The Oncologist

Jacobson, Anne

doi: 10.1093/oncolo/oyac011pmid: 35348782

Standard first-line treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer is endocrine therapy in combination with a cyclin dependent kinase (CDK) 4/6 inhibitor. Resistance to endocrine therapy and disease progression are common, leading to the need for subsequent-line therapy. Moreover, mutations in the PIK3 catalytic subunit alpha (PIK3CA) gene, which occur in approximately 40% of patients with HR-positive, HER2-negative breast cancer, predict worse survival outcomes. The phase II BYLieve trial is the first prospective study to evaluate alpelisib plus endocrine therapy (fulvestrant or letrozole) in patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer who have progressed on or after prior treatment with a CDK4/6 inhibitor.1–5 Patients enrolled in BYLieve (N = 336) were assigned to study cohorts (A-C) based on their most immediate prior treatment history (Table 1). Table 1. BYLieve patient cohorts and treatment assignments Cohort . Immediate prior therapy . Study treatment . A (n = 112) CDK4/6 inhibitor and an aromatase inhibitor Alpelisib 300mg once daily plus fulvestrant 500 mg B (n = 112) CDK4/6 inhibitor and fulvestrant Alpelisib 300mg once daily plus letrozole 2.5 mg C (n = 112) Chemotherapy or endocrine therapy Alpelisib 300mg once daily plus fulvestrant 500 mg Cohort . Immediate prior therapy . Study treatment . A (n = 112) CDK4/6 inhibitor and an aromatase inhibitor Alpelisib 300mg once daily plus fulvestrant 500 mg B (n = 112) CDK4/6 inhibitor and fulvestrant Alpelisib 300mg once daily plus letrozole 2.5 mg C (n = 112) Chemotherapy or endocrine therapy Alpelisib 300mg once daily plus fulvestrant 500 mg Open in new tab Table 1. BYLieve patient cohorts and treatment assignments Cohort . Immediate prior therapy . Study treatment . A (n = 112) CDK4/6 inhibitor and an aromatase inhibitor Alpelisib 300mg once daily plus fulvestrant 500 mg B (n = 112) CDK4/6 inhibitor and fulvestrant Alpelisib 300mg once daily plus letrozole 2.5 mg C (n = 112) Chemotherapy or endocrine therapy Alpelisib 300mg once daily plus fulvestrant 500 mg Cohort . Immediate prior therapy . Study treatment . A (n = 112) CDK4/6 inhibitor and an aromatase inhibitor Alpelisib 300mg once daily plus fulvestrant 500 mg B (n = 112) CDK4/6 inhibitor and fulvestrant Alpelisib 300mg once daily plus letrozole 2.5 mg C (n = 112) Chemotherapy or endocrine therapy Alpelisib 300mg once daily plus fulvestrant 500 mg Open in new tab Multiple updates from the BYLieve trial provide insights on the optimal management of these patients, including the potential role of clinical and genetic biomarkers in selecting treatment plans and predicting response to therapy.1–5 Cohort A Update: Alpelisib Plus Fulvestrant After Prior Therapy with a CDK4/6 Inhibitor and an AI Results from an updated BYLieve Cohort A analysis demonstrate the ongoing benefit of alpelisib plus fulvestrant in patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer whose disease progressed on or after treatment with a CDK4/6 inhibitor plus an aromatase inhibitor.1 With 18 months of follow-up, 22.2% of patients remained free from disease progression or death. The median overall survival was 26.4 months and the median progression-free survival (PFS) was 7.3 months. The overall response rate (ORR) was 19.0%, with 0.8% of patients achieving a complete response and 18.2% achieving a partial response. The median duration of response was 13.8 months. In the analysis of tumor reduction, 70.1% of patients had a reduction in tumor size from baseline that was maintained through the 6-month follow-up assessment. Cohort C Update: Alpelisib Plus Fulvestrant After Prior Chemotherapy or Endocrine Therapy An updated analysis from BYLieve Cohort C examined outcomes among patients whose cancer progressed on or after treatment with an aromatase inhibitor and who received chemotherapy or endocrine therapy as immediate prior treatment.2 Two-thirds of patients (67.5%) received prior treatment with a CDK4/6 inhibitor as well. At the 6-month assessment, 48.7% of patients treated with alpelisib plus fulvestrant were alive without disease progression. The median PFS was 5.6 months. At 6 months, 65.1% of patients experienced a decrease in tumor size from baseline. The ORR was 24.3%. Findings from the BYLieve Cohort C updated analysis support the clinical benefit of alpelisib plus fulvestrant in patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer who were treated primarily in the third-line setting. Clinical Biomarker: Duration of Prior CDK4/6 Inhibitor Therapy Another subgroup analysis examined PFS following treatment with alpelisib plus fulvestrant/letrozole by the duration of prior CDK4/6 inhibitor therapy.3 The median PFS following treatment with alpelisib plus fulvestrant (Cohort A) was 12.0 months for patients who discontinued prior CDK4/6 inhibitor therapy within 6 months, compared with 6.2 months among those who remained on prior therapy for longer than 6 months (HR, 0.51; 95% CI, 0.29-0.89) (Table 2). Table 2. Median progression-free survival by duration of prior CDK4/6 inhibitor therapy Endpoints . ≤6 months . >6 months . HR (95% CI) . Cohort A (n = 26) (n = 94) 0.51 (0.29-0.89)  PFS events 57.7% 79.8%  Median PFS 12.0 months 6.2 months Cohort B (n = 30) (n = 83) 0.72 (0.45-1.18)  PFS events 76.7% 77.1%  Median PFS 5.9 months 5.6 months Endpoints . ≤6 months . >6 months . HR (95% CI) . Cohort A (n = 26) (n = 94) 0.51 (0.29-0.89)  PFS events 57.7% 79.8%  Median PFS 12.0 months 6.2 months Cohort B (n = 30) (n = 83) 0.72 (0.45-1.18)  PFS events 76.7% 77.1%  Median PFS 5.9 months 5.6 months Open in new tab Table 2. Median progression-free survival by duration of prior CDK4/6 inhibitor therapy Endpoints . ≤6 months . >6 months . HR (95% CI) . Cohort A (n = 26) (n = 94) 0.51 (0.29-0.89)  PFS events 57.7% 79.8%  Median PFS 12.0 months 6.2 months Cohort B (n = 30) (n = 83) 0.72 (0.45-1.18)  PFS events 76.7% 77.1%  Median PFS 5.9 months 5.6 months Endpoints . ≤6 months . >6 months . HR (95% CI) . Cohort A (n = 26) (n = 94) 0.51 (0.29-0.89)  PFS events 57.7% 79.8%  Median PFS 12.0 months 6.2 months Cohort B (n = 30) (n = 83) 0.72 (0.45-1.18)  PFS events 76.7% 77.1%  Median PFS 5.9 months 5.6 months Open in new tab In contrast, there was no interaction between PFS following alpelisib plus letrozole and duration of prior CDK4/6 inhibitor therapy (Cohort B). Together, these findings support the use of alpelisib plus endocrine therapy as an immediate next-line option for patients whose disease progresses on or after prior CDK4/6 inhibitor therapy. Genetic Biomarker: ctDNA Fraction Another exploratory biomarker analysis examined potential predictors of treatment benefit among baseline biomarkers in patients in Cohorts A and B of the BYLieve trial.4 The analysis showed that alpelisib in combination with fulvestrant or letrozole is effective regardless of tumor genomic profile. However, there is an association between improved PFS and Low circulating tumor DNA (ctDNA) fraction, defined as <10% or undetectable Low tumor mutation burden (TMB), defined as <10 mutations/Mb Absence of amplifications in chromosome 8 and/or 11. In Cohort C, lower ctDNA fraction significantly predicted better PFS outcomes.2 The median PFS was 16.7 months in patients with low ctDNA fraction, compared with 5.4 months in patients with higher ctDNA (HR, 0.31; p =.00052). Genetic Biomarker: ESR1 Mutation Researchers also evaluated the relationship between PFS in patients treated with alpelisib plus fulvestrant/letrozole and ESR1 mutations detected via ctDNA, finding no interaction in Cohorts A or C.2,5 In contrast, in Cohort B, there was a numerical trend toward ESR1 mutations and shorter PFS.5 These findings suggest that treatment with alpelisib plus fulvestrant may be the preferred option for patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer when the presence of an ESR1 mutation is suspected. In summary, extended follow-up from the phase II BYLieve study support the sustained benefit of alpelisib plus endocrine therapy in patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer. Future BYLieve updates will provide further insights on PIK3CA-targeted treatment in this patient population, including the roles of clinical and genetic biomarkers in individualized therapy. Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. References 1. Ciruelos EM , Lerebours F, Rugo HS, et al. . Alpelisib + fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + aromatase inhibitor (AI): 18-month follow-up of BYLieve Cohort A. Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). 2021 . Abstract P1-18-03. 2. Rugo HS , Neven P, Saffie I, et al. . Alpelisib + fulvestrant in patients with PIK3CA-mutated, HR+, HER2— advanced breast cancer (ABC) who received chemotherapy or endocrine therapy (ET) as immediate prior treatment: BYLieve Cohort C primary results and exploratory biomarker analyses. Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). 2021 . Abstract PD13-05. 3. Chia S , Ciruelos EM, Rugo HS, et al. . Effect of duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy (≤6 mo or >6 mo) on alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) from BYLieve . Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). 2021 . Abstract P1-18-08. 4. Juric D , Turner N, Prat A, et al. . Alpelisib + endocrine therapy (ET) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i): Biomarker analyses from the Phase II BYLieve study. Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). 2021 . Abstract P5-13-03. 5. Turner N , Rugo HS, Ciruelos EM, et al. . Impact of ESR1 mutations on endocrine therapy (ET) plus alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced breast cancer (ABC) who progressed on or after prior cyclin-dependent kinase inhibitor (CDK4/6i) therapy in the BYLieve trial. Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). 2021 . Abstract PD15-01. © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Jacobson, Anne

doi: 10.1093/oncolo/oyac016pmid: 35348781

Estrogen receptor gene (ESR1) mutations restore the ligand-independent activity of the estrogen receptor (ER) in patients with ER-positive metastatic breast cancer. Although these mutations are associated with resistance to aromatase inhibitor (AI) therapy, tumors harboring mutated ESR1 retain their sensitivity to selective estrogen receptor degraders (SERDs). Mutations in ESR1 are rare at diagnosis, occurring in <5% of patients with metastatic breast cancer. However, the prevalence of ESR1 mutations increases to 30% to 40% among patients whose disease progresses on first-line aromatase inhibitor therapy. The presence of ESR1 mutations in the blood (bESR1), detected by cell-free circulating DNA analysis, is associated with resistance to aromatase inhibitor therapy, but not to treatment with fulvestrant or palbociclib. The phase III PADA-1 trial was designed to evaluate the feasibility of preventing or delaying tumor progression in patients receiving first-line treatment with palbociclib plus aromatase inhibitor therapy by switching from an AI to fulvestrant as soon as a bESR1 mutation becomes detectable, while also maintaining treatment with palbociclib. François-Clément Bidard, M.D., Ph.D., of the Institut Curie and Paris-Saclay University, presented findings from the PADA-1 trial.1 Study Design The PADA-1 trial enrolled 1,017 patients with ER-positive/HER2-negative metastatic breast cancer who were undergoing first-line treatment with palbociclib plus an aromatase inhibitor. Patients provided blood samples for bESR1 mutation screening at enrollment, at month 1, and every 2 months thereafter. Blood samples were monitored for several ESR1 mutations: E380, P535, L536, Y537, and D538. Monitoring revealed a new ESR1 mutation in 172 patients who did not experience concurrent disease progression. The median time from trial enrollment to detection of the ESR1 mutation was 14.2 months (range, 2.8 to 47.1 months). Patients with a newly detected mutation were randomly assigned to 1 of 2 treatment approaches: Maintain treatment with palbociclib plus an aromatase inhibitor (n = 84) Switch treatment to palbociclib plus fulvestrant (n = 88) The co-primary endpoints were progression-free survival (PFS) and grade ≥3 hematologic adverse events. Baseline characteristics were similar in both treatment groups (Table 1). The median patient age was approximately 61 years, and one-third of patients (34%-37%) had prior treatment with an aromatase inhibitor. Table 1. Baseline characteristics in ER-positive, ESR1-mutated metastatic breast cancer Characteristics . Palbociclib plus aromatase inhibitor (n = 84) . Palbociclib plus fulvestrant (n = 88) . Median age 60 years 62 years Prior adjuvant aromatase inhibitor therapy  Yes 37% 34%  No 63% 66% Metastatic sites  Bone only 23% 22%  Visceral 49% 48%  Non-visceral ± bone 29% 31% ECOG performance status  0 61% 57%  1-2 39% 43% Characteristics . Palbociclib plus aromatase inhibitor (n = 84) . Palbociclib plus fulvestrant (n = 88) . Median age 60 years 62 years Prior adjuvant aromatase inhibitor therapy  Yes 37% 34%  No 63% 66% Metastatic sites  Bone only 23% 22%  Visceral 49% 48%  Non-visceral ± bone 29% 31% ECOG performance status  0 61% 57%  1-2 39% 43% Open in new tab Table 1. Baseline characteristics in ER-positive, ESR1-mutated metastatic breast cancer Characteristics . Palbociclib plus aromatase inhibitor (n = 84) . Palbociclib plus fulvestrant (n = 88) . Median age 60 years 62 years Prior adjuvant aromatase inhibitor therapy  Yes 37% 34%  No 63% 66% Metastatic sites  Bone only 23% 22%  Visceral 49% 48%  Non-visceral ± bone 29% 31% ECOG performance status  0 61% 57%  1-2 39% 43% Characteristics . Palbociclib plus aromatase inhibitor (n = 84) . Palbociclib plus fulvestrant (n = 88) . Median age 60 years 62 years Prior adjuvant aromatase inhibitor therapy  Yes 37% 34%  No 63% 66% Metastatic sites  Bone only 23% 22%  Visceral 49% 48%  Non-visceral ± bone 29% 31% ECOG performance status  0 61% 57%  1-2 39% 43% Open in new tab Key Findings After a median follow-up of 26 months, the strategy of switching patients from an aromatase inhibitor to fulvestrant upon bESR1-mutation detection was associated with a 39% reduction in the risk of disease progression or death (Table 2). The median PFS for patients who were switched to fulvestrant was 11.9 months, compared with 5.7 months for patients who remained on an aromatase inhibitor (HR, 0.61; p =.005). Table 2. Progression-free survival in ER-positive, ESR1-mutated metastatic breast cancer Endpoint . Palbociclib plus aromatase inhibitor (n = 84) . Palbociclib plus fulvestrant (n = 88) . Stratified HR(95% CI) . p value . Median PFS 5.7 months 11.9 months 0.61(0.43-0.86) .005 Endpoint . Palbociclib plus aromatase inhibitor (n = 84) . Palbociclib plus fulvestrant (n = 88) . Stratified HR(95% CI) . p value . Median PFS 5.7 months 11.9 months 0.61(0.43-0.86) .005 Open in new tab Table 2. Progression-free survival in ER-positive, ESR1-mutated metastatic breast cancer Endpoint . Palbociclib plus aromatase inhibitor (n = 84) . Palbociclib plus fulvestrant (n = 88) . Stratified HR(95% CI) . p value . Median PFS 5.7 months 11.9 months 0.61(0.43-0.86) .005 Endpoint . Palbociclib plus aromatase inhibitor (n = 84) . Palbociclib plus fulvestrant (n = 88) . Stratified HR(95% CI) . p value . Median PFS 5.7 months 11.9 months 0.61(0.43-0.86) .005 Open in new tab Among those who were randomized to the aromatase inhibitor arm, 69 patients progressed and were given the option to crossover to the fulvestrant arm. Of those who switched to fulvestrant (n = 47), the second median PFS was 3.5 months. This suggests that second-line fulvestrant confers a benefit for a brief duration and underscores the importance of detecting ESR1 mutations early. The analysis of the co-primary endpoint of grade ≥3 hematologic adverse events found no safety signals associated with switching from an aromatase inhibitor to fulvestrant (Table 3). Dose reductions were similar in the palbociclib plus aromatase inhibitor (7.1%) and palbociclib plus fulvestrant (7.9%) groups. One patient in the fulvestrant group (1.1%) withdrew from the trial due to a treatment-related adverse event. Table 3. Grade 3-4 adverse events in patients with ER-positive metastatic breast cancer Adverse event . Palbociclib plus AI (n = 84) . Palbociclib plus fulvestrant (n = 88) . Leukopenia  Grade 3 6.0% 6.8% Neutropenia  Grade 3 34.5% 36.4%  Grade 4 2.4% 0% Anemia  Grade 3 2.4% 0% Thrombocytopenia  Grade 3 1.2% 2.3% Nausea  Grade 3 1.2% 0% Pneumopathy  Grade 3 3.6% 0% Pain  Grade 3 1.2% 4.5% Other  Grade 3 6.0% 0%  Grade 4 0% 1.1% Adverse event . Palbociclib plus AI (n = 84) . Palbociclib plus fulvestrant (n = 88) . Leukopenia  Grade 3 6.0% 6.8% Neutropenia  Grade 3 34.5% 36.4%  Grade 4 2.4% 0% Anemia  Grade 3 2.4% 0% Thrombocytopenia  Grade 3 1.2% 2.3% Nausea  Grade 3 1.2% 0% Pneumopathy  Grade 3 3.6% 0% Pain  Grade 3 1.2% 4.5% Other  Grade 3 6.0% 0%  Grade 4 0% 1.1% Open in new tab Table 3. Grade 3-4 adverse events in patients with ER-positive metastatic breast cancer Adverse event . Palbociclib plus AI (n = 84) . Palbociclib plus fulvestrant (n = 88) . Leukopenia  Grade 3 6.0% 6.8% Neutropenia  Grade 3 34.5% 36.4%  Grade 4 2.4% 0% Anemia  Grade 3 2.4% 0% Thrombocytopenia  Grade 3 1.2% 2.3% Nausea  Grade 3 1.2% 0% Pneumopathy  Grade 3 3.6% 0% Pain  Grade 3 1.2% 4.5% Other  Grade 3 6.0% 0%  Grade 4 0% 1.1% Adverse event . Palbociclib plus AI (n = 84) . Palbociclib plus fulvestrant (n = 88) . Leukopenia  Grade 3 6.0% 6.8% Neutropenia  Grade 3 34.5% 36.4%  Grade 4 2.4% 0% Anemia  Grade 3 2.4% 0% Thrombocytopenia  Grade 3 1.2% 2.3% Nausea  Grade 3 1.2% 0% Pneumopathy  Grade 3 3.6% 0% Pain  Grade 3 1.2% 4.5% Other  Grade 3 6.0% 0%  Grade 4 0% 1.1% Open in new tab Findings from the PADA-1 trial support a personalized approach to treatment modification based on the early detection of ESR1 mutations in patients with ER-positive metastatic breast cancer. Results also demonstrate the utility of targeting the brief window of opportunity—after the initiation of first-line therapy but before tumor progression—to improve patient outcomes in patients who develop resistance mutations. Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. Reference 1. Bidard FC , Hardy-Bessard AC, Bachelot T, et al. Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2-metastatic breast cancer patients: results of PADA-1, a UCBG-GINECO randomized phase 3 trial Abstract GS3-05. Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). December 7-10, 2021 . Abstract GS3-05. © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Jacobson, Anne

doi: 10.1093/oncolo/oyac008pmid: 35348785

Laura Spring, MD The Oncologist: Starting with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, we saw updates from the DESTINY-Breast03 trial, which compared trastuzumab deruxtecan and trastuzumab emtansine in patients with HER2-positive metastatic breast cancer. What are your thoughts on this trial, particularly the findings in patients with brain metastases? Dr. Spring: The DESTINY-Breast03 subgroup results were great to see. In particular, the development of brain metastases is a major issue in HER2-positive metastatic breast cancer, and we need more therapeutic strategies. We had previously seen some data suggesting trastuzumab deruxtecan may have some intracranial activity. With this update from DESTINY-Breast03, now we see further results showing many patients with brain metastases did benefit from trastuzumab deruxtecan, further suggesting that this can be an option for patients with brain metastases as well. The Oncologist: Another trial in the HER2-positive metastatic setting was the phase III PHOEBE trial comparing pyrotinib plus capecitabine with lapatinib plus capecitabine after prior treatment with trastuzumab and taxanes. What are the key take-home messages from this trial? Dr. Spring: Pyrotinib outperformed lapatinib, but the PHOEBE trial occurred during a time of active drug development in the HER2-positive space, making it difficult to know how the agent will fit into the landscape. However, being an oral agent, it may be a good option in areas where access to certain anti-HER2 therapies is limited. The Oncologist: We also saw several trials in hormone receptor (HR)-positive, HER2-negative breast cancer. The phase III EMERALD trial evaluated elacestrant in patients with previously treated estrogen receptor (ER)-positive metastatic breast cancer. What are your thoughts on this trial? Dr. Spring: The EMERALD trial was the first phase III study of a novel oral selective estrogen receptor degrader (SERD) to demonstrate a statistically significant improvement in progression-free survival (PFS) versus standard of care. The results suggest elacestrant may become a new treatment option for patients with metastatic breast cancer. The results were more impressive in patients with ESR1 mutations. Both arms of the study had a relatively short PFS, suggesting more work is needed to address the issue of endocrine-resistant disease. Being first in class is always important and has potential to lead to an approval. Although elacestrant outperformed the treatment of physician’s choice (fulvestrant or an aromatase inhibitor), the outcomes overall were somewhat disappointing in either arm. This highlights that we still have a lot of work to do for this disease. Many of these patients were likely resistant to estrogen-blocking therapy—this is subset that needs a lot of research focus. Ultimately the novel oral SERDS may be even more helpful in the adjuvant breast cancer setting, and trials are ongoing and planned. The Oncologist: The phase III PADA-1 trial examined the strategy of switching from palbociclib plus an aromatase inhibitor to palbociclib plus fulvestrant upon detection of the ESR1 resistance mutation in patients with ER-positive metastatic breast cancer. What can we learn from this trial? Dr. Spring: PADA-1 was an interesting study that looked at the impact of ESR1 mutations detected via circulating tumor DNA (ctDNA). These are mutations that typically breast cancers don’t have right off the bat; they develop later as a resistance mechanism to certain types of endocrine therapy. This trial asked, if you identify ESR1 mutations earlier and change the endocrine therapy backbone from an aromatase inhibitor to fulvestrant, is that helpful? This was an interesting proof-of-principle study. I don’t think it will change the standard of care right away, but it will influence other studies and it will be important to explore this paradigm more. The Oncologist: Updates from the phase III MONALEESA trials, which evaluated ribociclib plus endocrine therapy in patients with HR-positive, HER2-negative advanced breast cancer, focused on treatment outcomes across subgroups. What are the take-home messages from these updates? Dr. Spring: The updates from MONALEESA continued to show a treatment benefit with ribociclib regardless of tumor subtype or site of metastatic disease. Overall survival benefit was consistent across the intrinsic subtypes (luminal A, luminal B, and HER2-enriched), which is important because the intrinsic subtypes speak to disease biology. These different subtypes can behave quite differently, so it’s nice to see that ribociclib was still helpful regardless. In terms of the number and sites of metastases, which speaks to burden of disease, treatment with ribociclib was again helpful regardless of the situation. The Oncologist: Several updates from the phase II BYLieve trial also examined outcomes across patient subgroups—in this case, patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer who progressed on or after prior treatment with a cyclin dependent kinase (CDK) 4/6 inhibitor. What does this research tell us about the ability to identify predictive biomarkers? Dr. Spring: The BYLieve trial is important because the study that led to the approval of alpelisib, SOLAR-1, included relatively few patients treated with a CDK 4/6 inhibitor, as the standard of care was evolving at that time. The recent data presented at SABCS 2021 helps confirm the efficacy of alpelisib, even in patients with a short duration of prior treatment with CDK 4/6 inhibitors or with ESR1 mutations. A short duration of response to CDK 4/6 inhibitors and the presence of an ESR1 mutation can both suggest endocrine resistance, and so it was nice to see that alpelisib plus fulvestrant showed efficacy in these settings. Like many targeted therapies, alpelisib has side effects; ultimately it would be great for patients if we could better predict who may benefit more, and who may benefit less, from a drug. There is also interest in biomarkers that may help predict side effects, to help with personalization. As we heard with the EMERALD study, we’re going to continue to have more agents available, and therefore personalization of therapy selection becomes even more important. The Oncologist: Yes, speaking of personalized treatment, we also saw an update from the phase III Southwest Oncology Group (SWOG) S1007 RxPonder trial, which evaluated the benefit of adjuvant chemotherapy based on clinical and genetic risk factors in patients with HR-positive, HER2-negative, early breast cancer. What have we learned about personalizing therapy in this setting? Dr. Spring: This update confirmed previous overall findings from the RxPonder trial, which has helped many patients avoid unnecessary treatment with chemotherapy. One challenge involves the premenopausal subset, which continues to show benefit from adjuvant therapy regardless of Oncotype DX recurrence score according to the study results. The most recent RxPonder update reviewed how many premenopausal patients received ovarian function suppression (OFS), and that number was relatively low (6.3% in the chemoendocrine arm and 19.0% in the endocrine-only arm). Therefore, it is still an unanswered question whether OFS could replace chemotherapy and provide the same benefit. The RxPonder trial just wasn’t the right trial to answer the question, but it was informative to see data showing that not many premenopausal patients received OFS. The Oncologist: Lastly, updates from the KEYNOTE-355 and KEYNOTE-522 trials examined the role of checkpoint inhibition with pembrolizumab in patients with triple-negative breast cancer (TNBC). What are your thoughts on these trials? Dr. Spring: Updated results from KEYNOTE-522 and KEYNOTE-355 continue to establish the role of pembrolizumab both in programmed death-ligand 1 (PDL-1)-positive metastatic TNBC and in stage II and III TNBC regardless of PDL-1 subtype. KEYNOTE-355 more specifically examined the PDL-1 cutoff that identifies patients who are most likely to benefit from pembrolizumab, whereas KEYNOTE-522 focused on the updated event-free survival data. The further follow-up data from both trials helped solidify the role of this agent becoming a standard of care in TNBC. Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Jacobson, Anne

doi: 10.1093/oncolo/oyac013pmid: 35348780

Approximately 15% to 20% of patients with breast cancer have tumors that harbor alterations in human epidermal growth factor receptor 2 (HER2). Although HER2-targeted therapies such as trastuzumab are the established standard for patients with HER2-positive breast cancer, resistance to HER2-targeted therapy inevitably develops. Current options for patients with HER2-positive breast cancer that progresses on trastuzumab include lapatinib, a HER2-targeted tyrosine kinase inhibitor (TKI), in combination with capecitabine. Additional HER2-targeted therapies, such as trastuzumab emtansine (T-DM1), are emerging, although these agents are not approved for metastatic disease in many countries. Pyrotinib is an oral, small-molecule, irreversible, pan-HER TKI that targets HER2, HER4, and HER1, also known as epidermal growth factor receptor. The phase III PHOEBE trial was designed to compare pyrotinib plus capecitabine with lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes-based chemotherapy.1 In the primary analysis of the PHOEBE trial, reported earlier this year, pyrotinib reached the primary endpoint of improved progression-free survival (PFS) relative to lapatinib.1 Binghe Xu, M.D., Ph.D., of the Chinese Academy of Medical Sciences, presented updated results from the PHOEBE trial, including an analysis of overall survival (OS).2 Study Design The phase III PHOEBE trial enrolled 267 patients from China with pathologically confirmed HER2-positive metastatic breast cancer. All patients had been previously treated with trastuzumab and taxanes, with a maximum of 2 lines of prior chemotherapy in the metastatic setting. Patients were randomly assigned to treatment with pyrotinib plus capecitabine (n = 134) or lapatinib plus capecitabine (n = 132). The primary endpoint was PFS. Baseline characteristics were similar in both treatment groups (Table 1). Median patient age was approximately 50 years, and more than 70% of patients in each treatment arm had evidence of resistance to prior trastuzumab therapy. Table 1. Baseline characteristics of patients with HER2-positive metastatic breast cancer Characteristic . Pyrotinib plus capecitabine (n = 134) . Lapatinib plus capecitabine (n = 132) . Median age 50 years 49 years ECOG performance status  0 35% 33%  1 65% 67% Hormone receptor status  ER-positive and/or PR-positive 46% 44%  ER-negative and PR-negative 54% 56% Metastatic sites at screening  Visceral 77% 82%  Non-visceral 23% 18% Previous trastuzumab therapy  For advanced disease 59% 67%  As adjuvant or neoadjuvant therapy 56% 48%  Both 15% 15% Median duration of prior trastuzumab for advanced disease 5.9 months 4.7 months Resistance to prior trastuzumab  Yes 72% 76%  No 28% 24% Previous lines of chemotherapy for metastatic disease  0 43% 35%  1 42% 49%  2 16% 16% Characteristic . Pyrotinib plus capecitabine (n = 134) . Lapatinib plus capecitabine (n = 132) . Median age 50 years 49 years ECOG performance status  0 35% 33%  1 65% 67% Hormone receptor status  ER-positive and/or PR-positive 46% 44%  ER-negative and PR-negative 54% 56% Metastatic sites at screening  Visceral 77% 82%  Non-visceral 23% 18% Previous trastuzumab therapy  For advanced disease 59% 67%  As adjuvant or neoadjuvant therapy 56% 48%  Both 15% 15% Median duration of prior trastuzumab for advanced disease 5.9 months 4.7 months Resistance to prior trastuzumab  Yes 72% 76%  No 28% 24% Previous lines of chemotherapy for metastatic disease  0 43% 35%  1 42% 49%  2 16% 16% Abbreviations: ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PR, progesterone receptor. Open in new tab Table 1. Baseline characteristics of patients with HER2-positive metastatic breast cancer Characteristic . Pyrotinib plus capecitabine (n = 134) . Lapatinib plus capecitabine (n = 132) . Median age 50 years 49 years ECOG performance status  0 35% 33%  1 65% 67% Hormone receptor status  ER-positive and/or PR-positive 46% 44%  ER-negative and PR-negative 54% 56% Metastatic sites at screening  Visceral 77% 82%  Non-visceral 23% 18% Previous trastuzumab therapy  For advanced disease 59% 67%  As adjuvant or neoadjuvant therapy 56% 48%  Both 15% 15% Median duration of prior trastuzumab for advanced disease 5.9 months 4.7 months Resistance to prior trastuzumab  Yes 72% 76%  No 28% 24% Previous lines of chemotherapy for metastatic disease  0 43% 35%  1 42% 49%  2 16% 16% Characteristic . Pyrotinib plus capecitabine (n = 134) . Lapatinib plus capecitabine (n = 132) . Median age 50 years 49 years ECOG performance status  0 35% 33%  1 65% 67% Hormone receptor status  ER-positive and/or PR-positive 46% 44%  ER-negative and PR-negative 54% 56% Metastatic sites at screening  Visceral 77% 82%  Non-visceral 23% 18% Previous trastuzumab therapy  For advanced disease 59% 67%  As adjuvant or neoadjuvant therapy 56% 48%  Both 15% 15% Median duration of prior trastuzumab for advanced disease 5.9 months 4.7 months Resistance to prior trastuzumab  Yes 72% 76%  No 28% 24% Previous lines of chemotherapy for metastatic disease  0 43% 35%  1 42% 49%  2 16% 16% Abbreviations: ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PR, progesterone receptor. Open in new tab Key Findings In the updated analysis, the median follow-up was 33.2 months in the pyrotinib plus capecitabine arm and 31.8 months in the lapatinib plus capecitabine arm. In total, 40.3% of patients in the pyrotinib arm and 52.3% in the lapatinib arm had died. This represents a 31% reduction in the risk of death among patients treated with pyrotinib relative to those treated with lapatinib (HR, 0.69; p =.02) (Table 2). Table 2. Overall and progression-free survival in HER2-positive metastatic breast cancer Endpoint . Pyrotinib plus capecitabine(n = 134) . Lapatinib plus capecitabine(n = 132) . HR(95% CI) . p value . Median OS Not reached 26.9 months 0.69 (0.48-0.98) .02 Median PFS 5.6 months 12.5 months 0.48 (0.37-0.63) <.0001 Endpoint . Pyrotinib plus capecitabine(n = 134) . Lapatinib plus capecitabine(n = 132) . HR(95% CI) . p value . Median OS Not reached 26.9 months 0.69 (0.48-0.98) .02 Median PFS 5.6 months 12.5 months 0.48 (0.37-0.63) <.0001 Open in new tab Table 2. Overall and progression-free survival in HER2-positive metastatic breast cancer Endpoint . Pyrotinib plus capecitabine(n = 134) . Lapatinib plus capecitabine(n = 132) . HR(95% CI) . p value . Median OS Not reached 26.9 months 0.69 (0.48-0.98) .02 Median PFS 5.6 months 12.5 months 0.48 (0.37-0.63) <.0001 Endpoint . Pyrotinib plus capecitabine(n = 134) . Lapatinib plus capecitabine(n = 132) . HR(95% CI) . p value . Median OS Not reached 26.9 months 0.69 (0.48-0.98) .02 Median PFS 5.6 months 12.5 months 0.48 (0.37-0.63) <.0001 Open in new tab Median OS was not reached in the pyrotinib arm, compared with 26.9 months in the lapatinib arm. The 24-month OS rates were 66.6% and 58.8% in the pyrotinib and lapatinib groups, respectively. Pyrotinib was associated with a significant improvement in median PFS compared with lapatinib (5.6 months vs. 12.5 months). This represents a 52% reduction in the risk of disease progression with pyrotinib (HR, 0.48; p <.0001) (Table 2). The OS and PFS benefits of treatment with pyrotinib were consistent across most clinically relevant patient subgroups, including those with and without trastuzumab resistance. The analysis also favored pyrotinib regardless of the number of prior lines of chemotherapy. The combination of pyrotinib plus capecitabine was associated with a manageable safety profile. The full safety analysis was reported previously.1 In 2020, based on initial findings from the PHOEBE trial, pyrotinib plus capecitabine was approved in China as second-line treatment for patients with HER2-positive metastatic breast cancer.1 The current updated results demonstrating improved OS support the use of pyrotinib as a standard of care in this treatment setting. Xu and colleagues noted that pyrotinib may play a role in the second-line treatment of HER2-poisitve metastatic breast cancer in countries where access to novel HER2-directed therapies and antibody-drug conjugates such as pertuzumab or T-DM1 is limited. Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. References 1. Xu B , Yan M, Ma F, et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 ; 22 ( 3 ): 351 - 360 . doi: 10.1016/S1470-2045(20)30702-6 Google Scholar Crossref Search ADS PubMed WorldCat 2. Xu B , Yan M, Ma F, et al. Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer. Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). December 7-10, 2021. Abstract GS3-02. © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Jacobson, Anne

doi: 10.1093/oncolo/oyac015pmid: 35348779

Endocrine therapy in combination with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor has emerged as the standard of care for patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. However, most patients will experience disease progression on first-line therapy related to the development of treatment resistance, including resistance secondary to the development of ESR1 mutations. After progression on first-line therapy, options for patients with ER-positive/HER2-negative metastatic breast cancer include sequential endocrine therapy, with the goal of exhausting available endocrine therapies before switching to chemotherapy. Standard single-agent endocrine therapies such as fulvestrant are associated with poor progression-free survival (PFS), averaging approximately 2 months in the second- and third-line settings. Elacestrant is an investigational, oral, selective estrogen receptor degrader (SERD) that demonstrates antitumor activity in ER-positive/HER2-negative metastatic breast cancer previously treated with fulvestrant and CDK4/6 inhibition.1 Elacestrant also shows activity in tumors harboring ESR1 mutations.1 The phase III EMERALD trial was designed to evaluate elacestrant in patients with estrogen receptor (ER)-positive/HER2-negative metastatic breast cancers that progressed on prior treatment with endocrine and targeted therapies. Aditya Bardia, M.D., M.P.H., of Mass General Cancer Center, presented results from the EMERALD trial, the first phase III study to examine an oral SERD in advanced breast cancer.2 Study Design The EMERALD trial enrolled 477 men and postmenopausal women with ER-positive/HER2-negative metastatic breast cancer who had received 1-2 prior lines of endocrine therapy for advanced disease. Up to 1 prior line of chemotherapy in the advanced setting was also permitted. All patients progressed or relapsed on or after prior endocrine therapy given alone or in combination with a CDK4/6 inhibitor. Patients were randomly assigned to treatment with elacestrant or standard of care, defined as the investigator’s choice of fulvestrant or an aromatase inhibitor. The co-primary endpoints were PFS in all patients and PFS in patients with tumors harboring ESR1 mutations. Baseline characteristics were similar in both treatment groups (Table 1). At enrollment, 115 patients in the elacestrant arm and 113 patients in the standard-of-care arm had tumors with mutated ESR1. Table 1. Baseline characteristics of patients with ER-positive metastatic breast cancer Characteristic . Elacestrant (n = 239) . Standard of Care (n = 238) . Median age 63.0 years 63.5 years Female patients 97.5% 99.6% ECOG performance status  0 59.8% 56.7%  1 40.2% 42.9%  >1 0% 0.4% Visceral metastasis 68.2% 70.6% Bone-only disease 15.9% 12.2% Prior adjuvant therapy 66.1% 59.2% Number of prior lines of endocrine therapy  1 54.0% 59.2%  2 46.0% 40.8% Number of prior lines of chemotherapy  0 79.9% 75.6%  1 20.1% 24.4% Characteristic . Elacestrant (n = 239) . Standard of Care (n = 238) . Median age 63.0 years 63.5 years Female patients 97.5% 99.6% ECOG performance status  0 59.8% 56.7%  1 40.2% 42.9%  >1 0% 0.4% Visceral metastasis 68.2% 70.6% Bone-only disease 15.9% 12.2% Prior adjuvant therapy 66.1% 59.2% Number of prior lines of endocrine therapy  1 54.0% 59.2%  2 46.0% 40.8% Number of prior lines of chemotherapy  0 79.9% 75.6%  1 20.1% 24.4% Open in new tab Table 1. Baseline characteristics of patients with ER-positive metastatic breast cancer Characteristic . Elacestrant (n = 239) . Standard of Care (n = 238) . Median age 63.0 years 63.5 years Female patients 97.5% 99.6% ECOG performance status  0 59.8% 56.7%  1 40.2% 42.9%  >1 0% 0.4% Visceral metastasis 68.2% 70.6% Bone-only disease 15.9% 12.2% Prior adjuvant therapy 66.1% 59.2% Number of prior lines of endocrine therapy  1 54.0% 59.2%  2 46.0% 40.8% Number of prior lines of chemotherapy  0 79.9% 75.6%  1 20.1% 24.4% Characteristic . Elacestrant (n = 239) . Standard of Care (n = 238) . Median age 63.0 years 63.5 years Female patients 97.5% 99.6% ECOG performance status  0 59.8% 56.7%  1 40.2% 42.9%  >1 0% 0.4% Visceral metastasis 68.2% 70.6% Bone-only disease 15.9% 12.2% Prior adjuvant therapy 66.1% 59.2% Number of prior lines of endocrine therapy  1 54.0% 59.2%  2 46.0% 40.8% Number of prior lines of chemotherapy  0 79.9% 75.6%  1 20.1% 24.4% Open in new tab Key Findings Elacestrant significantly reduced the risk of disease progression or death compared with standard endocrine therapy (Table 2). In the overall study population, the median PFS was 2.79 months in the elacestrant group and 1.91 months in the standard of care group. This represents a 30% reduction in the risk of progression or death with the oral SERD (HR, 0.69; p =.0018). Table 2. Progression-free survival in patients with ER-positive metastatic breast cancer Endpoint . Elacestrant . Standard of Care . HR (95% CI) . p value . All patients (n = 239) (n = 238)  Median PFS 2.79 months 1.91 months 0.697 (0.552-0.880) .0018 Patients with mESR1-positive tumors (n = 115) (n = 113)  Median PFS 3.78 months 1.87 months 0.546 (0.387-0.768) .0005 Endpoint . Elacestrant . Standard of Care . HR (95% CI) . p value . All patients (n = 239) (n = 238)  Median PFS 2.79 months 1.91 months 0.697 (0.552-0.880) .0018 Patients with mESR1-positive tumors (n = 115) (n = 113)  Median PFS 3.78 months 1.87 months 0.546 (0.387-0.768) .0005 Open in new tab Table 2. Progression-free survival in patients with ER-positive metastatic breast cancer Endpoint . Elacestrant . Standard of Care . HR (95% CI) . p value . All patients (n = 239) (n = 238)  Median PFS 2.79 months 1.91 months 0.697 (0.552-0.880) .0018 Patients with mESR1-positive tumors (n = 115) (n = 113)  Median PFS 3.78 months 1.87 months 0.546 (0.387-0.768) .0005 Endpoint . Elacestrant . Standard of Care . HR (95% CI) . p value . All patients (n = 239) (n = 238)  Median PFS 2.79 months 1.91 months 0.697 (0.552-0.880) .0018 Patients with mESR1-positive tumors (n = 115) (n = 113)  Median PFS 3.78 months 1.87 months 0.546 (0.387-0.768) .0005 Open in new tab Among patients with tumors harboring mESR1, elacestrant was associated with a 45% reduction in the risk of progression or death compared with standard therapy. In this subgroup, the median PFS was 3.79 months with elacestrant and 1.87 months with standard endocrine therapy (HR, 0.54; p =.0005). Elacestrant was associated with a higher PFS compared with standard therapy at 6 months (34.3% vs. 20.4%) and 12 months (22.3% vs. 9.4%), suggesting a sustained benefit with oral SERD treatment. The observation of higher PFS was consistent for patients with tumors harboring mESR1. In this subgroup, elacestrant demonstrated a higher PFS rate compared with standard therapy at 6 months (40.8% vs. 19.1%) and at 12 months (26.8% vs. 8.2%). In the safety analysis, elacestrant demonstrated a predictable safety profile consistent with that of other endocrine therapies (Table 3). The most common adverse events in the elacestrant arm included nausea, fatigue, vomiting, decreased appetite, and arthralgia. Adverse events leading to treatment discontinuations were infrequent in the elacestrant and standard-of-care groups (6.3% and 4.4%, respectively). Table 3. Adverse events with elacestrant and standard endocrine therapy Adverse event . Elacestrant (n = 237) . Standard of Care (n = 229) . All grades . Grade 3-4 . All grades . Grade 3-4 . Nausea 35.0% 2.5% 18.8% 0.9% Fatigue 19.0% 0.8% 18.8% 0.9% Vomiting 19.0% 0.8% 8.3% 0% Decreased appetite 14.8% 0.8% 9.2% 0.4% Arthralgia 14.3% 0.8% 16.2% 0% Diarrhea 13.9% 0% 10.0% 0.9% Back pain 13.9% 2.5% 9.6% 0.4% Elevated aspartate aminotransferase 13.1% 1.7% 12.2% 0.9% Headache 12.2% 1.7% 12.2% 0.9% Constipation 12.2% 0% 6.6% 0% Hot flush 11.4% 0% 2.6% 0% Elevated alanine aminotransferase 9.3% 2.1% 10.0% 0.4% Adverse event . Elacestrant (n = 237) . Standard of Care (n = 229) . All grades . Grade 3-4 . All grades . Grade 3-4 . Nausea 35.0% 2.5% 18.8% 0.9% Fatigue 19.0% 0.8% 18.8% 0.9% Vomiting 19.0% 0.8% 8.3% 0% Decreased appetite 14.8% 0.8% 9.2% 0.4% Arthralgia 14.3% 0.8% 16.2% 0% Diarrhea 13.9% 0% 10.0% 0.9% Back pain 13.9% 2.5% 9.6% 0.4% Elevated aspartate aminotransferase 13.1% 1.7% 12.2% 0.9% Headache 12.2% 1.7% 12.2% 0.9% Constipation 12.2% 0% 6.6% 0% Hot flush 11.4% 0% 2.6% 0% Elevated alanine aminotransferase 9.3% 2.1% 10.0% 0.4% Open in new tab Table 3. Adverse events with elacestrant and standard endocrine therapy Adverse event . Elacestrant (n = 237) . Standard of Care (n = 229) . All grades . Grade 3-4 . All grades . Grade 3-4 . Nausea 35.0% 2.5% 18.8% 0.9% Fatigue 19.0% 0.8% 18.8% 0.9% Vomiting 19.0% 0.8% 8.3% 0% Decreased appetite 14.8% 0.8% 9.2% 0.4% Arthralgia 14.3% 0.8% 16.2% 0% Diarrhea 13.9% 0% 10.0% 0.9% Back pain 13.9% 2.5% 9.6% 0.4% Elevated aspartate aminotransferase 13.1% 1.7% 12.2% 0.9% Headache 12.2% 1.7% 12.2% 0.9% Constipation 12.2% 0% 6.6% 0% Hot flush 11.4% 0% 2.6% 0% Elevated alanine aminotransferase 9.3% 2.1% 10.0% 0.4% Adverse event . Elacestrant (n = 237) . Standard of Care (n = 229) . All grades . Grade 3-4 . All grades . Grade 3-4 . Nausea 35.0% 2.5% 18.8% 0.9% Fatigue 19.0% 0.8% 18.8% 0.9% Vomiting 19.0% 0.8% 8.3% 0% Decreased appetite 14.8% 0.8% 9.2% 0.4% Arthralgia 14.3% 0.8% 16.2% 0% Diarrhea 13.9% 0% 10.0% 0.9% Back pain 13.9% 2.5% 9.6% 0.4% Elevated aspartate aminotransferase 13.1% 1.7% 12.2% 0.9% Headache 12.2% 1.7% 12.2% 0.9% Constipation 12.2% 0% 6.6% 0% Hot flush 11.4% 0% 2.6% 0% Elevated alanine aminotransferase 9.3% 2.1% 10.0% 0.4% Open in new tab In summary, elacestrant is the first oral SERD to demonstrate a significant improvement in PFS in a phase III trial of patients with ER-positive/HER2-negative metastatic breast cancer, suggesting a potential role for this novel therapy in the second- and third-line treatment settings. Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. References 1. Bardia A , Kaklamani V, Wilks S, et al. Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2-negative advanced breast cancer. J Clin Oncol. 2021 ; 39 ( 12 ): 1360 - 1370 . doi: 10.1200/JCO.20.02272 Google Scholar Crossref Search ADS PubMed WorldCat 2. Bardia A , Neven P, Streich G, et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial . Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS) . December 7-10, 2021 . Abstract GS2-02. © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Jacobson, Anne

doi: 10.1093/oncolo/oyac012pmid: 35348778

Multigene prognostic scores hold the potential to guide treatment decisions, including the decision to forgo certain therapy when the risks outweigh the benefits. The 21-gene Oncotype DX recurrence score has been used to identify which women with node-negative, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer can safely forgo chemotherapy without increasing the risk of recurrence. The phase III Southwest Oncology Group (SWOG) S1007 RxPonder trial was designed to evaluate the benefit of chemotherapy added to standard adjuvant endocrine therapy in women with node-positive, HR-positive, HER2-negative early breast cancer with an Oncotype DX® recurrence score of 0-25. Preliminary findings from the RxPonder trial suggested that postmenopausal women can avoid adjuvant chemotherapy without compromising long-term clinical outcomes.1 In the current analysis, Kevin Kalinsky, M.D., of Emory University, presented updated results from the ongoing RxPonder trial.2,3 Study Design The SWOG S1077 RxPonder trial enrolled 5,018 patients with HR-positive, HER2-negative breast cancer with 1-3 positive axillary lymph nodes (nodal stage N1) and no distant metastasis. All patients had an Oncotype DX recurrence score of 0-25, indicating a low risk of recurrence. Patients were randomly assigned to treatment with chemotherapy plus standard adjuvant endocrine therapy (n = 2,507) or endocrine therapy alone (n = 2,511). The primary endpoint was invasive disease-free survival (IDFS). The median follow-up in the current analysis was 5.3 years. Baseline characteristics were similar in both treatment groups. The median patient age was 57.5 years (range, 18.3 to 87.6 years). At enrollment, one-third of patients (33.2%) were premenopausal and two-thirds (66.8%) were postmenopausal. Most patients (65.3%) had 1 positive node; 25.2% had 2 positive lymph nodes, and 9.2% had 3 positive nodes. Key Findings Results showed a statistically significant interaction between chemotherapy benefit, as measured by IDFS, and menopausal status (p =.008) (Table 1). Among postmenopausal women, the addition of chemotherapy did not improve IDFS at 5 years compared with endocrine therapy alone (91.3% vs. 91.9%). The hazard ratio (HR) for invasive disease recurrence, new primary breast or other cancer, or death was 1.02 (p =.89). Table 1. Invasive disease-free survival by adjuvant therapy regimen and menopausal status Patient subgroup . Chemotherapyplus ET (n = 2,487) . ET alone (n = 2,497) . HR (95% CI) . p value . All patients 92.2% 91.0% 0.86 (0.72-1.03) .10  Postmenopausal 91.3% 91.9% 1.02 (0.82-1.26) .89  Premenopausal 93.9% 89.0% 0.60 (0.43-0.83) .002 Patient subgroup . Chemotherapyplus ET (n = 2,487) . ET alone (n = 2,497) . HR (95% CI) . p value . All patients 92.2% 91.0% 0.86 (0.72-1.03) .10  Postmenopausal 91.3% 91.9% 1.02 (0.82-1.26) .89  Premenopausal 93.9% 89.0% 0.60 (0.43-0.83) .002 Abbreviations: CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; IDFS, invasive disease-free survival. Open in new tab Table 1. Invasive disease-free survival by adjuvant therapy regimen and menopausal status Patient subgroup . Chemotherapyplus ET (n = 2,487) . ET alone (n = 2,497) . HR (95% CI) . p value . All patients 92.2% 91.0% 0.86 (0.72-1.03) .10  Postmenopausal 91.3% 91.9% 1.02 (0.82-1.26) .89  Premenopausal 93.9% 89.0% 0.60 (0.43-0.83) .002 Patient subgroup . Chemotherapyplus ET (n = 2,487) . ET alone (n = 2,497) . HR (95% CI) . p value . All patients 92.2% 91.0% 0.86 (0.72-1.03) .10  Postmenopausal 91.3% 91.9% 1.02 (0.82-1.26) .89  Premenopausal 93.9% 89.0% 0.60 (0.43-0.83) .002 Abbreviations: CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; IDFS, invasive disease-free survival. Open in new tab In contrast, chemotherapy was associated with a significant improvement in IDFS among premenopausal women. In this subgroup, the 5-year IDFS was 93.9% among those who received chemotherapy plus endocrine therapy and 89.0% for those who received endocrine therapy alone. This represents a 40% reduction in the risk of IDFS events with the addition of chemotherapy to adjuvant endocrine therapy (HR, 0.60; p =.002). Distant relapse-free survival (DRFS) outcomes followed a similar pattern (Table 2). Among postmenopausal women, 5-year DRFS was 94.4% in both treatment groups (HR, 1.05; p =.70). By comparison, premenopausal women experienced a 42% reduction in the risk of DRFS events with the addition of chemotherapy to endocrine therapy. The 5-year DRFS rate was 96.1% in the chemotherapy plus endocrine therapy group and 92.8% for those treated with endocrine therapy alone (HR, 0.58; p =.009). Table 2. Distant relapse-free survival by adjuvant therapy regimen and menopausal status Patient subgroup . Chemotherapy plus ET (n = 2,487) . ET alone (n = 2,497) . HR (95% CI) . p value . All patients 94.9% 93.9% 0.88 (0.71-1.09) .25  Postmenopausal 94.4% 94.4% 1.05 (0.81-1.37) .70  Premenopausal 96.1% 92.8% 0.58 (0.39-0.87) .009 Patient subgroup . Chemotherapy plus ET (n = 2,487) . ET alone (n = 2,497) . HR (95% CI) . p value . All patients 94.9% 93.9% 0.88 (0.71-1.09) .25  Postmenopausal 94.4% 94.4% 1.05 (0.81-1.37) .70  Premenopausal 96.1% 92.8% 0.58 (0.39-0.87) .009 Abbreviations: CI, confidence interval; DRFS, disease relapse-free survival; ET, endocrine therapy; HR, hazard ratio. Open in new tab Table 2. Distant relapse-free survival by adjuvant therapy regimen and menopausal status Patient subgroup . Chemotherapy plus ET (n = 2,487) . ET alone (n = 2,497) . HR (95% CI) . p value . All patients 94.9% 93.9% 0.88 (0.71-1.09) .25  Postmenopausal 94.4% 94.4% 1.05 (0.81-1.37) .70  Premenopausal 96.1% 92.8% 0.58 (0.39-0.87) .009 Patient subgroup . Chemotherapy plus ET (n = 2,487) . ET alone (n = 2,497) . HR (95% CI) . p value . All patients 94.9% 93.9% 0.88 (0.71-1.09) .25  Postmenopausal 94.4% 94.4% 1.05 (0.81-1.37) .70  Premenopausal 96.1% 92.8% 0.58 (0.39-0.87) .009 Abbreviations: CI, confidence interval; DRFS, disease relapse-free survival; ET, endocrine therapy; HR, hazard ratio. Open in new tab Among premenopausal women, the benefit of chemotherapy was consistent across all patient subgroups, regardless of age, disease grade, tumor size, node status, or recurrence score. The relative benefit of chemotherapy did not increase as recurrence scores increased from 0 to 25. According to Dr. Kalinsky and colleagues, the updated and peer-reviewed findings from the RxPonder trial suggest that postmenopausal women HR-positive, HER2-negative early breast cancer with 1-3 positive lymph nodes and an Oncotype DX recurrence score of 0-25 can safely forgo adjuvant chemotherapy without compromising long-term IDFS and DRFS. Moreover, premenopausal women with the same characteristics are likely to benefit from chemotherapy added to adjuvant endocrine therapy. Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. References 1. Kalinsky K , Barlow WE, Meric-Bernstam F, et al. SWOG S1007: Adjuvant trial randomized ER+ patients who had a recurrence score <25 and 1-3 positive nodes to endocrine therapy (ET) versus ET + chemotherapy . Presented at the 2020 San Antonio Breast Cancer Symposium (SABCS). December 8-11, 2020. Abstract GS3-01. 2. Kalinsky KM , Barlow WE, Gralow JR, et al. Updated results from a phase 3 randomized clinical trial in participants (pts) with 1-3 positive lymph nodes (LN), hormone receptor-positive (HR+) and HER2-negative (HER2–) breast cancer (BC) with recurrence score (RS) <25 randomized to endocrine therapy (ET) +/– chemotherapy (CT): SWOG S1007 (RxPONDER) . Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). December 7-10, 2021. Abstract GS2-07. 3. Kalinsky K , Barlow WE, Gralow JR, et al. 21-Gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. 2021 ; 385 : 2336 - 2347 . doi: 10.1056/NEJMoa2108873. Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Jacobson, Anne

doi: 10.1093/oncolo/oyac014pmid: 35348777

Pembrolizumab targets the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway across a range of tumor types with varying degrees of PD-L1 expression. The phase III KEYNOTE-522 and KEYNOTE-355 trials evaluated the addition of pembrolizumab to standard chemotherapy in patients with early-stage and locally advanced or metastatic triple-negative breast cancer (TNBC), respectively 1, 2. Updated findings provide insights on the optimal role of pembrolizumab across TNBC treatment settings. KEYNOTE-522: Pembrolizumab in Early-Stage TNBC Peter Schmid, M.D., Ph.D., of Barts Cancer Institute, presented findings from KEYNOTE-522 showing a 37% improvement in event-free survival (EFS) associated with neoadjuvant and adjuvant pembrolizumab in early-stage TNBC 1. The phase III KEYNOTE-522 trial enrolled 1,174 patients with newly diagnosed, operable, stage II-III TNBC. Patients were randomly assigned 2:1 to receive both neoadjuvant and adjuvant therapy with pembrolizumab 200mg every 3 weeks (n = 784) or placebo (n = 390). During the neoadjuvant phase of the trial, patients received pembrolizumab or placebo in addition to chemotherapy with carboplatin plus paclitaxel for 12 weeks, followed by doxorubicin or epirubicin plus cyclophosphamide for an additional 12 weeks. Following surgery, patients received 9 additional cycles of adjuvant pembrolizumab or placebo. The co-primary endpoints were pathologic complete response and EFS. Pembrolizumab added to neoadjuvant and adjuvant therapy was associated with a statistically significant and clinically meaningful 37% improvement in EFS (HR, 0.63; p =.00031) (Table 1). The benefit of pembrolizumab was consistent across subgroups, including those defined by disease stage and nodal status. Table 1. Event-free survival by neoadjuvant and adjuvant therapy in early-stage TNBC Endpoint . Pembrolizumab (n = 784) . Placebo (n = 390) . HR (95% CI) . p value . EFS events 15.7% 23.8% 0.63 (0.48-0.82) .00031 EFS at 36 months 84.5% 76.8% Endpoint . Pembrolizumab (n = 784) . Placebo (n = 390) . HR (95% CI) . p value . EFS events 15.7% 23.8% 0.63 (0.48-0.82) .00031 EFS at 36 months 84.5% 76.8% Abbreviations: CI, confidence interval; EFS, event-free survival; HR, hazard ratio; TNBC, triple-negative breast cancer. Open in new tab Table 1. Event-free survival by neoadjuvant and adjuvant therapy in early-stage TNBC Endpoint . Pembrolizumab (n = 784) . Placebo (n = 390) . HR (95% CI) . p value . EFS events 15.7% 23.8% 0.63 (0.48-0.82) .00031 EFS at 36 months 84.5% 76.8% Endpoint . Pembrolizumab (n = 784) . Placebo (n = 390) . HR (95% CI) . p value . EFS events 15.7% 23.8% 0.63 (0.48-0.82) .00031 EFS at 36 months 84.5% 76.8% Abbreviations: CI, confidence interval; EFS, event-free survival; HR, hazard ratio; TNBC, triple-negative breast cancer. Open in new tab Results from the KEYNOTE-522 trial support the role of pembrolizumab plus platinum-based chemotherapy in the neoadjuvant setting, followed by adjuvant pembrolizumab after surgery, as a new standard of care for patients with early-stage TNBC. KEYNOTE-355: Pembrolizumab in Locally Advanced or Metastatic TNBC Javier Cortes, M.D., Ph.D., of the International Breast Cancer Center, presented results from KEYNOTE-355 demonstrating the optimal PD-L1 expression threshold for pembrolizumab benefit in advanced or metastatic TNBC 2. The phase III KEYNOTE-355 trial enrolled 847 patients with locally recurrent inoperable or metastatic TNBC that has not been previously treated with chemotherapy in the advanced setting. Tumor samples were graded for PD-L1 expression based on the combined positive score (CPS), which measures PD-L1 expression on tumor cells, lymphocytes, and macrophages. Patients were randomly assigned 2:1 to receive pembrolizumab every 3 weeks (n = 566) or placebo (n = 281) in addition to nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in 3 patient cohorts defined by PD-L1 expression: CPS ≥10 (n = 323), CPS ≥1 (n = 636), and the intent-to-treat (ITT) study population (N = 847). Pembrolizumab was associated with a statistically significant 27% improvement in OS in the subgroup of patients with high PD-L1 expression, defined as CPS ≥10 (HR, 0.73; p =.0093) (Table 2). Although pembrolizumab was associated with a trend toward improved survival in other subgroups, the benefit did not reach the prespecified threshold for statistical significance. Table 2. Overall survival in patients with locally advanced or metastatic TNBC Median Overall Survival . Pembrolizumab plus chemotherapy (n = 566) . Placebo plus chemotherapy (n = 281) . HR (95% CI) . p value . PD-L1 CPS ≥10 23.0 months 16.1 months 0.73(0.55-0.95) .0093 PD-L1 CPS ≥1 17.6 months 16.0 months 0.86(0.72-1.04) .0563∗ All patients 17.2 months 15.5 months 0.89(0.76-1.04) NR Median Overall Survival . Pembrolizumab plus chemotherapy (n = 566) . Placebo plus chemotherapy (n = 281) . HR (95% CI) . p value . PD-L1 CPS ≥10 23.0 months 16.1 months 0.73(0.55-0.95) .0093 PD-L1 CPS ≥1 17.6 months 16.0 months 0.86(0.72-1.04) .0563∗ All patients 17.2 months 15.5 months 0.89(0.76-1.04) NR ∗Prespecified p-value boundary of.0171 for statistical significance not met. Abbreviations: CI, confidence interval; CPS, combined positive score; HR, hazard ratio; NR, not reported; PD-L1, programmed death-ligand 1; TNBC, triple-negative breast cancer. Open in new tab Table 2. Overall survival in patients with locally advanced or metastatic TNBC Median Overall Survival . Pembrolizumab plus chemotherapy (n = 566) . Placebo plus chemotherapy (n = 281) . HR (95% CI) . p value . PD-L1 CPS ≥10 23.0 months 16.1 months 0.73(0.55-0.95) .0093 PD-L1 CPS ≥1 17.6 months 16.0 months 0.86(0.72-1.04) .0563∗ All patients 17.2 months 15.5 months 0.89(0.76-1.04) NR Median Overall Survival . Pembrolizumab plus chemotherapy (n = 566) . Placebo plus chemotherapy (n = 281) . HR (95% CI) . p value . PD-L1 CPS ≥10 23.0 months 16.1 months 0.73(0.55-0.95) .0093 PD-L1 CPS ≥1 17.6 months 16.0 months 0.86(0.72-1.04) .0563∗ All patients 17.2 months 15.5 months 0.89(0.76-1.04) NR ∗Prespecified p-value boundary of.0171 for statistical significance not met. Abbreviations: CI, confidence interval; CPS, combined positive score; HR, hazard ratio; NR, not reported; PD-L1, programmed death-ligand 1; TNBC, triple-negative breast cancer. Open in new tab Pembrolizumab showed a trend toward improved PFS in all groups (Table 3), although the benefit reached statistical significance only in the subgroup of patients with PD-L1 CPS ≥10. In this group, pembrolizumab improved PFS by 34% (HR, 0.66; 95% CI, 0.50-0.88). Table 3. Progression-free survival in locally advanced or metastatic TNBC Median PFS . Pembrolizumab plus chemotherapy (n = 566) . Placebo plus chemotherapy (n = 281) . HR (95% CI) . PD-L1 CPS ≥10 9.7 months 5.6 months 0.66 (0.50-0.88) PD-L1 CPS ≥1 7.6 months 5.6 months 0.75 (0.62-0.91) All patients 7.5 months 5.6 months 0.82 (0.70-0.98) Median PFS . Pembrolizumab plus chemotherapy (n = 566) . Placebo plus chemotherapy (n = 281) . HR (95% CI) . PD-L1 CPS ≥10 9.7 months 5.6 months 0.66 (0.50-0.88) PD-L1 CPS ≥1 7.6 months 5.6 months 0.75 (0.62-0.91) All patients 7.5 months 5.6 months 0.82 (0.70-0.98) Abbreviations: CI, confidence interval; CPS, combined positive score; HR, hazard ratio; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TNBC, triple-negative breast cancer. Open in new tab Table 3. Progression-free survival in locally advanced or metastatic TNBC Median PFS . Pembrolizumab plus chemotherapy (n = 566) . Placebo plus chemotherapy (n = 281) . HR (95% CI) . PD-L1 CPS ≥10 9.7 months 5.6 months 0.66 (0.50-0.88) PD-L1 CPS ≥1 7.6 months 5.6 months 0.75 (0.62-0.91) All patients 7.5 months 5.6 months 0.82 (0.70-0.98) Median PFS . Pembrolizumab plus chemotherapy (n = 566) . Placebo plus chemotherapy (n = 281) . HR (95% CI) . PD-L1 CPS ≥10 9.7 months 5.6 months 0.66 (0.50-0.88) PD-L1 CPS ≥1 7.6 months 5.6 months 0.75 (0.62-0.91) All patients 7.5 months 5.6 months 0.82 (0.70-0.98) Abbreviations: CI, confidence interval; CPS, combined positive score; HR, hazard ratio; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TNBC, triple-negative breast cancer. Open in new tab Based on these findings, the study authors concluded that CPS ≥10 is a reasonable threshold of tumor PD-L1 expression to define the population of patients with metastatic TNBC who are most likely to benefit from treatment with pembrolizumab in the advanced/metastatic setting. Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. References 1. Schmid P , Cortes J, Dent R et al. KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC: Event-free survival sensitivity and subgroup analyses. Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). December 7-10, 2021. Abstract GS1-01. 2. Cortes J , Cescon DW, Rugo HS et al. Final results of KEYNOTE-355: Randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer . Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). December 7-10, 2021. Abstract GS1-02. © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Jacobson, Anne

doi: 10.1093/oncolo/oyac010pmid: 35348783

When added to standard endocrine therapy (ET), cyclin dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced and metastatic breast cancer. Treatment with the CDK4/6 inhibitor ribociclib plus ET significantly improved overall survival (OS) relative to ET alone in the landmark phase III MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials, which represented the spectrum of premenopausal and postmenopausal patients with HR-positive, HER2-negative advanced breast cancer.1–3 Understanding how the magnitude of benefit with CDK4/6 inhibitor therapy varies by clinical and genomic subtype may enable oncologists to develop personalized treatment plans. In subgroup analyses from the MONALEESA trials, researchers evaluated OS outcomes by intrinsic tumor subtype and metastatic site.4,5 Ribociclib and Overall Survival by Intrinsic Tumor Subtype Lisa A. Carey, M.D., of the University of North Carolina at Chapel Hill, presented results from an analysis of overall survival in the MONALEESA-2, -3, and -7 trials by intrinsic tumor subtype.4 In the retrospective exploratory analysis, tumor samples from patients in the MONALEESA trials (n = 997) underwent gene expression profiling with the Prediction Analysis of Microarray 50 (PAM50) assay. Luminal A was the most common subtype (54.4%), followed by luminal B (27.9%), HER2-enriched (14.7%), and basal-like (3.0%). Across all patients, ribociclib added to ET significantly improved OS by 25% compared with ET alone (HR, 0.75; p .0012). However, results showed a significant interaction between tumor subtype and survival benefit (p = .0065) (Table 1). Ribociclib significantly improved OS for patients with luminal A (HR, 0.75; p = .021), luminal B (HR, 0.69; p = .023), and HER2-enriched tumor subtypes (HR, 0.60; p = .018). In contrast, ribociclib did not improve OS relative to placebo in patients with basal-like tumors (HR, 1.89; p = .148). Table 1. Overall survival by intrinsic tumor subtype and adjuvant therapy Tumor subtype . Ribociclib plus ET . ET alone . HR . p value . Luminal A (n = 542) 68.0 months 54.6 months .75 .021 Luminal B (n = 278) 58.8 months 44.9 months .69 .023 HER2E (n = 147) 40.3 months 29.4 months .60 .018 Basal like (n = 30) 19.4 months 21.2 months 1.89 .148 Tumor subtype . Ribociclib plus ET . ET alone . HR . p value . Luminal A (n = 542) 68.0 months 54.6 months .75 .021 Luminal B (n = 278) 58.8 months 44.9 months .69 .023 HER2E (n = 147) 40.3 months 29.4 months .60 .018 Basal like (n = 30) 19.4 months 21.2 months 1.89 .148 Abbreviations: ET, endocrine therapy; HER2E, HER2 enriched; HR, hazard ratio. Open in new tab Table 1. Overall survival by intrinsic tumor subtype and adjuvant therapy Tumor subtype . Ribociclib plus ET . ET alone . HR . p value . Luminal A (n = 542) 68.0 months 54.6 months .75 .021 Luminal B (n = 278) 58.8 months 44.9 months .69 .023 HER2E (n = 147) 40.3 months 29.4 months .60 .018 Basal like (n = 30) 19.4 months 21.2 months 1.89 .148 Tumor subtype . Ribociclib plus ET . ET alone . HR . p value . Luminal A (n = 542) 68.0 months 54.6 months .75 .021 Luminal B (n = 278) 58.8 months 44.9 months .69 .023 HER2E (n = 147) 40.3 months 29.4 months .60 .018 Basal like (n = 30) 19.4 months 21.2 months 1.89 .148 Abbreviations: ET, endocrine therapy; HER2E, HER2 enriched; HR, hazard ratio. Open in new tab Intrinsic tumor subtype was prognostic for survival outcomes (p < .001) after adjusting for clinical covariates. Patients with the basal-like subtype did not appear to benefit from CDK 4/6 inhibitor therapy, whereas those with HER2-enriched tumors experienced the greatest magnitude of survival benefit. The phase III HARMONIA trial will evaluate the activity of ribociclib plus ET in patients with HER2-enriched tumors, with the goal of providing further insight on developing personalized treatment plans for patients with HR+/HER2– metastatic breast cancer. Ribociclib and Overall Survival by Metastatic Site The phase III MONALEESA-2 trial evaluated first-line ribociclib plus letrozole, compared with placebo plus letrozole, in 668 postmenopausal women with HR+/HER- advanced breast cancer. In the overall study population, ribociclib significantly improved OS by 24% compared with ET alone (HR, 0.76; p = .004).1 Joyce O’Shaughnessy, M.D., of Texas Oncology-Baylor University Medical Center, presented findings from an exploratory analysis of OS by metastatic site in the MONALEESA-2 trial.5 Results showed a consistent survival benefit in favor of ribociclib plus letrozole relative to letrozole alone, regardless of metastatic site (Table 2). All comparisons favored treatment with ribociclib, though some comparisons did not reach statistical significance. Table 2. Overall survival by metastatic site in HR+/HER2– advanced breast cancer Metastatic site . Ribociclib plus letrozole . Placebo plus letrozole . HR (95% CI) . Bone-only metastases  Yes (n = 69) (n = 79)   Median OS 72.6 months 56.4 months 0.78 (0.50–1.21)   6-year OS 50.2% 33.8%  No (n = 265) (n = 255)   Median OS 61.5 months 50.3 months 0.77 (0.51–0.96)   6-year OS 42.6% 31.5% Liver metastases  Yes (n = 59) (n = 72)   Median OS 37.7 months 38.1 months 0.81 (0.54–1.24)   6-year OS 31.0% 18.9%  No (n = 275) (n = 262)   Median OS 68.0 months 56.9 months 0.77 (0.62–0.97)   6-year OS 46.8% 35.7% Liver or lung metastases  Yes (n = 182) (n = 190)   Median OS 55.5 months 51.4 months 0.81 (0.62–1.05)   6-year OS 31.0% 18.9%  No (n = 152) (n = 144)   Median OS 70.5 months 52.4 months 0.71 (0.53–0.96)   6-year OS 48.6% 33.2% Metastatic site . Ribociclib plus letrozole . Placebo plus letrozole . HR (95% CI) . Bone-only metastases  Yes (n = 69) (n = 79)   Median OS 72.6 months 56.4 months 0.78 (0.50–1.21)   6-year OS 50.2% 33.8%  No (n = 265) (n = 255)   Median OS 61.5 months 50.3 months 0.77 (0.51–0.96)   6-year OS 42.6% 31.5% Liver metastases  Yes (n = 59) (n = 72)   Median OS 37.7 months 38.1 months 0.81 (0.54–1.24)   6-year OS 31.0% 18.9%  No (n = 275) (n = 262)   Median OS 68.0 months 56.9 months 0.77 (0.62–0.97)   6-year OS 46.8% 35.7% Liver or lung metastases  Yes (n = 182) (n = 190)   Median OS 55.5 months 51.4 months 0.81 (0.62–1.05)   6-year OS 31.0% 18.9%  No (n = 152) (n = 144)   Median OS 70.5 months 52.4 months 0.71 (0.53–0.96)   6-year OS 48.6% 33.2% Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival. Open in new tab Table 2. Overall survival by metastatic site in HR+/HER2– advanced breast cancer Metastatic site . Ribociclib plus letrozole . Placebo plus letrozole . HR (95% CI) . Bone-only metastases  Yes (n = 69) (n = 79)   Median OS 72.6 months 56.4 months 0.78 (0.50–1.21)   6-year OS 50.2% 33.8%  No (n = 265) (n = 255)   Median OS 61.5 months 50.3 months 0.77 (0.51–0.96)   6-year OS 42.6% 31.5% Liver metastases  Yes (n = 59) (n = 72)   Median OS 37.7 months 38.1 months 0.81 (0.54–1.24)   6-year OS 31.0% 18.9%  No (n = 275) (n = 262)   Median OS 68.0 months 56.9 months 0.77 (0.62–0.97)   6-year OS 46.8% 35.7% Liver or lung metastases  Yes (n = 182) (n = 190)   Median OS 55.5 months 51.4 months 0.81 (0.62–1.05)   6-year OS 31.0% 18.9%  No (n = 152) (n = 144)   Median OS 70.5 months 52.4 months 0.71 (0.53–0.96)   6-year OS 48.6% 33.2% Metastatic site . Ribociclib plus letrozole . Placebo plus letrozole . HR (95% CI) . Bone-only metastases  Yes (n = 69) (n = 79)   Median OS 72.6 months 56.4 months 0.78 (0.50–1.21)   6-year OS 50.2% 33.8%  No (n = 265) (n = 255)   Median OS 61.5 months 50.3 months 0.77 (0.51–0.96)   6-year OS 42.6% 31.5% Liver metastases  Yes (n = 59) (n = 72)   Median OS 37.7 months 38.1 months 0.81 (0.54–1.24)   6-year OS 31.0% 18.9%  No (n = 275) (n = 262)   Median OS 68.0 months 56.9 months 0.77 (0.62–0.97)   6-year OS 46.8% 35.7% Liver or lung metastases  Yes (n = 182) (n = 190)   Median OS 55.5 months 51.4 months 0.81 (0.62–1.05)   6-year OS 31.0% 18.9%  No (n = 152) (n = 144)   Median OS 70.5 months 52.4 months 0.71 (0.53–0.96)   6-year OS 48.6% 33.2% Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival. Open in new tab Results also favored treatment with ribociclib regardless of the number of metastatic sites. Compared with letrozole alone, ribociclib plus letrozole improved OS for patients with <3 metastatic sites (HR, 0.78; 95% CI, 0.61–1.00) and for patients with ≥3 metastatic sites (HR, 0.71; 95% CI, 0.51–0.98). The survival benefit with ribociclib was similarly consistent regardless of prior adjuvant or neoadjuvant chemotherapy or endocrine therapy. Overall findings from the MONALEESA biomarker and clinical subgroup analyses demonstrate consistent and long-term improvements in OS with the addition of ribociclib to ET in patients with HR+/HR– advanced breast cancer.4,5 Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. References 1. Hortobágyi GN , Stemmer SM, Burris HA, et al. Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB) . Presented at the 2021 European Society for Medical Oncology (ESMO) Congress. 2021 . Abstract LBA17. 2. Slamon DJ , Neven P, Chia S, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020 ; 382 ( 6 ): 514 - 524 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Im SA , Lu YS, Bardia A, et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 ; 381 ( 4 ): 307 - 316 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Carey LA , Solovieff N, Andre F, et al. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer . Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). 2021 . Abstract GS2-00. 5. O’Shaughnessy J , Stemmer SM, Burris HA, et al. Overall survival subgroup analysis by metastatic site from the phase 3 MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with advanced HR+/HER2– breast cancer . Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). 2021 . Abstract GS2-01. © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Jacobson, Anne

doi: 10.1093/oncolo/oyac009pmid: 35348784

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer often progresses after standard first-line therapy, creating a need for effective second-line treatment options. In 2019, the U.S. Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (T-DXd) for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior HER2-targeted regimens. The phase III DESTINY-Breast03 trial is the first head-to-head trial comparing T-DXd with trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer in the second-line setting, after prior treatment with trastuzumab and a taxane.1,2 As reported at the 2021 European Society for Medical Oncology (ESMO) annual meeting, initial results from DESTINY-Breast03 showed a 72% improvement in progression-free survival (PFS) with T-DXd compared with T-DM1.1 The 12-month PFS rate was 75.8% and 34.1% in the T-DXd and T-DM1 groups, respectively (HR, 0.28; p <.0001). In the current analysis, Sara A. Hurvitz, M.D., of the David Geffen School of Medicine at the University of California, Los Angeles, presented findings from key patient subgroups in the DESTINY-Breast03 trial, including patients with brain metastases.2 Study Design The international DESTINY-Breast03 trial enrolled 524 patients with HER2-positive unresectable or metastatic breast cancer who were previously treated with trastuzumab and a taxane in the advanced or metastatic setting. Patients were randomly assigned to treatment with T-DXd (n = 261) or T-DM1 (n = 263). The primary endpoint was PFS. Baseline characteristics were similar in both treatment groups. The median patient age was 54 years. Approximately 50% of patients were treated with 0-1 prior lines of therapy in the metastatic setting, and 50% were treated with ≥2 prior treatment regimens. At baseline, 16.5% of patients in the T-DXd group and 14.8% of those in the T-DM1 group had brain metastases. Key Findings At a median follow-up of 15.9 months, T-DXd significantly improved PFS by 72% compared with T-DM1 across all patient subgroups (Table 1). Findings were consistent irrespective of hormone receptor status, prior treatment with pertuzumab, number of prior lines of therapy, presence or absence of visceral disease, and presence or absence of brain metastases. Table 1. Progression-free survival in HER2-positive metastatic breast cancer Patient subgroup . T-DXd . T-DM1 . HR (95% CI) . All patients (N = 524) Not reached 6.8 months 0.28 (0.22-0.37) Hormone receptor status  Positive (n = 272) 22.4 months 6.9 months 0.32 (0.22-0.46)  Negative (n = 248) Not reached 6.8 months 0.30 (0.20-0.44) Prior pertuzumab treatment  Yes (n = 320) Not reached 6.8 months 0.32 (0.22-0.46)  No (n = 204) Not reached 7.0 months 0.30 (0.19-0.47) Prior lines of therapy  0-1 (n = 258) 22.4 months 8.0 months 0.33 (0.23-0.48)  ≥2 (n = 266) Not reached 5.6 months 0.28 (0.19-0.41) Visceral metastases  Yes (n = 384) 22.2 months 5.7 months 0.28 (0.21-0.38)  No (n = 140) Not reached 11.3 months 0.32 (0.17-0.58) Brain metastases  Yes (n = 82) 15.0 months 3.0 months 0.25 (0.13-0.45)  No (n = 442) Not reached 7.1 months 0.32 (0.22-0.40) Patient subgroup . T-DXd . T-DM1 . HR (95% CI) . All patients (N = 524) Not reached 6.8 months 0.28 (0.22-0.37) Hormone receptor status  Positive (n = 272) 22.4 months 6.9 months 0.32 (0.22-0.46)  Negative (n = 248) Not reached 6.8 months 0.30 (0.20-0.44) Prior pertuzumab treatment  Yes (n = 320) Not reached 6.8 months 0.32 (0.22-0.46)  No (n = 204) Not reached 7.0 months 0.30 (0.19-0.47) Prior lines of therapy  0-1 (n = 258) 22.4 months 8.0 months 0.33 (0.23-0.48)  ≥2 (n = 266) Not reached 5.6 months 0.28 (0.19-0.41) Visceral metastases  Yes (n = 384) 22.2 months 5.7 months 0.28 (0.21-0.38)  No (n = 140) Not reached 11.3 months 0.32 (0.17-0.58) Brain metastases  Yes (n = 82) 15.0 months 3.0 months 0.25 (0.13-0.45)  No (n = 442) Not reached 7.1 months 0.32 (0.22-0.40) Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. Open in new tab Table 1. Progression-free survival in HER2-positive metastatic breast cancer Patient subgroup . T-DXd . T-DM1 . HR (95% CI) . All patients (N = 524) Not reached 6.8 months 0.28 (0.22-0.37) Hormone receptor status  Positive (n = 272) 22.4 months 6.9 months 0.32 (0.22-0.46)  Negative (n = 248) Not reached 6.8 months 0.30 (0.20-0.44) Prior pertuzumab treatment  Yes (n = 320) Not reached 6.8 months 0.32 (0.22-0.46)  No (n = 204) Not reached 7.0 months 0.30 (0.19-0.47) Prior lines of therapy  0-1 (n = 258) 22.4 months 8.0 months 0.33 (0.23-0.48)  ≥2 (n = 266) Not reached 5.6 months 0.28 (0.19-0.41) Visceral metastases  Yes (n = 384) 22.2 months 5.7 months 0.28 (0.21-0.38)  No (n = 140) Not reached 11.3 months 0.32 (0.17-0.58) Brain metastases  Yes (n = 82) 15.0 months 3.0 months 0.25 (0.13-0.45)  No (n = 442) Not reached 7.1 months 0.32 (0.22-0.40) Patient subgroup . T-DXd . T-DM1 . HR (95% CI) . All patients (N = 524) Not reached 6.8 months 0.28 (0.22-0.37) Hormone receptor status  Positive (n = 272) 22.4 months 6.9 months 0.32 (0.22-0.46)  Negative (n = 248) Not reached 6.8 months 0.30 (0.20-0.44) Prior pertuzumab treatment  Yes (n = 320) Not reached 6.8 months 0.32 (0.22-0.46)  No (n = 204) Not reached 7.0 months 0.30 (0.19-0.47) Prior lines of therapy  0-1 (n = 258) 22.4 months 8.0 months 0.33 (0.23-0.48)  ≥2 (n = 266) Not reached 5.6 months 0.28 (0.19-0.41) Visceral metastases  Yes (n = 384) 22.2 months 5.7 months 0.28 (0.21-0.38)  No (n = 140) Not reached 11.3 months 0.32 (0.17-0.58) Brain metastases  Yes (n = 82) 15.0 months 3.0 months 0.25 (0.13-0.45)  No (n = 442) Not reached 7.1 months 0.32 (0.22-0.40) Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. Open in new tab The overall response rate (ORR) in the overall study cohort was 79.7% and 34.2% in the T-DXd and T-DM1 groups, respectively, representing an absolute improvement in ORR of 45% with T-DXd. Findings were consistent across all patient subgroups, with the absolute improvement in ORR associated with T-DXd relative to T-DM1 ranging from 39% to 52%. Disease Control in Patients with Brain Metastases Treatment with T-DXd significantly improved PFS, ORR, and intracranial response in patients with brain metastases at baseline (n = 82). In this subgroup, T-DXd reduced the risk of disease progression or death by 75% relative to T-DM1. The 12-month PFS rate in this subgroup was 72.0% with T-DXd and 20.9% with T-DM1 (HR, 0.27; 95% CI, 0.13-0.45). Among those with brain metastases, the ORR was 67.4% and 20.5% in the T-DXd and T-DM1 treatment groups, respectively. The median duration of response was 12.9 months with T-DXd and 7.2 months with T-DM1. In the assessment of intracranial response, 27.8% of patients treated with T-DXd achieved a complete intracranial response, compared with 2.8% of patients treated with T-DM1. The overall intracranial response for patients with brain metastases was 63.8% in the T-DXd group and 33.3% in the T-DM1 group. Safety Treatment with T-DXd was associated with a manageable safety profile, with a similar rate of all adverse events (AEs) and grade ≥3 AEs compared with T-DM1. The most common grade ≥3 AEs in the T-DXd group were neutropenia (19.1%), thrombocytopenia (7.0%), nausea (6.6%), leukopenia (6.6%%), anemia (5.8%), and fatigue (5.1%). There were no grade 4 or 5 cases of interstitial lung disease or pneumonitis in either treatment group. In summary, T-DXd demonstrated a statistically significant and clinically meaningful improvement in PFS and ORR compared with T-DM1 across all patient groups, including those with baseline brain metastases. These findings support the use of T-DXd as a standard of care for patients with previously treated HER2-positive metastatic breast cancer. Please note that this content was created for the purpose of summarizing the content of the San Antonio Breast Cancer Symposium 2021 and has not been peer reviewed under the standard policies of The Oncologist. References 1. Cortes J , Kim , S, Chung W et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study . Presented at the 2021 European Society for Medical Oncology (ESMO) Congress . September 16-21, 2021 . Abstract LBA1. Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 2. Hurvitz S , Kim S-B, Chung W-P et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Subgroup analyses from the randomized phase 3 study DESTINY-Breast03 . Presented at the 2021 San Antonio Breast Cancer Symposium (SABCS) . December 7-10, 2021 . Abstract GS3-01. Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.