients with a CPS ≥ 1, and most pronounced in patients with a CPS ≥ 10. By PD-L1 enrichment, we saw some remarkable differences, with the CPS ≥ 10 subgroup having a median duration of response of 19.3 months with pembrolizumab vs 7.3 months with placebo.

The fact that pembrolizumab worked well with all regimens is especially reassuring, since IMpassion130 evaluated the checkpoint inhibitor atezolizumab only with nab-paclitaxel. We also have patients who cannot receive taxanes, and it is good to know we can use gemcitabine/carboplatin. We now await overall survival data.

Adjuvant Therapy With CDK4/6 Inhibitors

In two phase III trials in patients with early-stage hormone receptor–positive HER2-negative breast cancer, divergent results were reported for two different inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) in the adjuvant setting.

The primary outcome analysis of monarchE continued to show a significant benefit for abemaciclib, which reduced the risk of invasive disease recurrence by 28.7% vs endocrine therapy alone (HR = 0.713; two-sided P = .0009).3 At a median follow-up of 19 months, the findings reflect an additional 3.6 months of follow-up and 67 more events among the population of 5,637 patients, as well as outcomes in 2,498 patients with high-Ki67 tumors. Significant improvements in the abemaciclib arm were also observed in distant relapse–free survival and in invasive recurrence or death in the high-Ki67 subset (HR = 0.691; P = .0111), reported Priya Rastogi, MD (the first author was Joyce O’Shaughnessy, MD).

Priya Rastogi, MD

Priya Rastogi, MD

Joyce O’Shaughnessy, MD

Joyce O’Shaughnessy, MD

Meanwhile, the first results of the phase III Penelope-B trial found no benefit for adjuvant palbociclib,4 building upon the negative results from the previous PALLAS adjuvant trial.5 Penelope-B evaluated the benefit of 1 year of palbociclib plus endocrine therapy in 1,250 patients deemed to be at high risk for recurrence after neoadjuvant therapy. In contrast to monarchE, the approach failed to improve invasive disease–free survival over endocrine therapy alone (HR = 0.93; P = .525), with no subgroup benefiting, even patients with high Ki67 levels, according to Sibylle Loibl, MD, PhD.

Sibylle Loibl, MD, PhD

Sibylle Loibl, MD, PhD

Dr. Abraham: The results of monarchE are very encouraging, especially in subgroups with high tumor proliferation, who had a risk reduction of 31% with abemaciclib. But remember, the follow-up is rather short for estrogen receptor–positive disease, where disease can recur past 10 years. Given that CDK4/6 inhibitors are largely cytostatic rather than cytocidal (blocking cell proliferation rather than killing cells), the question remains: Will the invasive disease–free survival curves come together when the drug is stopped? If the results continue to be positive over time, monarchE could be practice-changing in this high-risk patient population.

It is interesting and provocative that a benefit of 4% was seen with abemaciclib at 2 years—greater than with palbociclib—but the curves later came together. If the study had been stopped then, it would have been positive. It is important to continue to follow monarchE patients to see if the benefit similarly declines over time.

The key question is why two drugs with comparable efficacy in the metastatic setting did not offer the same benefits in the adjuvant setting. Potential explanations pertain to different definitions of high risk and different eligibility requirements, the short duration of palbociclib treatment, the greater proportion of luminal A tumors in Penelope-B, and the possibility that abemaciclib may just be a more effective CDK4/6 inhibitor (though hazard ratios were similar in the metastatic trials).

Thus, the results of the NATALEE trial, which is evaluating 3 years of adjuvant ribociclib, will be very informative.

MONALEESA-7 Updated Analysis

In the metastatic setting, the addition of ribociclib to endocrine therapy continued to significantly improve overall survival and delay subsequent chemotherapy compared with endocrine therapy alone in pre- and perimenopausal patients with hormone receptor–positive, HER2-negative breast cancer. Additionally, this benefit was observed irrespective of the endocrine partner, according to an updated analysis of the phase III MONALEESA-7 trial.6

MONALEESA-7 randomly assigned 672 previously treated patients to ribociclib at 600 mg daily or placebo in combination with goserelin plus a nonsteroidal aromatase inhibitor or tamoxifen. At a median follow-up of 53.5 months, median overall survival was 58.7 months with the combination vs 48.0 months with endocrine therapy alone (HR = 0.763).

By choice of endocrine agent, median overall survival was 58.7 months with a nonsteroidal aromatase inhibitor plus ribociclib vs 47.7 months with endocrine therapy alone (HR = 0.798); for those receiving tamoxifen plus ribociclib, median survival was not reached, whereas it was 49.3 months with placebo (HR = 0.705), Debu Tripathy, MD, reported.

Debu Tripathy, MD

Debu Tripathy, MD

Other endpoints were also highly favorable for the combination, including the median time to chemotherapy (HR = 0.694), median chemotherapy-free survival (HR = 0.666), and median progression-free survival after first disease progression (HR = 0.683). Benefits were observed for all intrinsic subtypes except for basal-like, which had a poor prognosis in both arms.

Dr. Abraham: This exploratory analysis confirms the continued benefit of ribociclib in the first-line metastatic setting in pre- or perimenopausal patients with hormone receptor–positive, HER2-negative disease, regardless of endocrine partner. After 53.5 months of follow-up, the median overall survival of 58.7 months in the ribociclib arm is the longest we have seen among the phase III CDK4/6 inhibitor trials in this setting. The use of ribociclib also extended the time off chemotherapy, which is important in terms of quality of life for our patients, who often live many years.

Results from an exploratory subgroup analysis showed a consistent benefit regardless of endocrine partner, but these subgroups are small, the confidence intervals relatively wide, and these comparisons lack statistical power; therefore, they should be interpreted with caution. These findings offer continued evidence that we could consider ribociclib for our pre- and perimenopausal women with hormone receptor–positive metastatic breast cancer.

ADAPT HR+/HER2– Trial: Adjuvant Endocrine Therapy

Some patients with early breast cancer of the luminal subtype considered to be at intermediate or high risk (up to three positive nodes) may effectively be treated with neoadjuvant and adjuvant endocrine therapies alone, without chemotherapy, according to the results of the ADAPT HR+/HER2– trial.7 The study also showed the utility of the Ki67 assay in evaluating response to preoperative endocrine therapy.

ADAPT HR+/HER2– is a prospective phase II/III umbrella trial of women who are candidates for adjuvant chemotherapy by conventional prognostic criteria. Women undergo 3 weeks of endocrine therapy prior to surgery; based on their response, they are assigned to adjuvant endocrine therapy alone or to chemotherapy followed by adjuvant endocrine therapy.

Nadia Harbeck, MD, reported results for the 2,290 women assigned to endocrine therapy alone. They comprised two groups: recurrence score between 0 and 11 and recurrence score between 12 and 25 plus a response to endocrine therapy (post-treatment Ki67 index ≤ 10%). Outcomes were similar between these two groups. The 5-year invasive disease–free survival was 93.9% in the first group and 92.6% in the second, with similarly high rates of distant disease–free survival, 96.3% vs 95.6%, respectively, and overall survival, 98.0% vs 97.3%, respectively.

Nadia Harbeck, MD

Nadia Harbeck, MD

The 5-year distant disease–free survival did not differ by age or nodal subgroup, with the exception of one subgroup. The outcome was worse (75.9%) among patients with a recurrence score between 12 and 25 who responded to endocrine therapy and had three involved nodes. According to Dr. Harbeck, these particular patients are not candidates for endocrine therapy alone.

Dr. Abraham: Neoadjuvant endocrine therapy is not widely used in the United States. Hence, many patients with strongly hormone receptor–positive tumors with large tumors tend to undergo neoadjuvant chemotherapy with minimal benefit. The ADAPT study suggests that, irrespective of age, the following patients may be treated with endocrine therapy alone: patients with up to three involved lymph nodes and a recurrence score of between 0 and 11; and patients with up to two nodes, a recurrence score of between 12 and 25, and endocrine response after short preoperative endocrine therapy.

They also confirmed that dynamic Ki67 response testing is feasible in routine practice and complements baseline risk assessment to refine patient selection for therapy de-escalation and escalation.

BYLieve: Benefit of Alpelisib and Fulvestrant

The nonrandomized phase II BYLieve trial evaluated the combination of alpelisib (a PI3K inhibitor with inhibitory activity predominantly against PI3Kα) and fulvestrant in the treatment of patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor. As previously reported, the primary endpoint, 6-month progression-free survival, was met, with more than 50% of the 121 patients alive without disease progression at 6 months, and median progression-free survival of 7.3 months, as previously reported.8

At this meeting, Dr. Rugo reported the results for patients from Cohort B (n = 126), who received alpelisib plus letrozole following treatment with a CDK4/6 inhibitor and fulvestrant.9 The primary endpoint was again met in this cohort, with 46.1% of patients alive without disease progression at 6 months; median progression-free survival was 5.7 months. In patients with measurable disease, the response rate was 17.8%, and the clinical benefit rate was 31.7%. Reduction in tumor size was comparable to that in patients from Cohort A who received alpelisib plus fulvestrant after disease progression on a prior CDK4/6 inhibitor and an aromatase inhibitor.

The most common reasons for dose adjustments or interruptions were hyperglycemia (29%), diarrhea (10%), and rash (10%). The most frequent grade ≥ 3 adverse event was hyperglycemia (25%).

Dr. Abraham: In SOLAR-1, a treatment benefit with alpelisib was observed regardless of prior CDK4/6 inhibition, although the population of CDK4/6-exposed patients accounted for just 6% of those enrolled.10 BYLieve was designed to address the lack of prior CDK4/6 inhibitor treatment in the majority of patients who were enrolled in SOLAR-1. It showed the efficacy of alpelisib in a larger population and in patients who received a higher relative dose intensity.

Dr. Rugo’s report focused on Cohort B: most patients had experienced disease progression on an aromatase inhibitor, suggesting this population was endocrine-resistant. The combination of alpelisib and fulvestrant led to a median progression-free survival of 5.7 months, which exceeds the 3.6-month median progression-free survival in the real-world Flatiron Health database, with which Dr. Rugo compared the BYLieve outcomes. This is a relatively long remission for patients who are endocrine-resistant and are being re-treated with an aromatase inhibitor. We do continue to see some toxicity, though this is improving as clinicians understand more about how to treat hyperglycemia and manage rash.

After the standard first line of endocrine therapy and a CDK4/6 inhibitor, patients with a PIK3CA mutation might benefit from alpelisib combined with endocrine therapy. The companion endocrine therapy could either be an aromatase inhibitor or fulvestrant, depending on prior exposure in the CDK4/6 inhibitor–based line.

SOLAR-1 Update

SOLAR-1 evaluated alpelisib with fulvestrant in 572 chemotherapy-naive patients who experienced disease progression on an aromatase inhibitor, including 341 with PIK3CA mutations, which alpelisib targets.10 Mutations were detected in tumor tissue using polymerase chain reaction–based assays. An exploratory analysis presented by Eva Ciruelos, MD, PhD, assessed the clinical outcomes of patients with PIK3CA alterations as detected in plasma circulating tumor DNA (ctDNA) retrospectively through next--generation sequencing.11

Eva Ciruelos, MD, PhD

Eva Ciruelos, MD, PhD

As previously reported, in patients with mutations, alpelisib/fulvestrant significantly improved progression-free survival (HR = 0.65; P = .00065) and numerically improved overall survival, though the difference was not significant (HR = 0.75; 95% confidence interval = 0.52–1.08).10

The biomarker analysis found frequent discordance between tissue and ctDNA identification of PIK3CA alterations.11 Of note, clinical benefit was seen with alpelisib plus fulvestrant, regardless of the source of material (ctDNA or tissue). For example, for patients with PIK3CA alterations in tumor tissue, but not by ctDNA, median progression-free survival with alpelisib/fulvestrant was 22.1 months vs 10.1 months with placebo. Interestingly, however, in the small group of patients with alterations not detectable by polymerase chain reaction, no treatment benefit was shown.The investigators suggested that clinicians perform reflex testing with tissue samples when no PIK3CA alterations are detected by ctDNA.

Dr. Abraham: This analysis examined outcomes for patients with PIK3CA alterations detected in ctDNA. Findings were consistent with the overall data already presented for SOLAR-1, but the analysis gives us additional insight into how we look at PIK3CA alterations in tumor tissue by next-generation sequencing, polymerase chain reaction, and ctDNA.

The analysis showed the clinical benefit of alpelisib and fulvestrant in patients whose PIK3CA alterations were detected by next-generation sequencing in plasma ctDNA. For patients with an alteration detected by next-generation sequencing—but not by polymerase chain reaction—there was, however, no benefit. Of note, this was a small subgroup, and therefore we cannot draw conclusions. The findings were consistent whether patients had single or multiple alterations and whether alterations were in axon 9 or 20.

Some patients without alterations in ctDNA had alterations in tissue PIK3CA (possibly having to do with low allele frequency or variable DNA shedding rates). Therefore, if patients have a blood test first and that test does not reveal a mutation, it is important to test the tumor tissue, if possible, to select patients for this regimen. The most recent tissue sample should be used, since alterations can develop over time, although archival tumor tissue is relatively reliable. 

DISCLOSURE: Dr. Abraham has received institutional research funding from Pfizer, Daiichi Sankyo, Merck, and Seattle Genetics.


1. Kalinsky K, Barlow WE, Meric-Bernstam F, et al: First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy ± chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence score ≤ 25: SWOG S1007 (RxPonder). 2020 San Antonio Breast Cancer Symposium. Abstract GS3-00. Presented December 10, 2020.

2. Rugo HS, Schmid P, Cescon DW, et al: Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. 2020 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 10, 2020.

3. O’Shaughnessy JA, Johnston S, Harbeck N, et al: Primary outcome analysis of invasive disease-free survival for monarchE. 2020 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 9, 2020.

4. Loibl S, Marme F, Martin M, et al: Phase III study of palbociclib combined with endocrine therapy in patients with hormone-receptor-positive, HER2-negative primary breast cancer and high relapse risk after neoadjuvant chemotherapy. 2020 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 9, 2020.

5. BusinessWire: Pfizer provides update on phase 3 PALLAS trial of Ibrance (palbociclib) plus endocrine therapy in HR+, HER2– early breast cancer. May 29, 2020. Available at Accessed January 28, 2021.

6. Tripathy D, Im SA, Colleoni M, et al: Updated overall survival results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2– advanced breast cancer treated with endocrine therapy ± ribociclib. 2020 San Antonio Breast Cancer Symposium. Abstract PD2-04. Presented December 9, 2020.

7. Harbeck N, Gluz O, Kuemmel S, et al: Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), recurrence score <26 and Ki67 response after preoperative endocrine therapy. 2020 San Antonio Breast Cancer Symposium. Abstract GS4-04. Presented December 11, 2020.

8. Rugo HS, Lerebours F, Ciruelos E, et al: Alpelisib + fulvestrant in patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer previously treated with cyclin-dependent kinase 4/6 inhibitor + aromatase inhibitor: BYLieve study results. ASCO20 Virtual Scientific Program. Abstract 1006.

9. Rugo HS, Lerebours F, Juric D, et al: Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive, human epidermal growth factor receptor-2-negative advanced breast cancer previously treated with a cyclin-dependent kinase 4/6 inhibitor + fulvestrant. 2020 San Antonio Breast Cancer Symposium. Abstract PD2-07. Presented December 9, 2020.

10. André F, Ciruelos EM, Juric D, et al: Overall survival results from SOLAR-1, a phase III study of alpelisib plus fulvestrant for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. ESMO Virtual Congress 2020. Abstract LBA18. Presented September 19, 2020.

11. Ciruelos EM, Loibl S, Mayer IA, et al: Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing. 2020 San Antonio Breast Cancer Symposium. Abstract PD2-06. Presented December 9, 2020.