Tag: Breast Cancer

FDA Expands Adjuvant VERZENIO® Indication in High-Risk Early Breast Cancer

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SUMMARY: The FDA on March 3, 2023, approved VERZENIO® (Abemaciclib) with endocrine therapy (Tamoxifen or an Aromatase Inhibitor) for the adjuvant treatment of adult patients with Hormone Receptor (HR)-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence. Patients defined as high risk included those having either four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes and either tumor grade 3 or a tumor size 5 cm or more. VERZENIO® was previously approved for the above high-risk population with the additional requirement of having a Ki-67 score of 20% or more. The present approval removed the Ki-67 testing requirement.

Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and HR-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites. Factors associated with high risk of recurrence in HR-positive, HER2-negative early breast cancer include positive nodal status, the number of positive nodes, large tumor size (5 cm or more), and high tumor grade (Grade 3).

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, by binding to D-cyclins in the ER-positive breast cancer cell, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against Cyclin D1/CDK 4 and Cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

The monarchE trial is an international, open-label, two-cohort, randomized, Phase III study, conducted to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk, early breast cancer. This study included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, histologic Grade 3, or centrally tested high proliferation rate (Ki-67 of 20% or more). To be enrolled in Cohort 1 (N=5,120), which is the FDA-approved population, patients had to have 4 or more positive nodes or 1-3 positive nodes and either tumor grade 3 or a tumor size 5 cm or more. To be enrolled in Cohort 2 (N=517), patients could not be eligible for Cohort 1 and must have had 1-3 positive nodes and tumor Ki-67 score of 20% or more. Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5-10 years of physicians choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease Free Survival (IDFS), and Secondary end points included Distant Relapse Free Survival (DRFS), Overall Survival (OS), and Safety.

The FDA label expansion is supported by four-year data from the monarchE trial. There was significantly more Invasive Disease Free Survival (IDFS) benefit beyond the two-year treatment course with adjuvant VERZENIO® and the absolute difference in IDFS between the two treatment groups increased over time. The IDFS at 48 months was 85.5% for VERZENIO® plus standard endocrine therapy and 78.6% for standard endocrine therapy alone, with an absolute difference in IDFS of 6.9%. At two years and at three years, the absolute differences between treatment groups were 3.1% and 5.0%, respectively. The addition of VERZENIO® to standard endocrine therapy reduced the risk of recurrence by 35% compared to endocrine therapy alone (HR=0.653). This benefit was primarily among patients in Cohort 1 and there were no new safety findings. However, in Cohort 2, more deaths were observed with VERZENIO® plus standard endocrine therapy compared to standard endocrine therapy alone and the FDA label therefore is restricted to Cohort 1. The Overall Survival (OS) data was immature across the entire study, but there was an OS trend in favor of VERZENIO® in the Cohort 1 population.

It was concluded that the use of adjuvant VERZENIO® in patients with high-risk Hormone Receptor-positive, HER2-negative early breast cancer reduced the risk of recurrent disease, and this benefit was sustained beyond the completion of treatment, with an absolute increase noted at 4 years. Overall Survival data was immature at the time of this analysis.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Johnston SRD, Toi M, O’Shaughnessy J, et al. Lancet Oncol. 2023;24:77-90.

ESR1 Gene Mutation

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ESR1 (Estrogen Receptor 1) gene mutation is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers treated with prior Aromatase Inhibitor (AI) therapy in the metastatic setting, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. Approximately 40% of patients who had received AI therapy for metastatic breast cancer have ESR1 mutations. It is best to test for ESR1 mutations with a liquid biopsy following progression on an AI and CDK 4/6 inhibitor.

Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.

The median age at the time of breast cancer diagnosis in the US is 62 years and approximately 26% of breast cancer diagnoses are in women 65 to 74 years of age. Patient undergoing breast conserving surgery, often receive adjuvant breast radiation therapy to reduce the risk of local recurrence. Radiation therapy however is inconvenient, expensive and is associated with acute and late toxicities. Avoidance of radiation in elderly patients with low risk disease has remained controversial due to the lack of long term Level 1 evidence. In the LUMINA trial and PRIME II study of women over 55 years of age with low risk breast cancer, after a median follow up of 5 years, 5-year rate of ipsilateral breast tumor recurrence was low at 2-4% among those women who did not receive adjuvant whole-breast radiotherapy after breast-conserving surgery. The researchers herein reported the 10-year outcomes of the PRIME II trial.

PRIME II is a Phase III randomized clinical trial of the omission of breast irradiation, designed by the Scottish Cancer Trials Breast Group (SCTBG). This study included women 65 years of age or older, who had Hormone Receptor (HR)-positive, node-negative, T1 or T2 primary breast cancer (with tumors 3 cm or less in the largest dimension), treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were eligible if they had either cancer with Grade 3 histologic features or lymphovascular invasion but not both. A total of 1326 women were randomly assigned to receive 40-50 Gy whole-breast irradiation (N=658) or no radiation therapy (N=668). Both treatment groups were well balanced. The median patient age was 70 years and less than 10% of patients had ER-low tumors. The Primary end point was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and Overall Survival were also assessed. The median follow up was 9.1 years.

The cumulative incidence of local breast cancer recurrence after 10 years of follow up was 9.5% in the no-radiotherapy group and 0.9% in the radiotherapy group (HR=10.4; P<0.001). Even though local recurrence was more common in the group that did not receive radiotherapy, there was no substantial difference in the 10-year incidence of distant recurrence as the first event between the two treatment groups (1.6% without radiotherapy and 3.0% with radiotherapy). Overall Survival at 10 years was almost identical in the two groups, at 80.8% with no radiotherapy and 80.7% with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.

The authors concluded that omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event, or Overall Survival, among women 65 years of age or older, with Grade 1 or 2, Estrogen Receptor-high breast cancers, treated with breast-conserving surgery and 5 years of adjuvant endocrine therapy.

Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. Kunkler IH, Williams LJ, Jack WJL, et al. N Engl J Med 2023; 388:585-594.

A POSITIVE Trial for Hormone Receptor Positive Breast Cancer Survivors Desiring Pregnancy

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.

The median age at the time of breast cancer diagnosis in the US is 62 years. However approximately 5% of new diagnoses each year occur in those who are under 40 years. These young patients with Hormone Receptor (HR)-positive breast cancer receiving modern adjuvant endocrine therapy have excellent long-term outcomes. Nonetheless, 40-60% of patients who are diagnosed with breast cancer at age 40 or younger are concerned about their future fertility and pregnancy, as many have not completed their family planning at diagnosis due to delay in childbearing.

The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) trial is a multicenter, global, single-arm prospective study, designed to evaluate whether temporary interruption of adjuvant endocrine therapy to attempt pregnancy is associated with a higher risk of breast cancer recurrence. This study included 517 women with Stage I-III Hormone Receptor (HR)-positive early breast cancer, 42 years or less, who had received 18-30 months of adjuvant endocrine therapy and wished to interrupt endocrine therapy for pregnancy. The study permitted treatment interruption for up to 2 years (after a 3 month endocrine therapy washout period) to allow pregnancy, delivery and breastfeeding, followed by endocrine therapy resumption to complete the planned duration of 5-10 of adjuvant endocrine therapy. The median age was 37 years, 75% were nulliparous, fertility preservation was used by 51% of women, 93% had Stage I/II disease, 66% were node negative and 62% had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed endocrine therapy (42%), followed by Tamoxifen plus Ovarian Function Suppression (OFS) (35%).

The Primary endpoint of the study was Breast Cancer-Free Interval (BCFI), defined as the time from study enrollment to the first invasive breast cancer event (local/regional/distant recurrence or contralateral breast cancer). Three interim safety analyses were conducted by a Data Safety Monitoring Committee, and determined that the trial would be suspended if there were more than 46 breast cancer recurrences within approximately 3 years of average follow-up. This threshold however was not reached.

At a median follow up of 41 months, of the 497 patients evaluated for pregnancy status, 74% (N=368) had at least one pregnancy, with 70% of the pregnancies occurring within 2 years. Additionally, 63.8% (N=317) had at least one live birth, with a total of 365 babies born. Birth defects were low at 2% and the rates of conception and childbirth were similar to rates in the general public. The 3-year breast cancer recurrence rate among patients who halted therapy was 8.9%, similar to the 9.2% rate in an external control cohort from the SOFT/TEXT trials, which examined adjuvant endocrine therapy in premenopausal patients. Long term follow up is ongoing to assess recurrence risk over time, and trial participants were strongly recommended to resume endocrine therapy following their pregnancy attempts or success.

The authors concluded that these data provide guidance to younger patients diagnosed with early breast cancer on endocrine therapy, who may be hoping to have children. They added that such decisions should be made in close consultation with health professionals.

Pregnancy outcome and safety of interrupting therapy for women with endocrine responsive breast cancer: primary results from the POSITIVE trial (IBCSG 48-14 / BIG 8-13). Partridge A, Niman SM, Ruggeri M, et al. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

FDA Approves ORSERDU® for ESR-1 Mutated Advanced Breast Cancer

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SUMMARY: The FDA on January 27, 2023, approved ORSERDU® (Elacestrant) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, with disease progression following at least one line of endocrine therapy. FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with ORSERDU®.

Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 (Estrogen Receptor 1) gene mutation is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. In a previously published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%). It is estimated that 40% of ER-positive, HER2-negative advanced or metastatic breast cancer patients have tumors that harbor ESR1 mutations.

Fulvestrant (FASLODEX®) is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is the only SERD approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer. However, acquired ESR1 mutations can also occur following Fulvestrant treatment, possibly because of poor bioavailability and incomplete ER blockade when administered intramuscularly. There is therefore an urgent unmet need for an alternate SERD that has activity in tumors harboring ESR1 mutations, and has improved bioavailability allowing oral administration.

ORSERDU® (Elacestrant) is an oral, nonsteroidal, Selective Estrogen Receptor Degrader (SERD) that degrades the Estrogen Receptor (ER) in a dose-dependent manner and inhibits estradiol-dependent functions of ER target gene transcription induction and breast cancer cell proliferation. Estradiol-stimulated tumor growth was diminished by ORSERDU® in the HR-positive xenograft models derived from heavily pretreated patients, including models resistant to CDK 4/6 inhibitors, Fulvestrant and those harboring ESR1 mutations Y537S and D538G. In an early Phase I trial, ORSERDU® was noted to have an acceptable safety profile and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with HR-positive metastatic breast cancer.

The present FDA approval was based on the EMERALD trial, which is a multicenter, International, randomized, open-label, Phase III study, designed to evaluate the benefit of ORSERDU® in patients with ER+/HER2- advanced or metastatic breast cancer. In this study, 478 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either ORSERDU® 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=239). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain. In the study, 48% (N=228) had tumors with mutated ESR1 and 43% received two prior endocrine therapies. These patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.

This study met both co-Primary endpoints and treatment with ORSERDU® resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care treatment. In the group of patients whose tumors had ESR1 mutations, the median PFS was 3.8 months in the ORSERDU® group and 1.9 months in the Standard of Care group (HR=0.55; P=0.0005), reducing the risk of progression or death by 45%. A post-hoc analysis of the PFS results based on the duration of prior CDK4/6 inhibitors usage was presented at San Antonio Breast Cancer Symposium (SABCS) in December 2022. The median PFS was 8.6 months in the ORSERDU® group versus 1.9 months in the Standard of Care group, in those patients whose tumors harbored ESR1 mutations and had been treated with a CDK4/6 inhibitors for at least 12 months.

It can be concluded from this study that ORSERDU® is the first oral Selective Estrogen Receptor Degrader for ER-positive, HER2-negative advanced breast cancer patients with ESR1 mutations, and offers a novel therapeutic option for this patient group.

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Bidard F-C, Kaklamani VG, Neven P, et al. DOI: 10.1200/JCO.22.00338 Journal of Clinical Oncology. Published online May 18, 2022.

TAILORx Long Term Update for Patients with Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence.

Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early-stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early-stage breast cancer. Chemotherapy recommendations for Hormone Receptor positive, HER negative, early-stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay. Oncotype Dx assay categorizes patients based on Recurrence Scores into Low risk (0-10), Intermediate risk (11-25), and High risk (26-100). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, T1b-T2N0 early-stage axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone (N=3399) or endocrine therapy and adjuvant chemotherapy (N=3312). The Primary endpoint was invasive Disease-Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause. The researchers conducted an updated analysis, in which patients were followed for an additional 3.5 years, for an average of 11 years. The Primary endpoint in the updated analysis was invasive Disease-Free Survival (DFS) at a median follow-up of 11.0 years in the randomized population and 10.4 years in the overall population.

The previous TAILORx study conclusions remain unchanged. Among patients with a Recurrence Score of 11-25, endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy. The 5-year invasive DFS with endocrine therapy alone was 92.8% versus 93.1% with chemotherapy plus endocrine (HR=1.08; P=0.26). The 12-year invasive DFS with endocrine therapy alone was 76.8% versus 77.4% with chemotherapy plus endocrine therapy (HR =1.08). Although among those patients with a Recurrence Score of 0-25, less than 10% of patients had disease recurrence by 12 years, late recurrence events beyond 5 years exceeded earlier recurrence, regardless of treatment. There was also a higher risk of early recurrence in Black women.

It was concluded that with longer follow-up, the main TAILORx study findings remain unchanged, and clinicians should continue to use the 21-gene recurrence score results to guide decisions about the use of chemotherapy.

Trial Assigning Individualized Options for Treatment (TAILORx): An update including 12-year event rates. Sparano J, Gray RJ, Makower D, et al. Presented at SABCS 2022. December 6-10, 2022. Abstract GS1-05.

Neoadjuvant Chemotherapy, Endocrine Therapy and Targeted Therapy for Breast Cancer: ASCO Updated Guideline

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 290,560 new cases of breast cancer were diagnosed in 2022 and about 43,780 individuals died of the disease, largely due to metastatic recurrence.

Adjuvant or postoperative systemic therapy is the mainstay of treatment for early-stage breast cancer, to eradicate micrometastatic disease and reduce the likelihood of metastatic disease. Neoadjuvant refers to the use of systemic therapy prior to surgery. Neoadjuvant therapy was initially used in breast cancer for the treatment of inoperable, locally advanced disease. Subsequently, multiple studies of both chemotherapy and endocrine therapy have shown that neoadjuvant treatment can increase the likelihood of breast-conserving surgery, reduce the extent and morbidity of curative surgery, establishing neoadjuvant treatment as a viable option in patients with operable disease. Further, interest in neoadjuvant therapy has focused on examining the role of response to neoadjuvant treatment as a predictive marker for benefit in long term outcomes.

ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and the purpose of this guideline is to develop recommendations concerning the optimal use of systemic neoadjuvant therapy, including chemotherapy, endocrine therapy, and targeted therapy for patients with invasive breast cancer.

Guideline Question
What is the optimal use of neoadjuvant therapy for women with invasive, nonmetastatic breast cancer?

CLINICAL QUESTION 1
Which patients with breast cancer are appropriate candidates for neoadjuvant systemic therapy?

Recommendation 1.1.
Neoadjuvant chemotherapy is the treatment of choice for patients with inflammatory breast cancer or those with unresectable or locally advanced disease at presentation whose disease may be rendered resectable with neoadjuvant treatment
Recommendation 1.2.
Tumor histology, grade, stage and estrogen, progesterone, and HER2 expression should routinely be used to guide clinical decisions as to whether or not to pursue neoadjuvant chemotherapy. There is insufficient evidence to support the use of other immunochemical markers, morphological markers (eg, tumor-infiltrating lymphocytes) or genomic profiles to guide a clinical decision as to whether or not to pursue neoadjuvant chemotherapy
Recommendation 1.3.
Neoadjuvant systemic therapy should be offered to patients with high-risk HER2-positive or triple-negative breast cancer (TNBC) in whom the finding of residual disease would guide recommendations related to adjuvant therapy
Recommendation 1.4.
Neoadjuvant systemic therapy may be offered to reduce the extent of surgery (breast-conserving surgery and axillary lymph node dissection). Chemotherapy with or without targeted therapy, or endocrine therapy (if hormone receptor–positive [HR-positive]) may be offered
Recommendation 1.5.
In patients for whom a delay in surgery is preferable (eg, for genetic testing required for surgical treatment decision making, to allow time to consider reconstructive options) or unavoidable, neoadjuvant systemic therapy may be offered

CLINICAL QUESTION 2
How should response be measured in patients receiving neoadjuvant chemotherapy?

Recommendation 2.1.
Patients receiving neoadjuvant therapy should be monitored for response with clinical examination at regular intervals. Breast imaging may be used to confirm clinical suspicion of progression and for surgical planning. When imaging is used, the modality that was most informative at baseline-mammography, ultrasound, or magnetic resonance imaging—should be used at follow-up
Recommendation 2.2.
Blood- and tissue-based biomarkers should not be used for monitoring patients receiving neoadjuvant therapy
Recommendation 2.3.
Pathologic complete response (pCR), defined as absence of invasive disease in breast and lymph nodes, should be used to measure response to guide clinical decision making

CLINICAL QUESTION 3
What neoadjuvant treatment is recommended for patients with HR-positive/HER2-negative breast cancer?

Recommendation 3.1.
Neoadjuvant chemotherapy can be used instead of adjuvant chemotherapy in any patient with HR-positive, HER2-negative breast cancer in whom the chemotherapy decision can be made without surgical pathology data and/or tumor-specific genomic testing
Recommendation 3.2.
For postmenopausal patients with HR-positive/HER2-negative disease, neoadjuvant endocrine therapy with an aromatase inhibitor may be offered to increase locoregional treatment options. If there is no intent for surgery, endocrine therapy may be used for disease control
Recommendation 3.3.
For premenopausal patients with HR-positive/HER2-negative early-stage disease, neoadjuvant endocrine therapy should not be routinely offered outside of a clinical trial (Type: evidence-based; benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

CLINICAL QUESTION 4
What neoadjuvant treatment is recommended for patients with HER2-positive disease?

Recommendation 4.1.
Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy with an anthracycline and taxane or non–anthracycline-based regimen in combination with trastuzumab. Pertuzumab may be used with trastuzumab in the neoadjuvant setting
Recommendation 4.2.
Patients with T1a N0 and T1b N0, HER2-positive disease should not be routinely offered neoadjuvant chemotherapy or anti-HER2 agents outside of a clinical trial

CLINICAL QUESTION 5
What neoadjuvant systemic therapy regimens are recommended for patients with TNBC?

Recommendation 5.1.
Patients with TNBC who have clinically node-positive and/or at least T1c disease should be offered an anthracycline and taxane-containing regimen in the neoadjuvant setting
Recommendation 5.2.
Patients with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy outside of a clinical trial
Recommendation 5.3.
Carboplatin may be offered as part of a neoadjuvant regimen in patients with TNBC to increase likelihood of pCR. The decision to offer carboplatin should take into account the balance of potential benefits and harms
Recommendation 5.4. (UPDATED ASCO RECOMMENDATION FROM 2022: GUIDELINE RAPID RECOMMENDATION UPDATE)
For patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage TNBC, the Panel recommends use of pembrolizumab (200 mg once every 3 weeks or 400 mg once every 6 weeks) in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery. Adjuvant pembrolizumab may be given either concurrent with or after completion of radiation therapy. Given that irAEs associated with pembrolizumab therapy can be severe and permanent, careful screening for and management of common toxicities are required.

The guideline panel addressed some of the questions that clinicians may encounter as they incorporate these recommendations into clinical practice.

QUESTION: SHOULD PEMBROLIZUMAB BE CONTINUED IN PATIENTS WHO ACHIEVE pCR AFTER NEOADJUVANT CHEMOTHERAPY PLUS PEMBROLIZUMAB?
The panel supports continuation of pembrolizumab in the adjuvant setting in all patients while awaiting data from other trials addressing this question.

QUESTION: CAN A CHEMOTHERAPY REGIMEN DIFFERENT FROM THE ONE USED IN KEYNOTE-522 BE USED WITH PEMBROLIZUMAB?
The panel supports the use of the full KEYNOTE-522 regimen. However, if a patient experiences toxicity, it is not unreasonable to dose reduce or discontinue the drug. In patients with TNBC who have contraindications to anthracycline therapy and are being considered for regimens such as docetaxel and cyclophosphamide, it would be reasonable to add pembrolizumab to their regimen.

QUESTION: SHOULD ADJUVANT CAPECITABINE BE ADMINISTERED WITH PEMBROLIZUMAB IN PATIENTS WHO FAIL TO ACHIEVE pCR WITH PEMBROLIZUMAB-BASED NEOADJUVANT THERAPY?
Patients with TNBC who have residual disease after neoadjuvant chemotherapy are currently offered adjuvant capecitabine chemotherapy on the basis of improved survival shown in CREATE-X trial. It is reasonable to administer capecitabine concurrently or sequentially in patients at high risk of recurrence although the long-term safety of this combination is not known.

QUESTION: SHOULD OLAPARIB BE ADDED TO PEMBROLIZUMAB FOR gBRCA1m AND/OR gBRCA2m CARRIERS WITH TNBC WHO HAVE RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY?
Patients with TNBC are more likely to harbor a gBRCA1m and/or gBRCA2m, and such mutations have been reported in about 15% of patients with TNBC. The use of adjuvant pembrolizumab and olaparib concurrently or sequentially can be considered for eligible patients. The relative risks and benefits of a concurrent approach should be weighed, as the long-term safety of these combinations is not known.

QUESTION: SHOULD OTHER CHECKPOINT INHIBITORS BE USED IN THE NEOADJUVANT SETTING INSTEAD OF PEMBROLIZUMAB?
As only pembrolizumab has received regulatory approval, the panel does not recommend use of alternate immunotherapeutic agents.

QUESTION: SHOULD ADJUVANT PEMBROLIZUMAB BE USED IN PATIENTS WITH RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY WITHOUT PEMBROLIZUMAB?
There are currently no data to support adjuvant pembrolizumab use in patients who did not receive neoadjuvant pembrolizumab.

In summary, addition of pembrolizumab to chemotherapy in the neoadjuvant setting followed by continuation in the adjuvant setting is the new standard of care for patients with high-risk TNBC as defined in KEYNOTE-522.

Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer Guideline Expert Panel. Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk, Early-stage Triple Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update. Korde LA, Somerfield MR, Hershman DL, et al. J Clin Oncol. 2022;40:1696-1698.

Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. Korde LA, Somerfield MR, Carey LA, et al. DOI: 10.1200/JCO.20.03399 Journal of Clinical Oncology 39, no. 13 (May 01, 2021) 1485-1505.

Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

Patients with early stage breast cancer often receive adjuvant therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. A multitude of biomarker assays are presently available for the practicing Health Care Provider. Choosing the appropriate biomarker assay for a given patient can be a daunting task and the ASCO guidelines set forth herein, were developed by an expert panel based on  a systematic review of evidence published from January 2016 to October 2021, of 24 Phase III randomized clinical trials (RCTs), prospective-retrospective studies, and clinical experience. These guidelines are only applicable for patients with newly diagnosed, non-metastatic, primary breast cancer, to prognosticate and predict outcomes but they do not however comment on the choice of specific treatment or regimens based on recurrence score. Treatment decisions should take into consideration disease stage, comorbidities and patient preferences. Even though several tests are now recommended in the guidelines, only one test should be used to guide therapy for an individual patient.

Three important questions were addressed by this guideline update

  1. For patients with early-stage ER-positive, HER2-negative breast cancer, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy for a newly diagnosed cancer or in the extended setting?
  2. For patients with early-stage HER2-positive breast cancer, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy?
  3. For patients with early-stage triple-negative breast cancer, which biomarkers should be used to guide decisions on adjuvant chemotherapy?

 Newly Diagnosed ER-Positive, HER2-Negative Breast Cancer

Oncotype DX (21-gene recurrence score, 21-gene RS).

Recommendation 1.1. If a patient has node-negative breast cancer, the clinician may use the Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.2. In the group of patients in Recommendation 1.1 with Oncotype DX recurrence score ≥ 26, the clinician should offer chemoendocrine therapy

Recommendation 1.3. In the group of patients in Recommendation 1.1 who are 50 years of age or younger with Oncotype DX recurrence score 16 to 25, the clinician may offer chemoendocrine therapy

Recommendation 1.4. If a patient is postmenopausal and has node-positive breast cancer with 1-3 positive nodes, the clinician may use the Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.5. In the group of patients in Recommendation 1.4, the clinician should offer chemoendocrine therapy for those whose Oncotype DX recurrence score is ≥ 26

Recommendation 1.6. If a patient is premenopausal and has node-positive breast cancer with 1-3 positive nodes, the Oncotype DX test should not be offered to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.7. If a patient has node-positive breast cancer with ≥ 4 positive nodes, the evidence on the clinical utility of routine Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Qualifying statement: The genomic assay is prognostic and may be used for shared patient-physician treatment decision making.

MammaPrint (70-gene signature).

Recommendation 1.8. If a patient is older than 50 and has high clinical risk breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician may use the MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.9. If a patient is 50 years of age or younger and has high clinical risk, node-negative or node-positive with 1-3 positive nodes breast cancer, the clinician should not use the MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.10. If a patient has low clinical risk, regardless of age, the evidence on clinical utility of routine MammaPrint test is insufficient to recommend its use

Recommendation 1.11. If a patient has node-positive breast cancer with ≥ 4 positive nodes, the evidence on the clinical utility of routine MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Qualifying statement: The genomic assay is prognostic and may be used for shared patient-physician treatment decision making.

EndoPredict (12-gene risk score).

Recommendation 1.12. If a patient is postmenopausal and has breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician may use the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.13. If a patient is premenopausal and has breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician should not use the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.14. If a patient has breast cancer with ≥ 4 positive nodes, evidence on the clinical utility of routine use of the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy is insufficient

Prosigna (PAM50).

Recommendation 1.15. If a patient is postmenopausal and has breast cancer that is node-negative, the clinician may use the Prosigna test to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.16. If a patient is premenopausal and has node-negative or node-positive breast cancer, the clinician should not use the Prosigna test to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.17. If a patient is postmenopausal and has node-positive breast cancer with 1-3 positive nodes, the evidence is inconclusive to recommend the use of the Prosigna test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.18. If a patient has node-positive breast cancer with ≥ 4 positive nodes, evidence on the clinical utility of routine use of the Prosigna test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Ki67.

Recommendation 1.19. If a patient is postmenopausal and has stage I-II breast cancer, the clinician may use Ki67 expression in conjunction with other clinical and pathologic parameters to guide decisions on adjuvant endocrine and chemotherapy when multigene assays are not available. Ki67 expression levels are most informative for prognosis when the level is < 5% (low proliferation) or > 30% (high proliferation) because technical reliability of distinguishing values within this range is limited

Recommendation 1.20. If a patient is postmenopausal and has breast cancer, there is insufficient evidence to use baseline Ki67 expression or Ki67 level after 2 weeks of neoadjuvant aromatase inhibitor (AI) therapy to guide decisions on adjuvant endocrine and chemotherapy

Recommendation 1.21. Despite the limitations associated with Ki67 testing, a patient with node-positive breast cancer with a high risk of recurrence and a Ki67 score of ≥ 20% as determined by a US Food and Drug Administration (FDA)–approved test may be offered 2 years of abemaciclib plus endocrine therapy

Immunohistochemistry 4.

Recommendation 1.22. If a patient has node-negative or node-positive breast cancer with 1-3 positive nodes, the clinician may use immunohistochemistry 4 (IHC4) score to guide decisions for adjuvant endocrine and chemotherapy if the score has been validated in the performing laboratory and if multigene assays are not available

Extended Endocrine Therapy for ER-Positive HER2-Negative Breast Cancer

Oncotype DX, EndoPredict, Prosigna, Ki67, or IHC4.

Recommendation 1.23. If a patient has node-negative breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, there is insufficient evidence to use Oncotype DX, EndoPredict, Prosigna, Ki67, or IHC4 scores to guide decisions about extended endocrine therapy

Breast Cancer Index.

Recommendation 1.24. If a patient has node-negative or node-positive breast cancer with 1-3 positive nodes and has been treated with 5 years of primary endocrine therapy without evidence of recurrence, the clinician may offer the BCI test to guide decisions about extended endocrine therapy with either tamoxifen, an AI, or a sequence of tamoxifen followed by AI

Recommendation 1.25. If a patient has node-positive breast cancer with ≥ 4 positive nodes and has been treated with 5 years of primary endocrine therapy without evidence of recurrence, there is insufficient evidence to use the BCI test to guide decisions about extended endocrine therapy with either tamoxifen, an AI, or a sequence of tamoxifen followed by AI

Clinical treatment score post-5 years.

Recommendation 1.26. If a patient is postmenopausal and had invasive breast cancer and is recurrence-free after 5 years of adjuvant endocrine therapy, the clinical treatment score post-5 years (CTS5) web tool may be used to calculate the estimated risk of late recurrence (recurrence between years 5-10), which could assist in decisions about extended endocrine therapy

HER2-Positive Breast Cancer or Triple-Negative Breast Cancer

Oncotype DX, EndoPredict, MammaPrint, BCI, Prosigna, Ki67, or IHC4.

Recommendation 1.27. If a patient has HER2-positive breast cancer or TNBC, the clinician should not use multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, MammaPrint, BCI, Prosigna, Ki67, or IHC4) to guide decisions for adjuvant endocrine and chemotherapy

Emerging Biomarkers

Tumor-infiltrating lymphocytes.

Recommendation 1.28. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use TILs to guide decisions for (neo)adjuvant endocrine and chemotherapy

PD-L1 testing.

Recommendation 1.29. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use PD-L1 testing to guide decisions for (neo)adjuvant endocrine and chemotherapy

Circulating tumor cells.

Recommendation 1.30. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use circulating tumor cells (CTC) to guide decisions for adjuvant endocrine and chemotherapy

Circulating tumor DNA.

Recommendation 1.31. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use ctDNA to guide decisions for adjuvant endocrine and chemotherapy

ASCO additionally recommended that all patients should be given the opportunity to participate in cancer clinical trials.

Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update. Andre F, Ismaila N, Allison KH, et al. DOI: 10.1200/JCO.22.00069 Journal of Clinical Oncology 40, no. 16 (June 01, 2022) 1816-1837.

TUKYSA® Combination in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab), KADCYLA® (ado-Trastuzumab emtansine), ENHERTU® (Trastuzumab deruxtecan) and MARGENZA® (Margetuximab). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2-positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.

With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).

TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In a Phase 1b dose-escalation trial, TUKYSA® in combination with HERCEPTIN® and XELODA® (Capecitabine) showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.

HER2CLIMB is an international, randomized, double-blind, placebo-controlled trial in which the combination of TUKYSA® plus HERCEPTIN® and XELODA® was compared with placebo plus HERCEPTIN® and XELODA®. A total of 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer, who were previously treated with HERCEPTIN®, PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine) were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either TUKYSA® 300 mg orally twice daily throughout the treatment period (N=410) or placebo orally twice daily (N=201), in combination with HERCEPTIN® 6 mg/kg IV once every 21 days, following an initial loading dose of 8 mg/kg, and XELODA® 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle. Stratification factors included presence or absence of brain metastases, ECOG Performance Status and geographic region. The median patient age was 52 years and patient demographics as well as disease characteristics at baseline were well balanced between the two treatment groups. In the total treatment population, 47.5% had brain metastases at baseline, 48.3% in the TUKYSA® combination group and 46% in the placebo combination group. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), PFS among patients with brain metastases, confirmed Objective Response Rate (ORR), and Safety.

At median follow-up of 29.6 months, median OS in all patients with brain metastases at baseline was 9.1 months longer in the TUKYSA® combination group compared to the placebo combination group (21.6 versus 12.5 months, HR=0.60; P<0.001), with a 40% reduction in the risk of death with the TUKYSA® combination. The estimated 1-year OS was 70.0% for the TUKYSA® combination group and 50.6% for the placebo combination group and the estimated 2-year OS was 48.5% and 25.1% respectively.

The researchers in this exploratory subgroup analyses reported efficacy outcomes for patients with brain metastases, as well as time to new brain lesion(s) as the site of first progression or death, in all patients enrolled in HER2CLIMB trial, at a median follow up of 29.6 months.

There was greater CNS Progression Free Survival in the TUKYSA® combination group compared with the placebo combination group and was 5.7 months longer (9.9 versus 4.2 months, HR=0.39; P<0.001), with a 61% reduction in the risk of CNS progression with the TUKYSA® combination. The estimated 1 and 2-year CNS Progression Free Survivals were 38.4% versus 7.9% and 19.3% versus 0%, respectively.

Among those with active brain metastases and measurable disease at baseline, the intracranial Objective Response Rates for the TUKYSA® combination group were 47.3% versus 20.0% for the placebo combination group, with a median duration of intra cranial response of 8.6 versus 3.0 months, respectively.

The risk of developing new brain lesions as the site of first progression or death was reduced by 45% in the TUKYSA® combination group versus the placebo-combination group (HR=0.55; P =0.006).

The authors concluded that in this exploratory subgroup analysis, TUKYSA® in combination with HERCEPTIN® and XELODA® provided a clinically meaningful survival benefit, while reducing the risk of developing new brain lesions. The authors added that HER2CLIMB is currently the only double-blind, randomized, controlled clinical trial for patients with HER2-positive metastatic breast cancer, that prospectively included patients with both active and stable brain metastases.

Tucatinib vs Placebo, Both in Combination with Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. Lin NU, Murthy RK, Abramson V, et al. JAMA Oncol. Published online December 1, 2022. doi:10.1001/jamaoncol.2022.5610

Sustained Benefit with Adjuvant VERZENIO® in High-Risk Early Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years, while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against Cyclin D1/CDK 4 and Cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk, early breast cancer. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, or histologic Grade 3 disease (Cohort 1). A smaller group of patients with 1-3 positive axillary lymph nodes and centrally determined Ki-67 score of 20% or more were enrolled in Cohort 2. Ki-67 score was also determined centrally in Cohort 1 patients, but Ki-67 determination was not required for enrollment in this cohort. Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5-10 years of physician’s choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease-Free Survival (IDFS) in the Intent to Treat (ITT) population (Cohorts 1 and 2). Secondary end points included IDFS in patients with high Ki-67 score (in the ITT population and in the Cohort 1 population), Distant Relapse-Free Survival (DRFS), Overall Survival (OS), and Safety. The researchers reported updated results from an interim analysis to assess overall survival, as well as Invasive Disease-Free Survival and Distant Relapse-Free Survival, with additional follow-up.

At a median follow-up of 42 months (3.5 years), the median Invasive Disease-Free Survival (IDFS) was not reached in either group, and the IDFS benefit previously reported was sustained. The risk of developing invasive disease was reduced by 33.6% (HR=0.664; nominal P<0.0001). The 4-year IDFS rate was 85.8% for patients treated with VERZENIO® plus endocrine therapy, compared to 79.4% for patients treated with endocrine therapy alone, reflecting an absolute difference of 6.4% (compared to 2.8% at two years). The majority of the IDFS events were distant metastatic disease. Adjuvant VERZENIO® also reduced the risk of developing metastatic disease by 34.1% (HR=0.659; nominal P<0.0001). The 4-year DRFS rate was 88.4% for patients treated with VERZENIO® plus endocrine therapy, compared to 82.5% for patients treated with endocrine therapy alone, an absolute difference of 5.9% (compared to 2.5% at two years). As was noted in the previous analyses, a high Ki-67 score correlated with increased risk of recurrence, but this IDFS and DRFS benefit was seen across all prespecified subgroups, regardless of Ki-67 score. Overall Survival (OS) data were immature at the time of this analyses. However, fewer deaths were observed in the VERZENIO® plus endocrine therapy group, compared to endocrine therapy alone. There were no new safety findings, and overall results were consistent with the safety profile for VERZENIO®.

It was concluded that adjuvant VERZENIO® combined with endocrine therapy continued to demonstrate statistically significant and clinically meaningful improvement in Invasive Disease Free Survival and Distant Relapse Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer, regardless of Ki-67 status. These benefits were sustained after patients completed 2 years of adjuvant treatment with VERZENIO®, with an absolute increase at 4 years. The authors added that further follow-up is needed to establish whether Overall Survival can be improved with VERZENIO® plus endocrine therapy in this patient group.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Johnston SRD, Toi M, O’Shaughnessy J, et al. The Lancet Oncology. Published:December 06, 2022. DOI:https://doi.org/10.1016/S1470-2045(22)00694-5